Use of ras inhibitors for treating cancer

Abstract

The disclosure features the use of a RAS(ON) inhibitor therapy in methods of treating subjects with a RAS mutant cancer by administering a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor.

Description

[0001] PATENT

[0002] ATTORNEY DOCKET NO.: 51432-080WO5

[0003] USE OF RAS INHIBITORS FOR TREATING CANCER

[0004] Field

[0005] The present disclosure relates to the use of a RAS(ON) combination therapy comprising a RAS(ON) multi-selective tri-complex inhibitor, such as Compound A (daraxonrasib, RMC-6236, RM-031), and a RAS(ON) G12D-selective tri-complex inhibitor, such as Compound B (zoldonrasib, RMC-9805, RM-036), for the treatment of cancer.

[0006] Background

[0007] The vast majority of small molecule drugs act by binding a functionally important pocket on a target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many such drug / target interacting pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins provided a reasonable amount of time, effort, and resources. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. The other 90% are currently considered refractory or intractable toward the abovementioned small molecule drug discovery. Such targets are commonly referred to as “undruggable.” These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets. Among such historically intractable targets are the RAS family of small GTPases (KRAS, HRAS, and NRAS), which for decades were considered ‘undruggable’ due to their high affinity for GTP and lack of suitable binding pockets.

[0008] It has been well established in literature that RAS proteins (KRAS, HRAS, and NRAS) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in RAS proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of RAS proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in RAS are frequently found in human cancer. For example, activating mutations at codon 12 in RAS proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins to the “on” (GTP-bound) state (RAS(ON)), leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, enabling RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61 K) of RAS are also responsible for oncogenic activity in some cancers.

[0009] In normal cells, RAS proteins play a critical role in regulating cell growth, differentiation, and survival, acting as molecular switches, relaying signals from cell surface receptors to intracellular pathways that control key cellular processes. Genetic studies have demonstrated that complete deletion of RAS genes is lethal in mouse models and leads to the absence of cellular proliferation in vitro (Drosten et al. Oncogene 33, 2857-2865 (2014); Drosten et al. EMBO J. 29, 1091-1104 (2010)). Furthermore, KRAS conditional knockout in adult bone marrow has been shown to induce significant hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number PATENT

[0010] ATTORNEY DOCKET NO.: 51432-080WO5

[0011] (Zhang et. al., Stem Cells; 34(7):1859-71 (2016)). Targeting the mutant form of RAS, rather than wild-type RAS, has emerged as a strategy to treat RAS mutant cancer due to its specific involvement in oncogenic signaling. Despite extensive drug discovery efforts against RAS during the last several decades, only two agents targeting the KRAS G12C mutant have been approved in the U. S. (sotorasib and adagrasib). However, there are no approved targeted therapies for RAS G12D driven cancers.

[0012] Accordingly, there remains an unmet need for therapeutic regimens capable of targeting cancers harboring RAS G12D mutations, including those resistant to existing RAS- or MAPK-directed therapies.

[0013] Summary

[0014] In one aspect, the disclosure features a method of treating a cancer in a human subject in need thereof, the method including administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor therapy including a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor.

[0015] In some embodiments, the RAS(ON) multi-selective inhibitor is Compound A:

[0016]

[0017] In some embodiments, Compound A is administered in a total daily dose between 100 mg to 400 mg.

[0018] In some embodiments, Compound B is administered in a total daily dose between 400 mg to 1400 mg.

[0019] In some embodiments, a total daily dose of 100 mg Compound A and a total daily dose of 600 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 100 mg Compound A and a total daily dose of 900 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 100 mg Compound A and a total daily dose of 1200 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg daily Compound A and PATENT

[0020] ATTORNEY DOCKET NO.: 51432-080WO5

[0021] a total daily dose of 600 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg Compound A and a total daily dose of 900 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg Compound A and a total daily dose of 1200 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and a total daily dose of 600 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and a total daily dose of 900 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and a total daily dose of 1200 mg Compound B is administered to the subject. In some embodiments, a total daily dose of 100 mg Compound A and 300 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 100 mg Compound A and 450 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 100 mg Compound A and 600 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg Compound A and 300 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg Compound A and 450 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 200 mg Compound A and 600 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and 300 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and 450 mg twice daily dose of Compound B is administered to the subject. In some embodiments, a total daily dose of 300 mg Compound A and 600 mg twice daily dose of Compound B is administered to the subject.

[0022] In some embodiments, Compound A and Compound B are administered concurrently in the AM. In some embodiments, Compound A and Compound B are administered concurrently in the PM. In some embodiments, Compound A is administered in the AM and Compound B is administered in the PM.

[0023] In some embodiments, Compound B is administered in the AM and Compound A is administered in the PM.

[0024] In some embodiments, Compound A is administered in the AM and Compound B is administered twice daily.

[0025] In some embodiments, Compound A is administered in the PM and Compound B is administered twice daily.

[0026] In some embodiments, the RAS(ON) inhibitor therapy is administered orally.

[0027] In some embodiments, the RAS(ON) inhibitor therapy is administered with food. In some embodiments, the RAS(ON) inhibitor therapy is administered without food. In some embodiments, Compound A is administered without food and Compound B is administered with food. In some embodiments, Compound A is administered with food and Compound B is administered without food.

[0028] In some embodiments, the RAS(ON) inhibitor therapy is administered once per week. In some embodiments, the RAS(ON) inhibitor therapy is administered 2 times per week. In some embodiments, the RAS(ON) inhibitor therapy is administered 3 times per week. In some embodiments, the RAS(ON) inhibitor therapy is administered 4 times per week. In some embodiments, the RAS(ON) inhibitor therapy is administered 5 times per week. In some embodiments, the RAS(ON) inhibitor therapy is administered PATENT

[0029] ATTORNEY DOCKET NO.: 51432-080WO5

[0030] 6 times per week. In some embodiments, the RAS(ON) inhibitor therapy is administered 7 times per week.

[0031] In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 1 month. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 2 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 3 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 4 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 5 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 6 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 7 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 8 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 9 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 10 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 11 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 12 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 15 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 18 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 21 months. In some embodiments, the RAS(ON) inhibitor therapy is administered for at least 23 months.

[0032] In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 7 days. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 14 days. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 21 days. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 28 days. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 1 month. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 2 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 3 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 4 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 5 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 6 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 7 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 8 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 9 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 10 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 11 months. In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles and each treatment cycle is 1 year.

[0033] In some embodiments, the subject undergoes one treatment cycle. In some embodiments, the subject undergoes two treatment cycles. In some embodiments, the subject undergoes three treatment PATENT

[0034] ATTORNEY DOCKET NO.: 51432-080WO5

[0035] cycles. In some embodiments, the subject undergoes four treatment cycles. In some embodiments, the subject undergoes five treatment cycles.

[0036] In some embodiments, the cancer includes a RAS mutation.

[0037] In some embodiments, the RAS mutation is G12D.

[0038] In some embodiments, the RAS is KRAS.

[0039] In some embodiments, the cancer is locally advanced or metastatic.

[0040] In some embodiments, the cancer is pancreatic cancer, optionally pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma.

[0041] In some embodiments, the cancer is lung cancer, optionally non-small lung cancer.

[0042] In some embodiments, the cancer is colorectal cancer.

[0043] In some embodiments, the subject does not consume food for at least 4 hours after administration of the RAS(ON) inhibitor therapy.

[0044] In some embodiments, the subject does not consume food for at least 8 hours prior to administration of the RAS(ON) inhibitor therapy.

[0045] In some embodiments, the subject does not consume food for at least 10 hours prior to administration of the RAS(ON) inhibitor therapy and the subject does not consume food for at least 4 hours after administration of the RAS(ON) inhibitor therapy.

[0046] In some embodiments, the subject is in a fasted state upon administration of the RAS(ON) inhibitor therapy.

[0047] In some embodiments, the subject does not consume water 1 hour prior to administration of the RAS(ON) inhibitor therapy and / or 1 hour after administration of the RAS(ON) inhibitor therapy.

[0048] In some embodiments, the subject does not have brain metastases prior to administration of the RAS(ON) inhibitor therapy.

[0049] In some embodiments, the subject has not previously been treated with a cancer therapy, such that the RAS(ON) inhibitor therapy is a first-line therapy.

[0050] In some embodiments, the subject has been treated with one prior cancer therapy, such that the RAS(ON) inhibitor therapy is a second-line therapy.

[0051] In some embodiments, the subject has been treated with two prior cancer therapy, such that the RAS(ON) inhibitor therapy is a third-line therapy.

[0052] In some embodiments, the subject exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

[0053] In any of the above embodiments, the disclosure features a use of a RAS(ON) inhibitor therapy. In any of the above embodiments, the disclosure features a use of a RAS(ON) inhibitor therapy in the manufacture of a medicament.

[0054] In another aspect, the disclosure features a method of treating a cancer in a human subject in need thereof, the method including administering to the subject a therapeutically effective amount of a RAS(ON) multi-selective inhibitor, a RAS(ON) G12D-selective inhibitor, and an immune checkpoint inhibitor. PATENT

[0055] ATTORNEY DOCKET NO.: 51432-080WO5

[0056] In some embodiments, the RAS(ON) multi-selective inhibitor is Compound A:

[0057]

[0058] In some embodiments, the immune checkpoint inhibitor is one or more of anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, anti-B7.1, anti-B7H3, anti-B7H4, anti-TIM3, anti-VISTA, anti-CD137, anti-OX40, anti-CD40, anti-CD27, anti-CCR4, anti-GITR, anti-NKG2D, and anti-KIR.

[0059] In some embodiments, the anti-PD1 is one or more of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, and XmAb20717.

[0060] In some embodiments, the immune checkpoint inhibitor is ivonescimab (SMT112).

[0061] In some embodiments, the cancer includes a RAS mutation.

[0062] In some embodiments, the RAS mutation is G12D.

[0063] In some embodiments, the cancer is locally advanced or metastatic.

[0064] In some embodiments, the cancer is pancreatic cancer, optionally pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma.

[0065] In some embodiments, the cancer is lung cancer, optionally non-small lung cancer.

[0066] In some embodiments, the cancer is colorectal cancer.

[0067] In yet another aspect, the invention features a method of treating a cancer comprising a RAS G12D amplification in a human subject in need thereof, the method comprising, administering to the subject a therapeutically effective amount of a RAS(ON) multi-selective inhibitor, a RAS(ON) G12D-selective inhibitor. In some embodiments, the subject’s cancer progress on a RAS(ON) multi-selective inhibitor or RAS(ON) G12D-selective inhibitor monotherapy. In some embodiments, the subject has been previously treated with a RAS(ON) inhibitor therapy. In some embodiments, the subject’s cancer PATENT

[0068] ATTORNEY DOCKET NO.: 51432-080WO5

[0069] progressed on a RAS(ON) inhibitor prior to treatment with the RAS(ON) multi-selective inhibitor and RAS(ON) G12D-selective inhibitor. In some embodiments, the RAS(ON) multi-selective inhibitor is

[0070]

[0071] In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small lung cancer), or colorectal cancer.

[0072] Brief Description of the Figures

[0073] FIG. 1 shows the RAS(ON) inhibitor doublet therapy (i.e., Compound A (daraxonrasib) in combination with Compound B (zoldonrasib)) improves the depth and durability of antitumor response in KRAS G12D colorectal cancer (CRC) xenograft models.

[0074] FIG.2 shows the RAS(ON) inhibitor doublet therapy (Compound A plus Compound B) improves the depth and durability of antitumor response in KRAS G12D pancreatic ductal adenocarcinoma (PDAC) allograft models and provides durable suppression of RAS pathway signaling in the KPCYc3 model.

[0075] FIG.3 shows the RAS(ON) inhibitor doublet therapy (Compound A plus Compound B) promotes antitumor immunity in the KPCYc3 model.

[0076] FIG.4 shows tissue staining of eCMT93 tumors. The top panels depict hematoxylin and eosin (H& E) staining of eCMT93 tumors at subcutaneous, hepatic, and colonic inoculation sites. The bottom panels present immunohistochemical staining of subcutaneous eCMT93 tumors using CK19, CK20, CK7, and Alcian Blue. Black arrows indicate tumor budding at the invasive front.

[0077] FIG. 5A and FIG. 5B show the KRAS G12D dependency of the eCMT93 model and the suppression of the RAS signaling pathway following treatment with an exemplary RAS(ON) inhibitor therapy in vivo. FIG. 5A graphically depicts the reduction of phosphorylated ERK (pERK) levels and decreased cell proliferation in the eCMT93 model upon monotherapy with Compound A or Compound B.

[0078] FIG. 5B shows a histological assessment of pERK expression in eCMT93 tumors at 24 hours following four days of treatment with an exemplary RAS(ON) inhibitor therapy (Compound A plus Compound B). PATENT

[0079] ATTORNEY DOCKET NO.: 51432-080WO5

[0080] FIG.6 shows the reduction in tumor volume and enhanced durability of response in eCMT93 tumors following treatment with an exemplary RAS(ON) inhibitor therapy (Compound A plus Compound B), as compared to single-agent therapy.

[0081] FIG.7 shows modulation of the tumor microenvironment following treatment with an exemplary RAS(ON) inhibitor therapy. The left panels depict histological quantification of CD8+ T cells in eCMT93 tumors at 24 hours after four days of treatment with Compound C, a RAS(ON) multi-selective inhibitor, Compound D, a RAS(ON) G12D mutant-selective inhibitor, or the combination thereof. Black arrows indicate CD8+ T cells within the tumor core. Statistical analysis was performed using an unpaired t-test (p<0.01 ). The right panels present transcriptomic analysis of whole tumor tissue at 24 hours posttreatment, evaluated using gene set analysis performed with Rosalind.

[0082] FIG.8 shows that durable complete tumor regressions are achieved following treatment with a RAS(ON) inhibitor doublet therapy (Compound A plus Compound B) in combination with an anti-PD-1 therapy.

[0083] FIG.9 shows the identified molecular features and mechanisms of resistance which reactivate RAS pathway signaling. An acquired alteration was defined as an ’’Oncogenic” or “Likely Oncogenic” variant annotated by OncoKBTM and not detected in pre-treatment ctDNA. SV = short variant, defined as single nucleotide variant (SNV) or short indel; CNV = copy number variant, defined as ‘focal amplification’ (for oncogenes) or ‘homozygous deletion’ (for tumor suppressor genes); Fusion = requires at least one of the partner genes to be in pathway of interest. TRUNC = variant resulting in predicted truncated protein, defined as nonsense mutation, splice site or indel.

[0084] FIG. 10 shows that amplification of mutant KRAS G12R in HuPT3 cells confers resistance to Compound A in vitro, as shown by cell-viability and pERK analysis.

[0085] FIG. 11 shows the RAS(ON) inhibitor doublet (Compound A plus Compound B) provides durable response in three KPCY (KRASG12D / +; Trp53LSL-R172H / + models: KPCYc3 (2838c3), c4 (6499c4), and c5(6419c5). Progression is defined as tumor doubling from baseline. Log-rank test (*p<0.05, ****p<0.0001). Percentage of P-ERK positivity relative to vehicle-treated control, measured by IHC in panCK+ tumor cells. N = 3 tumors per treatment group per timepoint after single dose of daraxonrasib (Compound A), zoldonrasib (Compound B), or the combination of both. Representative IHC images of P-ERK staining at 8h post dose.

[0086] FIG. 12 shows a 5-day 2D cellular viability assay was performed with HPAC parental and resistant cell line to assess sensitivity to single agents RAS(ON) multi-selective inhibition and RAS(ON) G12D-selective inhibition. 5-day 2D cellular viability assay was performed with HPAC parental and resistant cell lines to assess sensitivity to RAS(ON) inhibitor combination treatments (Compound A plus Compound B). Data are presented in a matrix as % of DMSO and as dose response curves.

[0087] FIG. 13 shows the RAS(ON) inhibitor doublet provides durable tumor stasis in an HPAF-II model with acquired resistance to RAS(ON) multi-selective inhibitors. HPAF-II tumor bearing mice were orally administered with a single dose (parental model) of vehicle or Compound C at 10 mg / kg or with daily repeat doses (Compound C treatment-resistant model) of Compound C at 10 mg / kg. Tumors were harvested at indicated timepoints (n = 3 / timepoint / group) and subjected to Western blot analyses of RAS pathway targets. HPAF-II resistant tumor bearing mice were orally administered daily with vehicle, Compound A at 25 mg / kg, Compound B at 100 mg / kg or combination of Compound A at 10 mg / kg and PATENT

[0088] ATTORNEY DOCKET NO.: 51432-080WO5

[0089] Compound B at 100 mg / kg (n = 9 per group). Mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and specific treatment group were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group (“, P < 0.05; ***, P < 0.001). The dotted line indicates the initial average tumor volume. Error bars indicate ±SEM.

[0090] FIG. 14 shows the RAS(ON) inhibitor doublet leads to sustained RAS pathway inhibition and combinatorial benefit in KRAS G12D CRC in vivo. Antitumor activity of 100 mg / kg po qd Compound B and 10 mg / kg po qd Compound A as single agents or in combination in CRC043 subcutaneous PDX model. Quantification of pERK IHC post treatments of 100 mg / kg Compound B and 10 mg / kg Compound A as single agents or in combination and representative pERK IHC images.

[0091] Detailed Description

[0092] In patients with KRAS-mutant tumors, the G12D mutation is the most frequently occurring KRAS mutation. In the United States, approximately 58,000 new cases of cancer harboring KRAS G12D mutations are observed annually, with the majority of those cases occurring in patients with colorectal cancer (CRC, 39%) and pancreatic ductal adenocarcinoma (PDAC, 39%), followed by non-small-cell lung cancer (NSCLC, 14%) and other cancers (8%).

[0093] Currently, there is no approved RAS-targeted therapy for patients with KRAS G12D-mutant cancers, representing a significant unmet medical need for this population, which typically exhibits low response rates to standard-of-care therapies and consequently a poor prognosis.

[0094] Targeted therapies directed at RAS mutants or other nodes in the MAPK signaling cascade have historically been associated with safety and tolerability challenges, limiting their clinical utility both as monotherapies and in combination regimens.

[0095] For instance, KRAS(OFF) G12C inhibitors such as adagrasib have demonstrated notable adverse-event profiles. In the KRYSTAL-1 phase II study involving patients with KRAS G12C-mutated CRC, treatment-related adverse events (TRAEs) of any grade occurred in 93% of patients receiving adagrasib monotherapy, with 34% experiencing grade 3 or 4 TRAEs, including anemia and diarrhea. Similarly, sotorasib, another KRAS(OFF) G12C inhibitor, has been associated with gastrointestinal toxicities and hepatotoxicity, which can present significant safety concerns even in monotherapy settings.

[0096] MEK inhibitors, which target downstream components of the MAPK pathway, also present considerable safety concerns. For example, trametinib has been associated with rash, diarrhea, and peripheral edema. In the METRIC study, these adverse events were commonly observed and frequently required dose modifications.

[0097] Combination therapies involving RAS or MAPK-pathway inhibitors have, in some instances, further exacerbated toxicity issues. For example, combining KRAS(OFF) G12C inhibitors with immune-checkpoint inhibitors has led to increased hepatotoxicity, particularly when sotorasib is administered proximate to checkpoint-inhibitor therapy. Additionally, combinations of BRAF and MEK inhibitors have been associated with cardiovascular adverse events, including pulmonary embolism and decreased left-ventricular ejection fraction.

[0098] In view of this well-documented toxicity landscape, and the potential for overlapping toxicities associated with the combination of Compound A (daraxonrasib) and Compound B (zoldonrasib) (e.g., nausea, vomiting, and diarrhea, which might be expected to increase in frequency and severity relative to PATENT

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[0100] monotherapy), the observed safety and tolerability of this combination are both surprising and unexpected.

[0101] In addition, as described herein, the combination exhibits, in part, enhanced and durable suppression of RAS-pathway signaling, address RAS(ON) multi-selective inhibitor acquired resistance (e.g., resistance associated with RAS gene amplification), and favorably modulates the tumor immune microenvironment and responsiveness to immune checkpoint inhibition.

[0102] Collectively, these findings represent an unexpected advantage relative to prior RAS- and MAPK-directed approaches and support the methods described herein, which comprise, in part, treating subjects with KRAS G12D-mutant cancers using the RAS(ON) inhibitor combination therapy.

[0103] Definitions

[0104] In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included.

[0105] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0106] Note that when a range or amount is provided in the disclosure herein, ± 5% of each range endpoint or specific amount is included, unless otherwise indicated. For example, a range of 100 mg to 400 mg of Compound A is understood to encompass 100 ± 5% mg to 400 ± 5% mg, e.g., 95 mg to 420 mg of Compound A.

[0107] As used herein, the term “administration” refers to the administration of a composition comprising the RAS(ON) inhibitor therapy to a subject or system. Administration also includes administering a prodrug derivative or analog or pharmaceutically acceptable salt to the subject, which can form an equivalent amount of active compound within the subject’s body. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal or vitreal. In some embodiments, a composition comprising the RAS(ON) inhibitor therapy is administered orally.

[0108] As used herein, ‘biosimilar’ means a biological product that is similar to a reference biological product, notwithstanding minor differences in clinically inactive components, and that has no clinically meaningful differences from the reference product in terms of safety, purity, or potency, consistent with PATENT

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[0110] applicable regulatory standards (e.g., FDA, EMA). In some embodiments, a biosimilar includes a product licensed under 42 U. S. C. §262(k), Article 10(4) of Directive 2001 / 83 / EC, or an equivalent pathway.

[0111] The term “combination therapy” refers to a method of treatment including administering to a subject at least two active therapeutic agents, as one or more pharmaceutical compositions, as part of a therapeutic regimen. For example, a combination therapy may include administration of a single pharmaceutical composition including at least two therapeutic agents and one or more pharmaceutically acceptable carrier, excipient, diluent, or surfactant. A combination therapy may include administration of two or more pharmaceutical compositions, each composition including one or more therapeutic agent and one or more pharmaceutically acceptable carrier, excipient, diluent, or surfactant. The two or more agents may optionally be administered simultaneously (as a single or as separate compositions) or sequentially (as separate compositions). The therapeutic agents may be administered in an effective amount. The therapeutic agent may be administered in a therapeutically effective amount. In some embodiments, the effective amount of one or more of the therapeutic agents may be lower when used in a combination therapy than the therapeutic amount of the same therapeutic agent when it is used as a monotherapy, e.g., due to an additive or synergistic effect of combining the two or more therapeutics.

[0112] As used herein, the term “dosage form” refers to a physically discrete unit of a compound (e.g., the RAS(ON) inhibitor therapy) for administration to a subject. Each unit contains a predetermined quantity of compound. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0113] As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., the RAS(ON) inhibitor therapy) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen includes a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen includes a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen or “therapy”).

[0114] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0115] The terms "inhibit," "block," and "suppress" are used interchangeably and refer to any statistically significant decrease in a biological activity, including full blocking of the activity. As used herein, the term PATENT

[0116] ATTORNEY DOCKET NO.: 51432-080WO5

[0117] “inhibitor” refers to a compound that prevents a biomolecule, (e.g., a protein, nucleic acid) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, uncompetitive, or noncompetitive means, for example. With respect to its binding mechanism, an inhibitor may be an irreversible inhibitor or a reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimetics, peptides, peptidomimetics, antibodies, small molecules, chemicals, analogs that mimic the binding site of an enzyme, receptor, or other protein. In some embodiments, the inhibitor is a small molecule, e.g., a low molecular weight organic compound, e.g., an organic compound having a molecular weight (MW) of less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In some embodiments, the MW is less than 900 Da. In some embodiments, the range of the MW of the small molecule is between 800 Da and 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecules inhibitors include natural products, derivatives, and analogs thereof. Small molecule inhibitors can include a covalent cross-linking group capable of forming a covalent cross-link, e.g., with an amino acid side-chain of a target protein.

[0118] As used herein “patient” or “subject” are used interchangeably and refer to a mammal, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, sports animals, and zoo animals including, for example, humans, nonhuman primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and cattle. In certain embodiments, the subject has been diagnosed with cancer. In certain embodiments, the subject is a human afflicted with a tumor (e.g., cancer) who has been diagnosed with a need for treatment for a tumor (e.g., cancer).

[0119] As used herein, the term “pharmaceutical composition” refers to a compound, such as Compound A or Compound B disclosed herein, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0120] A “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and noninflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. See, e.g., Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, PATENT

[0121] ATTORNEY DOCKET NO.: 51432-080WO5

[0122] Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients.

[0123] The term “pharmaceutically acceptable salt,” as use herein, refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:119, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), WileyVCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

[0124] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein to refer to a signal transduction cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives a variety of cellular effector events that determine the proliferation, activation, differentiation, mobilization, and other functional properties of the cell. SHP2 conveys positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS as well as GTP-accelerating proteins (GAPs, such as NF1) that facilitate termination of the signals by conversion of GTP to GDP. GTP-bound RAS produced by this cycle conveys essential positive signals to a series of serine / threonine kinases including RAF and MAP kinases, from which emanate additional signals to various cellular effector functions.

[0125] The terms “RAS inhibitor” and “inhibitor of [a] RAS” are used interchangeably to refer to any inhibitor that targets, that is, selectively binds to or inhibits a RAS protein.

[0126] As used herein, the term “RAS(ON) inhibitor” refers to an inhibitor that targets, that is, selectively binds to or inhibits, the GTP-bound, active state of RAS (e.g., selective over the GDP-bound, inactive state of RAS). Inhibition of the GTP-bound, active state of RAS includes, for example, the inhibition of oncogenic signaling from the GTP-bound, active state of RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound, active state of RAS. In certain embodiments, RAS(ON) inhibitors may also bind to or inhibit the GDP-bound, inactive state of RAS (e.g., with a lower affinity or inhibition constant than for the GTP-bound, active state of RAS). In certain embodiments, a RAS(ON) inhibitor useful in the present disclosure may form a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., RAS), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of RAS described herein induce a new binding pocket in RAS by driving formation of a high affinity tri-complex, or conjugate, between the RAS protein and the widely expressed cytosolic chaperone, cyclophilin A (CypA). A RAS(ON) inhibitor may be an antibody-drug conjugate. See also doi.org / 10.1021 / acs.jmedchem.4c02929.

[0127] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets, that is, selectively binds to or inhibits, the GDP-bound, inactive state of RAS (e.g., selective over the GTP-bound, active PATENT

[0128] ATTORNEY DOCKET NO.: 51432-080WO5

[0129] state of RAS). RAS(OFF) inhibitors are known in the art and described. Exemplary RAS(OFF) inhibitors are described herein.

[0130] As used herein, the terms “RAS(ON) multi-selective inhibitor,” “RASMULTI inhibitor,” “RASMULTI(ON) inhibitor,” and “RAS(MULTI) inhibitor” refer to a RAS inhibitor of at least three RAS isoforms, including wild-type and / or variants with missense mutations at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib, Compound A) refers to a RAS inhibitor of at least three RAS variants with missense mutations at one of the following positions: 12, 13, and 61. Exemplary RAS(ON) multi-selective inhibitors are described herein.

[0131] As used herein, the terms “RAS(ON) mutant-selective inhibitor” refers to a RAS inhibitor selective for a RAS(ON) variant with missense mutation at one of the following positions: 12, 13, or 61. Non-limiting examples of RAS(ON) mutant-selective inhibitors include RAS(ON) G12C-selective inhibitors (e.g., elironrasib or RMC-6291), RAS(ON) G12D-selective inhibitors (e.g., zoldonrasib, Compound B), RAS(ON) Q61 H-selective inhibitors (e.g., RMC-0708), RAS(ON) G12V-selective inhibitors (e.g. RMC-5127), and RAS(ON) G13D-selective inhibitors. Exemplary RAS(ON) mutant-selective inhibitors are described herein.

[0132] A “therapeutic agent” is any substance, e.g., a compound or composition, capable of treating a disease or disorder. In some embodiments, therapeutic agents that are useful in connection with the present disclosure include RAS inhibitors and cancer chemotherapeutics. Many such therapeutic agents are known in the art and are disclosed herein.

[0133] The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be “refractory” to a “therapeutically effective amount.” In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.

[0134] The term “treatment” (also “treat” or “treating”), in its broadest sense, refers to any administration of a substance (e.g., a combination therapy as disclosed herein) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who is diagnosed with the disease, disorder or condition but PATENT

[0135] ATTORNEY DOCKET NO.: 51432-080WO5

[0136] does not exhibit signs of the relevant disease, disorder, or condition or of a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In any treatment method herein, a patient or subject may be in need of such treatment.

[0137] Treatment Methods and Uses

[0138] The present disclosure provides, inter alia, the use of a RAS(ON) inhibitor therapy comprising two or more RAS(ON) inhibitors in methods of treating subjects with RASG12D-mutant cancers. In various embodiments, the RAS(ON) inhibitor therapy as disclosed herein comprises a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor. In various embodiments, the RAS(ON) multi-selective inhibitor is Compound A. In various embodiments, the RAS(ON) G12D-selective inhibitor is Compound B.

[0139] Accordingly, a RAS(ON) multi-selective inhibitor useful in the RAS(ON) inhibitor therapy according to the present disclosure is a compound such as Compound A

[0140]

[0141] Compound A (also known as daraxonrasib, RMC-6236 or RM-031).

[0142] Compound A is a RAS inhibitor - more specifically, a RAS(ON) multi-selective, tri-complex inhibitor that is selective for the active, GTP-bound state, of both mutant and wild-type variants of the canonical RAS isoforms. Compound A binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream RAS signaling. Jiang et al., Cancer Discovery 14:1-24 (2024).

[0143] Compound A may exist as a conformational stereoisomer, such as an atropisomer.

[0144] Pharmaceutically acceptable salts of Compound A are also contemplated, as are solvates, hydrates and polymorphs. See, e.g., WO 2022060836 and WO 2024216048, incorporated herein by reference in its entirety. Compound A can be prepared as generally described in WO 2021091956 or as specifically described in WO 2022060836 or WO 2024216048, each incorporated herein by reference in its entirety.

[0145] Compound A can be present as a pharmaceutically acceptable isotopically labeled version, wherein one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O, and18O, respectively. These radio-labeled compounds could be useful to help determine or measure the effectiveness of Compound A, by characterizing, for example, the site or mode of action. Certain isotopically labeled versions of Compound PATENT

[0146] ATTORNEY DOCKET NO.: 51432-080WO5

[0147] A, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Non-limiting examples of such incorporation can be seen in, e.g., WO 2022060836.

[0148] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution with positron emitting isotopes, such as11C,15O and13N, can be useful in Positron Emission Topography (PET) studies.

[0149] A RAS(ON) G12D-selective inhibitor useful in the RAS(ON) inhibitor therapy according to the present disclosure is a compound such as Compound B

[0150]

[0151] Compound B (also known as zoldonrasib, RMC-9805 or RM-036).

[0152] Compound B is RAS inhibitor - more specifically, an oral RAS(ON) G12D-selective, covalent tricomplex inhibitor, that is selective for the active, GTP-bound state, of the canonical RAS isoforms harboring a G12D mutation. Compound B binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that covalently binds to RAS(ON) G12D to form a tricomplex, blocking downstream RAS signaling, see e.g., Weller etal., Science, Vol 389, Issue 6758, (2025).

[0153] Compound B may exist as a conformational stereoisomer, such as an atropisomer.

[0154] Pharmaceutically acceptable salts of Compound B are also contemplated, as are solvates, hydrates and polymorphs. Compound B can be prepared as described in WO 2023060253, incorporated herein by reference in its entirety.

[0155] Compound B can be present as a pharmaceutically acceptable isotopically labeled version, wherein one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compound B include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O, and18O, respectively. These radio-labeled compounds could be useful to help determine or measure the effectiveness of Compound B, by characterizing, for example, the site or mode of action. Certain isotopically labeled versions of Compound B, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Non-limiting examples of such incorporation can be seen in, e.g., WO 2023060253. PATENT

[0156] ATTORNEY DOCKET NO.: 51432-080WO5

[0157] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution with positron emitting isotopes, such as11C,15O and13N, can be useful in PET studies.

[0158] Further provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor therapy according to the present disclosure. The cancer may, for example, be pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), colorectal cancer (e.g., microsatellite stable, microsatellite instability-high, or microsatellite instability-low), non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, melanoma, thyroid gland adenocarcinoma, renal cancer, bladder cancer, biliary / gall bladder cancer, gastroesophageal cancer, uterine / endometrial cancer, a myelodysplastic syndrome, head and neck squamous cell carcinoma, or squamous cell lung carcinoma. In some embodiments, the cancer comprises a RAS mutation, such as KRAS G12D. In some embodiments, the cancer comprises a KRAS G12D mutation and one or more additional cancer cells having RAS mutations selected from KRAS G12C, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61 R, KRAS Q61 K, or KRAS Q61 L, or a combination thereof. In some embodiments, the cancer comprises an additional RAS mutation, such as NRAS G12D, NRAS Q61 R, NRAS Q61 K, NRAS Q61 L, NRAS Q61 H, or NRAS Q61 P, or a combination thereof. Other RAS mutations are described herein.

[0159] In various embodiments of the disclosure, the subject in need thereof is administered the RAS(ON) inhibitor therapy of the present disclosure comprising a total daily dose between 100 mg to 400 mg of Compound A. In some embodiments, Compound A is administered in a total daily dose of 200 mg. In some embodiments, Compound A is administered in a total daily dose of 300 mg. In various embodiments, Compound A is administered once daily. In various embodiments, Compound A is administered in a divided daily dose, such as two, three, four, five, six or more times a day. In various embodiments, Compound A is administered orally. In some embodiments of the methods disclosed herein, the subject is administered 100 mg, 200 mg, or 300 mg of Compound A, orally, once daily (QD). In various embodiments, the Compound A is administered with food. In various embodiments, Compound A is administered without food. In various embodiments, Compound A is administered once daily in the morning (AM dosing). In various embodiments, Compound A is administered once daily in the evening (PM dosing).

[0160] In various embodiments of the disclosure, the subject in need thereof is administered the RAS(ON) inhibitor therapy of the present disclosure comprising a total daily dose between 400 mg to 1400 mg of Compound B. In some embodiments, Compound B is administered in a total daily dose of 600 mg. In some embodiments, Compound B is administered in a total daily dose of 900 mg. In some embodiments, Compound B is administered in a total daily dose of 1200 mg. In various embodiments, Compound B is administered once daily. In various embodiments, Compound B is administered in a divided daily dose, such as two, three, four, five, six or more times a day. In various embodiments, Compound B is administered twice daily (BID). In some embodiments, 300 mg of Compound B is administered twice daily. In some embodiments, 450 mg of Compound B is administered twice daily. In some embodiments, 600 mg of Compound B is administered twice daily. In various embodiments, Compound B is administered orally. In some embodiments of the methods disclosed herein, the subject is PATENT

[0161] ATTORNEY DOCKET NO.: 51432-080WO5

[0162] administered Compound B, orally, once or twice daily (QD or BID). In various embodiments, Compound B is administered with food. In various embodiments, Compound B is administered without food. In various embodiments, Compound B is administered once daily in the morning (AM dosing). In various embodiments, Compound B is administered once daily in the evening (PM dosing).

[0163] Administration of Compound A and Compound B may occur concurrently or sequentially. In various embodiments, the RAS(ON) inhibitor therapy is administered concurrently in the AM. In various embodiments, the RAS(ON) inhibitor therapy is administered concurrently in the PM. In various embodiments, Compound A is administered in the AM and Compound B is administered in the PM. In various embodiments, Compound B is administered in the AM and Compound A is administered in the PM. In various embodiments, Compound A is administered in the AM and Compound B is administered twice daily. In various embodiments, Compound A is administered in the PM and Compound B is administered twice daily.

[0164] In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and a total daily dose of 600 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and a total daily dose of 900 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and a total daily dose of 1200 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg daily Compound A and a total daily dose of 600 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg Compound A and a total daily dose of 900 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg Compound A and a total daily dose of 1200 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and a total daily dose of 600 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and a total daily dose of 900 mg Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and a total daily dose of 1200 mg Compound B.

[0165] In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and 300 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and 450 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 100 mg Compound A and 600 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg Compound A and 300 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg Compound A and 450 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 200 mg Compound A and 600 mg twice daily of Compound B. PATENT

[0166] ATTORNEY DOCKET NO.: 51432-080WO5

[0167] In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and 300 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and 450 mg twice daily of Compound B. In various embodiments, the methods of the disclosure include administering to a subject in need thereof a total daily dose of 300 mg Compound A and 600 mg twice daily of Compound B.

[0168] In various embodiments, the RAS(ON) inhibitor therapy is administered with food. In various embodiments, the RAS(ON) inhibitor therapy is administered without food.

[0169] In various embodiments, the RAS(ON) inhibitor therapy is administered 1, 2, 3, 4, 5, 6 or 7 times per week. In various embodiments, the RAS(ON) inhibitor therapy is administered 7 days per week. In various embodiments, the RAS(ON) inhibitor therapy is administered 6 days per week. For example, the RAS(ON) inhibitor therapy is administered on days 1, 2, 3, 4, 5, and 6 days of each 7 days. In various embodiments, the RAS(ON) inhibitor therapy is administered 5 days per week. For example, the RAS(ON) inhibitor therapy is administered on days 1, 2, 3, 4, and 5 days of each 7 days. In various embodiments, the RAS(ON) inhibitor therapy is administered 4 days per week. For example, the RAS(ON) inhibitor therapy is administered on days 1, 2, 3, and 4 days of each 7 days. In various embodiments, the RAS(ON) inhibitor therapy is administered 3 days per week. For example, the RAS(ON) inhibitor therapy is administered on days 1, 2, and 3 of each 7 days. In various embodiments, the RAS(ON) inhibitor therapy is administered 2 days per week. For example, the RAS(ON) inhibitor therapy is administered on days 1 and 2 of each 7 days.

[0170] In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months or longer. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 1 month. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 3 months. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 6 months. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 8 months. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 10 months. In various embodiments, the subject is administered the RAS(ON) inhibitor therapy for at least 12 months.

[0171] In some embodiments, the RAS(ON) inhibitor therapy is administered in treatment cycles. In some embodiments, the treatment cycle is 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year. In various embodiments, the subject undergoes 1, 2, 3, 4, or more treatment cycles. In some embodiments, the subject undergoes at least 3 treatment cycles, at least 5 treatment cycles, at least 8 treatment cycles, at least 10 treatment cycles, at least 15 treatment cycles, at least 20 treatment cycles, at least 25 treatment cycles or more. PATENT

[0172] ATTORNEY DOCKET NO.: 51432-080WO5

[0173] Response rates or results for subjects administered the RAS(ON) inhibitor therapy in the methods disclosed herein can be measured in various ways, after the subject has been taking the RAS(ON) inhibitor therapy a suitable length of time, as is known to those of skill in the art.

[0174] The subject can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). RECIST v1.1 is discussed in detail in the examples below. An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., “at least SD” = SD+PR+CR, often referred to as disease control). In various embodiments, the stable disease has neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient exhibits at least a partial response (i.e., “at least PR” = PR+CR, often referred to as objective response).

[0175] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In various embodiments, the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.

[0176] Several criteria and definitions published in the literature can be used to determine the effect of one or more treatments on tumors in a subject suffering from cancer. Based on these criteria, tumors are defined as “responsive,” “stable,” or “progressive” when they improve, remain the same, or worsen during treatment, respectively. The amount of a tumor in an individual is the "tumor burden" which can be measured as the number, volume, and / or weight of the tumor.

[0177] Examples of the commonly used criteria published in the literature include Response Evaluation Criteria in Solid Tumors (RECIST), Modified Response Evaluation Criteria in Solid Tumors (mRECIST), PET Response Criteria in Solid Tumors (PERCIST), Choi Criteria, Lugano Response Criteria, European Association for the Study of the Liver (EASL) Criteria, Response Evaluation Criteria in the Cancer of the Liver (RECICL), and WHO Criteria in Tumor Response.

[0178] As used herein, "progression free survival" or “PFS” is the time from treatment to the date of the first confirmed disease progression per RECIST 1.1 criteria. In various embodiments, the patient exhibits a PFS of at least 1 month. In various embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.

[0179] “RECIST” shall mean an acronym that stands for “Response Evaluation Criteria in Solid Tumors” and is a set of published rules that define when cancer patients improve (“respond”), stay the same (“stable”) or worsen (“progression”) during treatments. Response as defined by RECIST criteria have been published, for example, a Journal of the National Cancer Institute, Vol. 92, No. 3, Feb. 2, 2000, and RECIST criteria can include other similar published definitions and rule sets. One skilled in the art would understand definitions that go with RECIST criteria, as used herein, such as “Partial Response (PR),” “Complete Response (CR),” “Stable Disease (SD)” and “Progressive Disease (PD).”

[0180] As used herein, "survival" refers to the subject remaining alive, and includes overall survival as well as progression free survival. PATENT

[0181] ATTORNEY DOCKET NO.: 51432-080WO5

[0182] As used herein, "reducing the tumor," means reducing the size, volume, or weight of the tumor, reducing the number of metastases, reducing the size or weight of a metastasis, or combinations thereof. In certain embodiments, a metastasis is cutaneous or subcutaneous. Thus, in certain embodiments, administration of the immune checkpoint inhibitor reduces the size or volume of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) inhibitor therapy, reduces the weight of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) inhibitor therapy, reduces the size or volume of a metastasis by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) inhibitor therapy or combination therapy comprising the same, reduces the number of metastases by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99% for example, relative to a control drug in a subject of the same genotype. In certain embodiments, combinations of these effects are achieved.

[0183] In some embodiments, a biological sample obtained from the subject is used to determine response to treatment with the RAS(ON) inhibitor therapy. As used herein, the term "biological sample" refers to any sample obtained from a subject. A biological sample can be obtained from a subject prior to or subsequent to a diagnosis, at one or more time points prior to or following treatment or therapy, at one or more time points during which there is no treatment or therapy or can be collected from a healthy subject. The biological sample can be a tissue sample or a fluid sample. In certain embodiments, the biological sample includes a tissue sample, a biopsy sample, a tumor aspirate, a bone marrow aspirate, or a blood sample (or a fraction thereof, such as blood or serum). In certain embodiments, the biological sample includes a tumor cell or cancer cell, for example a circulating tumor cell present in a fluid sample, for example, blood or a fraction thereof. In certain embodiments, the biological sample includes a cell free nucleic acid present in a fluid sample, for example, blood or a fraction thereof. In one embodiment, the biological sample comprises a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (for example a polypeptide or nucleic acid). The cell lysate can include proteins, nuclear and / or mitochondrial fractions. In certain embodiments, the cell lysate includes a cytosolic fraction. In certain embodiments, the cell lysate includes a nuclear / mitochondrial fraction and a cytosolic fraction.

[0184] The source of a biological sample can be solid tissue as from a fresh, frozen and / or preserved organ, tissue sample, biopsy, or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid; or cells from any time in gestation or PATENT

[0185] ATTORNEY DOCKET NO.: 51432-080WO5

[0186] development of the subject. The biological sample can contain compounds that are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. The biological sample can be preserved as a frozen sample or as formaldehyde- or paraformaldehyde-fixed paraffin- embedded (FFPE) tissue preparation. For example, the sample can be embedded in a matrix, for example, an FFPE block or a frozen sample. However, other tissue and sample types are amenable for use herein. In one embodiment, the other tissue and sample types can be fresh frozen tissue, wash fluids, or cell pellets, or the like. A biological sample can be a tumor sample, which contains nucleic acid molecules from a tumor or cancer. A biological sample that is a tumor sample can be DNA, for example, genomic DNA, or cDNA derived from RNA. In one embodiment, the tumor nucleic acid sample is purified or isolated (for example, it is removed from its natural state). In one embodiment, the sample is a tissue (for example, a tumor biopsy), a CTC or cell free nucleic acid.

[0187] In certain embodiments, a tumor sample is isolated from a human subject. In certain embodiments, the analysis is performed on a tumor biopsy embedded in paraffin wax. In one embodiment, the sample can be a fresh frozen tissue sample. In certain embodiments, the sample is a bodily fluid obtained from the subject. The bodily fluid can be blood or fractions thereof (specifically, serum, plasma, urine, saliva, sputum, or cerebrospinal fluid (CSF). The sample can contain cellular as well as extracellular sources of nucleic acid. The extracellular sources can be cell-free nucleic acids and / or exosomes. The methods described herein, including the RT-PCR methods, are sensitive, precise and have multi-analyte capability for use with paraffin embedded samples. See, for example, Cronin et al., Am. J Pathol. 164(1 ):35-42 (2004).

[0188] Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein.

[0189] In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject the RAS(ON) inhibitor therapy in an amount described herein. Accordingly, one embodiment of the present disclosure provides a method treating a subject in need thereof by administering a pharmaceutical composition containing the RAS(ON) inhibitor therapy in an amount described herein, and a pharmaceutically acceptable excipient, as well as methods of using the RAS(ON) inhibitor therapy to prepare such compositions.

[0190] In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0191] For use as treatment of subjects, the RAS(ON) inhibitor therapy can be formulated as pharmaceutical compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the RAS(ON) inhibitor therapy is formulated in ways consonant with these parameters. A summary of such techniques may be found in PATENT

[0192] ATTORNEY DOCKET NO.: 51432-080WO5

[0193] Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrickand J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0194] Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of Compound A or Compound B, by weight or volume. In some embodiments, Compound A or Compound B may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.

[0195] The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive or oral mucosa. Thus, the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.

[0196] Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. Compounds, or a pharmaceutically acceptable salt thereof, can be administered also in liposomal compositions or as microemulsions.

[0197] For injection, formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like. Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.

[0198] Various sustained release systems for drugs have also been devised. See, for example, U. S. Patent No. 5,624,677.

[0199] Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds of the invention, or a pharmaceutically acceptable salt thereof. Suitable forms include syrups, capsules, and tablets, as is understood in the art. In one embodiment the therapeutically effective amount of the RAS(ON) inhibitor therapy is administered orally in the form of a tablet or multiple tablets.

[0200] The RAS(ON) inhibitor therapy, as described herein, may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Other modalities of combination therapy are described herein. PATENT

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[0202] The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one subject, multiple uses for a particular subject (at a constant dose or in which the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0203] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, optionally substituted hydroxylpropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0204] Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.

[0205] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein Compound A or Compound B is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein Compound A or Compound B is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0206] Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating Compound A or Compound B into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-optionally substituted hydroxylmethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycols. In a PATENT

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[0208] controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

[0209] The liquid forms in which the RAS(ON) inhibitor therapy, or a composition thereof, can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0210] In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, compounds, or a pharmaceutically acceptable salt thereof, will be formulated into suitable compositions to permit facile delivery. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.

[0211] It will be appreciated that the RAS(ON) inhibitor therapy and pharmaceutical compositions thereof can be formulated and employed in combination therapies, that is, the RAS(ON) inhibitor therapy and pharmaceutical compositions thereof can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).

[0212] The RAS(ON) inhibitor therapy described herein may be administered in combination with an immune checkpoint inhibitor (ICI). An immune checkpoint inhibitor may be co-formulated or administered separately as part of a combination therapy with a RAS(ON) inhibitor therapy.

[0213] Immune checkpoints are regulatory pathways intrinsic to the immune system that maintain selftolerance and modulate immune responses to prevent excessive tissue damage during pathogenic infections. However, tumors often exploit these checkpoints to evade immune surveillance by dysregulating immune checkpoint protein expression, thereby suppressing anti-tumor immunity.

[0214] Since many immune checkpoint pathways are mediated by ligand-receptor interactions, they can be therapeutically targeted using antibodies or recombinant forms of ligands or receptors. Immune checkpoint inhibition has been employed to enhance anti-tumor immunity, leading to the development of FDA-approved therapies such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and lymphocyte activation gene 3 (LAG3) inhibitors. Inhibitors of immune checkpoint proteins have demonstrated broad potential to sustain anti-tumor immune responses and produce durable clinical outcomes in various tumor types.

[0215] T cell activation through immune checkpoint blockade remains a central strategy for augmenting endogenous anti-tumor immunity. T cells possess the ability to selectively recognize peptides from intracellular and extracellular proteins, directly eliminate antigen-expressing cells (CD8+ cytotoxic T lymphocytes), and coordinate adaptive and innate immune responses (CD4+ helper T cells). As such, therapeutic agents that either activate co-stimulatory receptors or inhibit suppressive signaling pathways PATENT

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[0217] to amplify antigen-specific T cell responses are of significant clinical interest. Table 1 summarizes a nonlimiting list of immune checkpoint targets.

[0218] Table 1. Non-limiting list of immune checkpoint targets.

[0219]

[0220] CTLA4, cytotoxic T-lymphocyte-associated antigen 4; LAG3, lymphocyte activation gene 3; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand; TIM3, T cell membrane protein 3; VISTA, V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation; KIR, killer IgG-like receptor.

[0221] ICIs approved or in development include, but are not limited to, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, relatimab, galiximab, MDX-1106, BMS-936558, MEDI4736, MPDL3280A, MEDI6469, BMS-986016, BMS-663513, PF-05082566, IPH2101, KW-0761, CDX-1127, CP-870, CP-893, GSK2831781, MSB0010718C, MK3475, CT-011, AMP-224, MDX-1105, IMP321, and MGA271, as well as numerous other antibodies or fusion proteins directed to the immune checkpoint proteins noted in Table 1. Common immune checkpoint proteins that may be targeted by ICIs include, but are not limited to B7.1, B7-H3, LAG3, CD137, KIR, CCR4, CD27, 0X40, GITR, CD40, CTLA4, PD-1, and PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of a target selected from the group comprising or consisting of programmed cell death protein- 1, ligand of PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), B7 homolog 3 protein (B7-H3), B- and T-lymphocyte attenuator (BTLA), Sialic acid binding Ig-like lectin 15 (Siglec-15), cytokine-inducible SH2-containing protein (CISH), and combination thereof.

[0222] In some embodiments, the ICI therapy is selected from one or more of anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-LAG3, anti-B7.1, anti-B7H3, anti-B7H4, anti-TIM3, anti-VISTA, anti-CD137, anti-GX40, PATENT

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[0224] anti-CD40, anti-CD27, anti-CCR4, anti-GITR, anti-NKG2D, and anti-KIR. In some embodiments, the ICI therapy is an antibody (e.g., a monoclonal antibody selective for any of the targets in Table 1). In some embodiments the ICI is an anti-PD-1 antibody. The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (also known as tislelizumab; BeiGene & Celgene) or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0225] In some embodiments, the immune checkpoint inhibitor is an inhibitor of programmed cell death protein- 1 (PD-1) or an inhibitor of the ligand of PD-1 (PDL-1).

[0226] Programmed cell death protein-1 is herein interchangeably referred to as PD-1, PD1, PDCD1, PDCD-1, SLEB2, SLE1 and CD279.

[0227] In humans, PD-1 typically has the sequence as disclosed in UniProtKB Ref. Q15116, incorporated herein by reference.

[0228] Programmed death-ligand 1 is herein interchangeably referred to as PDL-1, PD-LI, PDL1, PDCD1 L1, PDCD1 LG1, CD274, B7-H1, B7-H, B7H1.

[0229] In humans, PD-L1 typically has the sequence as disclosed in UniProtKB Ref. Q9NZQ7, incorporated herein by reference.

[0230] In some embodiments, the anti-PD1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717.

[0231] In some embodiments, the PD-1 inhibitor is a bispecific antibody specific for PD-1 and VEGF. In some embodiments, the bispecific antibody is ivonescimab (SMT112). PATENT

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[0233] In some embodiments, the anti-PDL1 antibody is atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-07Z.

[0234] In some embodiments, the disclosure provides a method of treating a cancer that is characterized by aberrant RAS activity due to a RAS G12D mutation.

[0235] Accordingly, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an amount of the RAS(ON) inhibitor therapy as disclosed herein or a pharmaceutical composition comprising the same. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, Gl neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal, endometrial or melanoma. Also provided is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0236] As used herein, the terms "cancer" or "tumor" refer to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer cells are often in the form of a tumor, but such cells can exist isolated within an animal, or can be non-tumorigenic, such as a leukemia cell. Cancers include, but are not limited to, B cell malignancies, for example, multiple myeloma, the heavy chain diseases, such as, for example, alpha chain disease, gamma chain disease, and mu chain disease, benign monoclonal gammopathy, and immunocytic amyloidosis, skin cancer, breast cancer, lung cancer, bronchus cancer, colorectal cancer, prostate cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematological tissues, and the like. Other non-limiting examples of types of cancers applicable to the methods encompassed by the present disclosure include human sarcomas and carcinomas, for example, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, PATENT

[0237] ATTORNEY DOCKET NO.: 51432-080WO5

[0238] cervical cancer, bone cancer, brain tumor, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, for example, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, the cancer is an epithelial cancer such as, but not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, gynecologic cancers, renal cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In still other embodiments, the epithelial cancer is nonsmall-cell lung cancer, nonpapillary renal cell carcinoma, cervical carcinoma, ovarian carcinoma (for example, serous ovarian carcinoma), or breast carcinoma.

[0239] In some embodiments, the RAS(ON) inhibitor therapy, pharmaceutical compositions comprising the RAS(ON) inhibitor therapy, and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated and methods of the disclosure include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example:

[0240] Cardiac, for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

[0241] Lung, for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

[0242] Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0243] Genitourinary tract, for example: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

[0244] Liver, for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0245] Biliary tract, for example: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; PATENT

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[0247] Bone, for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

[0248] Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);

[0249] Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);

[0250] Hematologic, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0251] Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0252] In some embodiments, the cancer comprises a KRAS G12D mutation. In some embodiments the cancer comprises a RAS G12D amplification or wild-type RAS amplification. In some embodiments, a mutation is a G12D mutation, and one or more mutations selected from:

[0253] (a) the following KRAS mutants: G12C, G12V, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof;

[0254] (b) the following HRAS mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and

[0255] (c) the following NRAS mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof;

[0256] or a combination of any of the foregoing. In some embodiments, the cancer comprises at least two RAS mutations, a G12D mutation and at least one mutation selected from the group consisting of G13C, G13D, G13S, G13V, Q61H, Q61K, Q61L, or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12D. In some embodiments, the cancer is colorectal cancer and the RAS mutation comprises a KRAS mutation, PATENT

[0257] ATTORNEY DOCKET NO.: 51432-080WO5

[0258] such as KRAS G12D. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma) and the RAS mutation comprises an KRAS G12D mutation. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is colorectal cancer.

[0259] In some embodiments, the cancer comprises an NRAS G12D mutation. In some embodiments, the cancer comprises an HRAS G12D mutation. In some embodiments, the cancer comprises a NRAS G12D mutation and a KRAS G12D mutation.

[0260] Methods of detecting RAS mutations are known in the art. Such means include, but are not limited to direct sequencing, and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark), e.g., as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNACIamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See, also, e.g., WO 2020106640.

[0261] In some embodiments, the cancer is non-small cell lung cancer and the RAS mutation comprises a KRAS G12D mutation and a KRAS G12C, KRAS G12V or KRAS G12C mutation. In some embodiments, the cancer is colorectal cancer and the RAS mutation comprises a KRAS G12D mutation, and a KRAS G12C, or KRAS G12V mutation. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma) and the RAS mutation comprises a KRAS mutation, such as KRAS G12D. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is non-small cell lung cancer.

[0262] In some embodiments, the subject being treated by the RAS(ON) inhibitor therapy in the disclosed methods is one who has undergone at least one or more prior systemic cancer therapies (e.g., the RAS(ON) inhibitor therapy is a second- or third-line therapy). In some embodiments, the subject being treated by the RAS(ON) inhibitor therapy in the disclosed methods is one who has disease progression following at least one prior systemic cancer therapy (i.e., the RAS(ON) inhibitor therapy is a second-line therapy). In some embodiments, the subject being treated by the RAS(ON) inhibitor therapy in the disclosed methods is one who has disease progression following at least two prior systemic cancer therapies (i.e., the RAS(ON) inhibitor therapy is a third line therapy). Prior systemic cancer therapies can be any therapy approved by a regulatory authority (e.g., the FDA or EMA) as treatment given type and stage of cancer. In some cases, the prior systemic cancer therapy is a cancer therapy not yet approved by a regulatory' authority but undergoing clinical trials. If a subject has had a prior systemic cancer therapy, in some cases, the subject has not undergone any systemic cancer therapy for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months prior to starting therapy as disclosed herein with the RAS(ON) inhibitor therapy.

[0263] In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject a composition comprising the RAS(ON) inhibitor therapy in an amount disclosed herein or combination of compounds described herein, wherein the subject has one or more tumors that are resistant or unresponsive to treatment. In various embodiments, the subject has one or more tumors that are resistant or unresponsive to one or more treatments selected from the group consisting of surgery, radiation, chemotherapy, biologic agents, small molecules, cell-based therapy, hormone therapy, and immunotherapy. In various embodiments, treatment is a standard of care therapy, first-line therapy, second-line therapy, or third-line therapy. In various embodiments, the subject has one PATENT

[0264] ATTORNEY DOCKET NO.: 51432-080WO5

[0265] or more tumors that have progressed during one or more treatments, wherein the treatments are standard of care therapy, first-line therapy, second-line therapy, or third-line therapy.

[0266] First-line therapy is defined as a treatment that is administered to a subject suffering from cancer who has not received any prior treatment. Second-line therapy is defined as treatment that is administered to a subject suffering from cancer who has received prior first-line therapy but experienced disease progression during first-line treatment. Third-line therapy is defined as treatment that is administered to a subject suffering from cancer who has received prior first and second-line treatment but has experienced disease progression during second-line treatment. Each particular type of cancer has a first-line, second-line, and third-line therapy. The first-, second-, and third-line therapies for types of cancer are known in the art. In addition, FDA approved drug labels will indicate if a particular drug is approved as a first-, second-, or third- line therapy.

[0267] In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject a composition comprising the RAS(ON) inhibitor therapy in an amount disclosed herein or combination of compounds described herein, wherein the subject cannot tolerate standard of care therapy, first-line therapy, second-line therapy, or third-line therapy. In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject the RAS(ON) inhibitor therapy or combination therapy including the RAS(ON) inhibitor therapy, wherein the subject has experienced tumor recurrence after surgical resection of the primary tumor. In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject a composition comprising the RAS(ON) inhibitor therapy in an amount disclosed herein or combination of compounds described herein, wherein the subject has a tumor that cannot be surgically removed. In various embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject a composition comprising the RAS(ON) inhibitor therapy in an amount disclosed herein or combination of compounds described herein, wherein the subject has no treatment options available.

[0268] In some embodiments, the cancer includes a mutation in RAS and the cancer is resistant to treatment with a RAS(ON) inhibitor or RAS(OFF) inhibitor. In some embodiments, the cancer is resistant to a KRASG12C(OFF) inhibitor, a KRASG12D(OFF) inhibitor, a KRASG12V(OFF) inhibitor or a pan-KRAS inhibitor. In some embodiments, the cancer is resistant to a RAS(ON) multi-selective inhibitor or a RAS(ON) mutant-selective inhibitor. As used herein, the term “resistant to treatment” refers to a treatment of a disorder with a therapeutic agent, where the therapeutic agent is ineffective or where the therapeutic agent was previously effective and has become less effective over time. Resistance to treatment includes acquired and / or adaptive resistance to treatment, which refers to a decrease in the efficacy of a treatment over a period of time where the subject is being administered the therapeutic agent. Acquired resistance to treatment may result from the acquisition of a mutation in a target protein that renders the treatment ineffective or less effective. Accordingly, resistance to treatment may persist even after cessation of administration of the therapeutic agent. In particular, a cancer may become resistant to treatment with a RAS(ON) inhibitor or RAS(OFF) inhibitor that decreases the efficacy of the RAS(ON) inhibitor or RAS(OFF) inhibitor, respectively. Measurement of a decrease in the efficacy of the treatment will depend on the disorder being treated, and such methods are known to those of skill in the art. For example, efficacy of a cancer treatment may be measured by the progression of the disease. An effective treatment PATENT

[0269] ATTORNEY DOCKET NO.: 51432-080WO5

[0270] may slow or halt the progression of the disease. A cancer that is resistant to treatment with a therapeutic agent, e.g., a RAS(ON) inhibitor or RAS(OFF) inhibitor, may fail to slow or halt the progression of the disease. In some embodiments, the cancer has acquired resistance to a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib). In some embodiments, the acquired resistance is a amplification of RAS.

[0271] A subject undergoing a therapy is monitored for adverse events (AE) during the course of the therapy. A treatment related AE is an AE that is related to the treatment drug. A treatment emergent AE is one that a subject develops undergoing the treatment that was not present prior to start of therapy. In some cases, the treatment emergent AE is not or suspected not to be related to the treatment itself. AEs are characterized as one of five grades - grade I is a mild AE; grade 2 is a moderate AE; grade 3 is a severe AE; grade 4 is a life-threatening or disabling AE; and grade 5 is death related to AE. In some cases, the subject does not exhibit any grade 3 AE that is treatment related. In some cases, the subject does not exhibit any grade 3 AE. In some cases, the subject does not exhibit any grade 4 AE that is treatment related. In some cases, the subject does not exhibit any grade 4 AE. In various cases, the subject does not exhibit a grade 3 or grade 4 AE that is treatment related after administration of the RAS(ON) inhibitor therapy for at least one month, or at least three months.

[0272] In various cases, the subject being treated with the RAS(ON) inhibitor therapy in the methods disclosed herein, does not exhibit any dose limiting toxicities (DLT) at the dose administered. A DLT is any AE meeting the criteria listed below occurring during the first treatment cycle of the RAS(ON) inhibitor therapy (day 1 through day 21) where relationship to the drug cannot be ruled out.

[0273] In various cases, the subject of the disclosed methods exhibits a response to the therapy. In some cases, the subject exhibits at least a stable disease (SD) due to administration of the RAS(ON) inhibitor therapy. In some cases, the subject exhibits at least a partial response (PR) due to administration of the RAS(ON) inhibitor therapy. The response of a subject is assessed by the criteria as defined by RECIST 1.1, e.g., as discussed in Eisenhauer et al., Eur J Cancer, 45:228-247 (2009). A complete response (CR) is disappearance of all target lesions and any pathological lymph nodes have a reduction in short axis to less than 10 mm. A partial response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. A progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest on study), and there must be an absolute increase of at least 5 mm in addition to the relative increase of 20%. A stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. A controlled disease state is when a patient may alternate between exhibiting a stable disease and a partial response. The tumor size can be measured by radiographic scan.

[0274] In various embodiments, the subject has not had a prior therapy with a direct RAS-targeted therapy (e.g., a RAS degrader and / or RAS inhibitor, such as a RAS(OFF) inhibitor).

[0275] In another aspect, the disclosure features a method of administering a RAS(ON) inhibitor therapy as disclosed herein (e.g., Compound A in combination with Compound B) to a subject in need thereof, the method including administering to the subject a therapeutically effective amount of RAS(ON) inhibitor therapy and avoiding co-administration of a cytochrome p450 (CYP) 3A4 inhibitor, wherein said subject is also in need of a CYP3A4 inhibitor. In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject who has discontinued use or avoids concomitant use of products comprising PATENT

[0276] ATTORNEY DOCKET NO.: 51432-080WO5

[0277] a CYP3A4 inhibitor. In various embodiments, the subject is in further need of treatment with a CYP3A4 inhibitor. In some embodiments, the subject is not administered a CYP3A4 inhibitor in combination with the RAS(ON) inhibitor therapy. Exemplary CYP3A4 inhibitors include, but are not limited to, boceprevir, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and / or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole. In some embodiments, the subject has a RAS G12D mutant cancer.

[0278] In another aspect, the disclosure provides methods of administering a RAS(ON) inhibitor therapy to a subject in need thereof, the methods include discontinuing administration of a CYP3A4 inhibitor to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 inhibitor is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 inhibitor is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the CYP3A4 inhibitor can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0279] In another aspect, the disclosure provides methods of administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a CYP3A4 inhibitor, the method including administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding CYP3A4 inhibitor co-administration, and any one or more of the following:

[0280] (a) advising the subject that the CYP3A4 inhibitor should be avoided or discontinued,

[0281] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with the CYP3A4 inhibitor can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy, (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with the CYP3A4 inhibitor is contraindicated, or

[0282] (d) advising the subject that CYP3A4 inhibitors should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the CYP3A4 inhibitor. In some embodiments, the method further includes discontinuing administration of the CYP3A4 inhibitor.

[0283] In yet another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy as disclosed herein (e.g., Compound A in combination with Compound B) to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of a cytochrome p450 (CYP) 3A4 substrate, wherein said subject is also in need of the CYP3A4 substrate. Exemplary CYP3A4 substrates include, but are not limited to, alfentanil, alprazolam, aprepitant, atorvastatin, avanafil, budesonide, buspirone, colchicine, conivaptan, darifenacin, darunavir, dasatinib, dipivefrine, dronedarone, ebastine, eletriptan, eliglustat, eplerenone, everolimus, felodipine, ibrutinib, indinavir, isavuconazole, ivabradine, lemborexant, lomitapide, lovastatin, lurasidone, maraviroc, midazolam, mobocertinib, naloxegol, nisoldipine, pimozide, quetiapine, rivaroxaban, saquinavir, simvastatin, sirolimus, tacrolimus, tadalafil, ticagrelor, tipranavir, PATENT

[0284] ATTORNEY DOCKET NO.: 51432-080WO5

[0285] tolvaptan, triazolam, vardenafil, astemizole, conivaptan, cyclosporine, dronedarone, everolimus, levomethadyl acetate, lomitapide, pimozide, quinidine, sirolimus, tacrolimus, tolvaptan, and venetoclax.

[0286] In some embodiments, the methods include administering the RAS(ON) inhibitor to a subject in need thereof, the method including discontinuing administration of a CYP3A4 substrate to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 substrate is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 substrate is discontinued within 2 weeks prior to being administered Compound A. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the CYP3A4 substrate can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0287] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a CYP3A4 substrate, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding CYP3A4 substrate co-administration, and any one or more of the following:

[0288] (a) advising the subject that CYP3A4 substrate should be avoided or discontinued,

[0289] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy A with CYP3A4 substrates can alter the therapeutic effect or adverse reaction profile of Compound A,

[0290] (c) advising the subject that use of the RAS(ON) inhibitor therapy the RAS(ON) inhibitor therapy in subjects being treated with CYP3A4 substrates is contraindicated, or

[0291] (d) advising the subject that CYP3A4 substrates should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the CYP3A4 substrate. In some embodiments, the method further includes discontinuing administration of the CYP3A4 substrate.

[0292] In yet another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of a cytochrome p450 (CYP) 3A4 inducer, wherein said subject is also in need of the CYP3A4 inducer. Exemplary CYP3A4 inducers include, but are not limited to, apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, St. John’s wort, and rifampin.

[0293] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof, the method includes discontinuing administration of a CYP3A4 inducer to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 inducer is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the CYP3A4 inducer is discontinued within 2 weeks prior to being administered Compound A. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the CYP3A4 inducer can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy. PATENT

[0294] ATTORNEY DOCKET NO.: 51432-080WO5

[0295] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a CYP3A4 inducer, the method includes administering a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding CYP3A4 inducer coadministration, and any one or more of the following:

[0296] (a) advising the subject that CYP3A4 inducer should be avoided or discontinued,

[0297] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with CYP3A4 inducer can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy, (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with CYP3A4 inducer is contraindicated, or

[0298] (d) advising the subject that CYP3A4 inducers should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the CYP3A4 inducer. In some embodiments, the method further includes discontinuing administration of the CYP3A4 inducer.

[0299] In another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of a proton pump inhibitor (PPI), wherein said subject is also in need of the PPI. Exemplary PPIs include, but are not limited to, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

[0300] In some embodiments, the methods include administering the RAS(ON) inhibitor therapy to a subject in need thereof, the method includes discontinuing administration of a PPI to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the PPI is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the PPI is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the PPI can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0301] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a PPI, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding PPI co-administration, and any one or more of the following:

[0302] (a) advising the subject that a PPI should be avoided or discontinued,

[0303] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a PPI can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy,

[0304] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a PPI is contraindicated, or

[0305] (d) advising the subject that PPIs should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method PATENT

[0306] ATTORNEY DOCKET NO.: 51432-080WO5

[0307] further includes avoiding administering the PPI. In some embodiments, the method further includes discontinuing administration of the PPI.

[0308] In still another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of a H-2 receptor antagonists (H2 blockers), wherein said subject is also in need of the H2 blockers. Exemplary H2 blockers include, but are not limited to, cimetidine, famotidine, nizatidine, and ranitidine.

[0309] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof, the method includes discontinuing administration of a H2 blocker to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the H2 blocker is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the H2 blocker is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the H2 blocker can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0310] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a H2 blocker, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding H2 blocker co-administration, and any one or more of the following:

[0311] (a) advising the subject that a H2 blocker should be avoided or discontinued,

[0312] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a H2 blocker can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy,

[0313] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a H2 blocker is contraindicated, or

[0314] (d) advising the subject that H2 blockers should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the H2 blocker. In some embodiments, the method further includes discontinuing administration of the H2 blocker.

[0315] In another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of disease-modifying antirheumaic drugs (DMARDS), wherein said subject is also in need of the DMARDS. Exemplary DMARDS include, but are not limited to, abatacept, apremilast, azathioprine, belimumab, ciclosporin, hydroxychloroquine, ixekizumab, leflunomide, methotrexate, mycophenolate, rituximab, sarilumab, secukinumab, sulfasalazine, tocilizumab, and ustekinumab.

[0316] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof, the method includes discontinuing administration of a DMARD to avoid an adverse drug interaction with RAS(ON) inhibitor therapy, and administering to the subject a PATENT

[0317] ATTORNEY DOCKET NO.: 51432-080WO5

[0318] therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the DMARD is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the DMARD is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the DMARD can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0319] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a DMARD, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding DMARD coadministration, and any one or more of the following:

[0320] (a) advising the subject that a DMARD should be avoided or discontinued,

[0321] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a DMARD can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy,

[0322] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a DMARD is contraindicated, or

[0323] (d) advising the subject that DMARDS should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the DMARD. In some embodiments, the method further includes discontinuing administration of the DMARD.

[0324] In yet another aspect, the disclosure features methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the methods include administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy and avoiding co-administration of an immunosuppressive agent, wherein said subject is also in need of the immunosuppressive agent. Exemplary immunosuppressive agents include, but are not limited to, adalimumab, anakinra, certolizumab, cyclosporine, etanercept, everolimus, golimumab, infliximab, natalizumab, sirolimus, tacrolimus, tofacitinib, and vedolizumab.

[0325] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of an immunosuppressive agent to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the immunosuppressive agent is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the immunosuppressive agent is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the immunosuppressive agent can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0326] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of an immunosuppressive agent, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following: PATENT

[0327] ATTORNEY DOCKET NO.: 51432-080WO5

[0328] (a) advising the subject that an immunosuppressive agent should be avoided or discontinued, (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with an immunosuppressive agent can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy,

[0329] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with an immunosuppressive agent is contraindicated, or

[0330] (d) advising the subject that immunosuppressive agents should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the immunosuppressive agent. In some embodiments, the method further includes discontinuing administration of the immunosuppressive agent.

[0331] In another aspect, the disclosures provides methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy, and avoiding co-administration of a P-glycoprotein (P-gp) substrate, wherein said subject is also in need of P-gp substrate. Exemplary P-gp substrates include, but are not limited to, dabigatran, etexilate, and fexofenadine.

[0332] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of a P-gp substrate to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the P-gp substrate is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the P-gp substrate is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the P-gp substrate can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0333] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a P-gp substrate, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following:

[0334] (a) advising the subject that a P-gp substrate should be avoided or discontinued,

[0335] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a P-gp substrate can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy, (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a P-gp substrate is contraindicated, or

[0336] (d) advising the subject that P-gp substrates should be used with caution in subjects receiving the RAS(ON) inhibitor therapy A due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the P-gp substrate. In some embodiments, the method further includes discontinuing administration of the P-gp substrate.

[0337] In still another aspect, the disclosures provides methods of administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, the method includes PATENT

[0338] ATTORNEY DOCKET NO.: 51432-080WO5

[0339] administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy, and avoiding co-administration of a P-glycoprotein (P-gp) inhibitor, wherein said subject is also in need of P-gp inhibitor. Exemplary P-gp inhibitors include, but are not limited to, amiodarone, carvedilol, clarithromycin, dronedarone, gleceprevir and pibrentavir, indinavir, indinavir and ritonavir, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, valspodar, and verapamil.

[0340] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of a P-gp inhibitor to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the P-gp inhibitor is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the P-gp inhibitor is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the P-gp inhibitor can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0341] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a P-gp inhibitor, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following:

[0342] (a) advising the subject that a P-gp inhibitor should be avoided or discontinued,

[0343] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a P-gp inhibitor can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy, (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a P-gp inhibitor is contraindicated, or

[0344] (d) advising the subject that P-gp inhibitors should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the P-gp inhibitor. In some embodiments, the method further includes discontinuing administration of the P-gp inhibitor.

[0345] In another aspect, the disclosures provides methods of administering a RAS(ON) inhibitor therapy to a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy, and avoiding co-administration of an organic anion-transporting polypeptide 1 B1 or 1 B3 (OATP1 B1 or OATP1 B3) substrate, wherein said subject is also in need of a OATP1 B1 or OATP1 B3 substrate. Exemplary OATP1 B1 or OATP1 B3 substrates include, but are not limited to, asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, rosuvastatin, and simvastatin acid.

[0346] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of a OATP1 B1 or OATP1 B3 substrate to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the OATP1 B1 or OATP1 B3 substrate is discontinued within 1 month prior to being administered the RAS(ON) inhibitor PATENT

[0347] ATTORNEY DOCKET NO.: 51432-080WO5

[0348] therapy. In some embodiments, the OATP1 B1 or OATP1 B3 substrate is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the OATP1 B1 or OATP1 B3 substrate can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0349] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a OATP1 B1 or OATP1 B3 substrate, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following:

[0350] (a) advising the subject that a OATP1 B1 or OATP1 B3 substrate should be avoided or discontinued,

[0351] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a OATP1 B1 or OATP1 B3 substrate can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy,

[0352] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a OATP1 B1 or OATP1 B3 substrate is contraindicated, or

[0353] (d) advising the subject that OATP1 B1 or OATP1 B3 substrates should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the OATP1B1 or OATP1B3 substrate. In some embodiments, the method further includes discontinuing administration of the OATP1 B1 or OATP1 B3 substrate.

[0354] In another aspect, the disclosures provides methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A and Compound B) to a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy, and avoiding co-administration of a breast cancer resistance protein B3 (BCRP) substrate, wherein said subject is also in need of a BCRP substrate. Exemplary BCRP substrates include, but are not limited to, rosuvastatin, simvastatin, and sulfasalazine.

[0355] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of a BCRP substrate to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the BCRP substrate is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the BCRP substrate is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of the RAS(ON) inhibitor therapy and the BCRP substrate can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0356] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a BCRP substrate, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following: PATENT

[0357] ATTORNEY DOCKET NO.: 51432-080WO5

[0358] (a) advising the subject that a BCRP substrate should be avoided or discontinued,

[0359] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a BCRP substrate can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy, (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a BCRP substrate is contraindicated, or

[0360] (d) advising the subject that BCRP substrates should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the BCRP substrate. In some embodiments, the method further includes discontinuing administration of the BCRP substrate.

[0361] In another aspect, the disclosures provides methods of administering a RAS(ON) inhibitor therapy (e.g., Compound A in combination with Compound B) to a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy, and avoiding co-administration of a drug known to prolong QTc interval, wherein said subject is also in need of a drug known to prolong QTc interval. Exemplary drugs known to prolong QTc interval include, but are not limited to, amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, oxaliplatin, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib.

[0362] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy to a subject in need thereof comprising discontinuing administration of a drug known to prolong QTc interval to avoid an adverse drug interaction with the RAS(ON) inhibitor therapy, and administering to the subject a therapeutically effective amount of the RAS(ON) inhibitor therapy. In some embodiments, the drug known to prolong QTc interval is discontinued within 1 month prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the drug known to prolong QTc interval is discontinued within 2 weeks prior to being administered the RAS(ON) inhibitor therapy. In some embodiments, the subject is advised that co-administration of Compound A and the drug known to prolong QTc interval can alter the therapeutic effect or adverse reaction profile of the RAS(ON) inhibitor therapy.

[0363] In some embodiments, the methods include administering a RAS(ON) inhibitor therapy comprising Compound A and Compound B to a subject in need thereof, wherein said subject is also in need of a drug known to prolong QTc interval, the method includes administering to the subject a total daily dosage from 100 mg to 300 mg of Compound A and from 600 mg to 1200 mg Compound B while avoiding immunosuppressive agent co-administration, and any one or more of the following:

[0364] (a) advising the subject that a drug known to prolong QTc interval should be avoided or discontinued,

[0365] (b) advising the subject that co-administration of the RAS(ON) inhibitor therapy with a drug known to prolong QTc interval can alter the therapeutic effect or adverse reaction profile the RAS(ON) inhibitor therapy,

[0366] (c) advising the subject that use of the RAS(ON) inhibitor therapy in subjects being treated with a drug known to prolong QTc interval is contraindicated, or PATENT

[0367] ATTORNEY DOCKET NO.: 51432-080WO5

[0368] (d) advising the subject that drugs known to prolong QTc interval should be used with caution in subjects receiving the RAS(ON) inhibitor therapy due to the potential for an adverse reaction profile. In some embodiments, the method further includes avoiding administering the drug known to prolong QTc interval. In some embodiments, the method further includes discontinuing administration of the drug known to prolong QTc interval.

[0369] In various embodiments, the disclosure provides a method of treating a subject in need of a RAS(ON) inhibitor therapy comprising Compound A and Compound B, the method generally comprising administering Compound A and Compound B at an initial dose and, upon the occurrence of an adverse event, administering a reduced dose of Compound A. In some embodiments, the method generally comprise administering Compound A and Compound B at an initial dose and, upon the occurrence of an adverse event, administering a reduced dose of Compound B. The adverse event may be any treatment-related adverse event, intolerance, or clinical finding warranting dose modification. In some cases, the adverse event prompting dose reduction may include but is not limited to fatigue, gastrointestinal toxicity, rash, or laboratory abnormalities such as elevated liver enzymes. The dose reduction maintains therapeutic exposure while minimizing further toxicity. The dose reduction may occur after temporary interruption of treatment with Compound A or Compound B or without interruption, depending on the severity of the adverse event. Dose reductions may be implemented sequentially or as a single step, and may occur with either once daily (QD) or twice daily (BID) dosing regimens. The reduced dose may be maintained until the adverse event resolves or stabilizes, and the subject may optionally be re-escalated to the initial dose or further reduced in dose as clinically indicated.

[0370] In some embodiments, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound A is administered at a dose of about 300 mg QD and, upon observation of an adverse event, administering to the subject Compound B subsequent dose of about 200 mg QD. In another embodiment, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound A is administered at a dose of about 200 mg QD and, upon occurrence of an adverse event, administering to the subject Compound A at a subsequent dose of about 150 mg QD. In another embodiment, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound A is administered at a dose of about 200 mg QD and, upon occurrence of an adverse event, administering to the subject Compound B at a subsequent dose of about 140 mg QD. In another embodiment, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound A is administered at a dose of 140 or 150 mg QD and, upon occurrence of an adverse event, administering to the subject Compound B at a subsequent dose of about 100 mg QD.

[0371] In some embodiments, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound B is administered at a dose of about 1200 mg (QD or BID) and, upon observation of an adverse event, administering to the subject Compound B subsequent dose of about 900 mg (QD or BID). In another embodiment, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound B is administered at a dose of about 900 mg (QD or BID) and, upon occurrence of an adverse event, administering to the subject Compound B at a subsequent dose of about 600 mg (QD or BID). In another embodiment, the method comprises administering the RAS(ON) inhibitor therapy to the subject, wherein Compound B is administered at a dose of about 600 mg (QD or PATENT

[0372] ATTORNEY DOCKET NO.: 51432-080WO5

[0373] BID) and, upon occurrence of an adverse event, administering to the subject Compound B at a subsequent dose of about 300 mg (QD or BID).

[0374] In some embodiments, the subject is monitored for the occurrence, severity, and resolution of adverse events throughout the course of treatment. Monitoring may include clinical assessment, physical examination, laboratory testing, or patient-reported outcomes.

[0375] In some embodiments, the method further comprises re-initiating treatment at the next lower dose following temporary discontinuation, or maintaining the reduced dose for the remainder of therapy. The dose-reduction sequence for Compound A may proceed stepwise through one or more levels, for example from about 300 mg total daily dose, to about 200 mg total daily dose, to about 150 or 140 mg total daily, dose to about 100 mg total daily dose, as necessary to maintain tolerability while preserving clinical efficacy. The dose-reduction sequence for Compound B may proceed stepwise through one or more levels, for example from about 1200 mg total daily dose, to about 900 mg total daily dose, to about 600 mg total daily, dose to about 300 mg total daily dose, as necessary to maintain tolerability while preserving clinical efficacy.

[0376] Combination Therapy

[0377] The methods of the disclosure may include a RAS(ON) inhibitor therapy of the present disclosure used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0378] A RAS(ON) inhibitor therapy of the present invention may be administered before, after, or concurrently with one or more of such additional therapies. When combined, dosages of a RAS(ON) inhibitor therapy of the invention and dosages of the one or more additional therapies (e.g., non-drug treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). A RAS(ON) inhibitor therapy of the present disclosure and an additional therapy, such as an anticancer agent, may be administered together, such as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.

[0379] In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor therapy of the present disclosure and one additional therapeutic agent. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor therapy of the present invention and two additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor therapy of the present invention and three additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor therapy of the present invention and four or more additional therapeutic agents.

[0380] Also provided are pharmaceutical compositions including the combinations, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Compositions comprising a combination of therapeutic agents may be used in methods of modulating RAS (e.g., in a subject or in a cell) and in methods of treating RAS related diseases and disorders (e.g., cancer), as described herein. PATENT

[0381] ATTORNEY DOCKET NO.: 51432-080WO5

[0382] The present disclosure provides, inter alia, compositions, methods, and kits for treating or preventing a RAS related disease or disorder.

[0383] Exemplary agents that may be used in combination with a RAS(ON) inhibitor therapy of the present disclosure are described below. All references herein are incorporated by reference for the agents described, including compound or molecular structures disclosed therein, whether explicitly stated as such or not.

[0384] a. RAS(ON) Inhibitors

[0385] Compositions of the present disclosure may include one or more RAS(ON) inhibitor compounds. RAS(ON) inhibitors disclosed herein may be administered or formulated in combination with an additional therapeutic agent described herein. In some embodiments, the present disclosure provides non-covalent binding of RAS by a RAS(ON) multi-selective inhibitor.

[0386] One or more RAS(ON) multi-selective inhibitors useful according to the present disclosure can be found in any of the following patent applications: WO 2025209533, WO 2025201453, WO 2025162395, WO 2025119392, WO2025087431, WO 2025051241, WO 2025045233, WO 2024249299, WO 2024222864, WO 2024206858, WO 2024169914, WO 2024153208, WO 2024149214, WO 2024104364, WO 2024067857, WO 2024060966, WO 2024017859, WO 2024008834, WO 2023240263, WO 2023025832, WO 2022060836, WO 2021091956, CN 120441594, CN 119350371, CN 117903169, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685, CN 117534684, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0387] In some embodiments, the RAS(ON) inhibitor is a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib (RMC-6236), AN9025, BPI-572270, compound 6A of WO 2024 / 067857, ERAS-0015,

[0388] GFH276, GFH547, HJ-099, RMC-7977 (Compound

[0389]

[0390] 680, RCZY-690, RG6505, AUBE00.

[0391] In some embodiments, the RAS(ON) multi-selective inhibitor is daraxonrasib (RMC-6236)

[0392]

[0393] PATENT

[0394] ATTORNEY DOCKET NO.: 51432-080WO5

[0395] In some embodiments, the RAS(ON) multi-selective inhibitor is compound 6A of WO 2024067857

[0396]

[0397] The RAS(ON) multi-selective compounds useful according to the present disclosure exhibit inhibitory activities across a variety of RAS mutants. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type RAS. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type KRAS. In some embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G12X, G13X, and / or Q61X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue.

[0398] In certain embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G12X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue.

[0399] In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G13X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue.

[0400] In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at Q61X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue. In other instances, X is H, K, R, or L amino acid residue.

[0401] A variety of RAS proteins may be inhibited by a RAS(ON) multi-selective compound (e.g., KRAS, NRAS, HRAS, and mutants thereof at positions 12, 13 and 61, such as G12A, G12C, G12D, G12V, G12S, G12R, G13C, G13D, Q61H, Q61K, Q61 R and Q61L, and others described herein, or a combination thereof). In some embodiments, a RAS(ON) multi-selective compound inhibits a G12A, G12C, G12D, G12R, G12S, G12V, or Q61H mutant of RAS, or a combination thereof.

[0402] Compositions and methods described herein may include one or more RAS(ON) mutant-selective inhibitors. Numerous RAS(ON) mutant-selective inhibitors have been disclosed.

[0403] In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) Q61 H-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12V-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12R-selective inhibitor.

[0404] RAS(ON) mutant-selective inhibitors useful in combinations according to the methods of the present disclosure can be found in any one of the following patent applications: WO 2025104149, WO PATENT

[0405] ATTORNEY DOCKET NO.: 51432-080WO5

[0406] 2025093625, WO 2025080946, WO 2024249299, WO 2024211663, WO 2024211712, WO 2024208934, WO 2024149819, WO 2024008610, WO 2024102421, WO 2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO 2023232776, WO 2023086341, WO 2023060253, WO 2023015559, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO 2021108683, WO 2020132597, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0407] In some embodiments, the RAS(ON) mutant-selective inhibitor useful according to the present disclosure is a G12D-selective inhibitor, such as zoldonrasib (RMC-9805) or RMC-9945 (Compound D,

[0408]

[0409] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12C-selective inhibitor, such as elironrasib (RMC-6291) or RMC-4998.

[0410] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12V-selective inhibitor, such as RMC-5127.

[0411] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G13C-selective inhibitor, such as RMC-8839. In some embodiments, the RAS(ON) mutant-selective inhibitor is a Q61 H-selective inhibitor, such as RMC-0708. In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12R-selective inhibitor, such as RMC-8264.

[0412] The RAS(ON) inhibitor compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes. By way of example, the RAS(ON) compounds can be synthesized using the methods described in WO 2022060836, WO 2021091956, or WO 2021091982, or any of the other RAS(ON) references cited herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.

[0413] A RAS(ON) inhibitor may be an antibody-drug conjugate, such as WO 2025051241 and WO 2024189481. See also doi.org / 10.1021 / acs.jmedchem.4c02929. RAS(OFF) inhibitors are also known, such as WO 2025171055.

[0414] In some embodiments, the combination therapy comprising a RAS(ON) inhibitor therapy of the present disclosure may include one or more RAS(ON) inhibitors, for example, a RAS(ON) inhibitor therapy of the present disclosure plus one or more RAS(ON) multi-selective inhibitors and / or one or more RAS(ON) mutant-selective inhibitors.

[0415] b) RAS / MAPK Inhibitors

[0416] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives a variety of PATENT

[0417] ATTORNEY DOCKET NO.: 51432-080WO5

[0418] cellular effector events that determine the proliferation, activation, differentiation, mobilization, and other functional properties of the cell. SHP2 conveys positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS as well as GTP-accelerating proteins (GAPs, such as NF1) that facilitate termination of the signals by conversion of GTP to GDP. GTP-bound RAS produced by this cycle conveys essential positive signals to a series of serine / threonine kinases including RAF and MAP kinases, from which emanate additional signals to various cellular effector functions. In some embodiments, a therapeutic agent that may be combined with a RAS(ON) inhibitor is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK pathway inhibitor”). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766;

[0419] MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). The MAPK pathway inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120. A MAPK pathway inhibitor may be a PI3Ka: RAS breaker, such as BBG-10203.

[0420] i. RAS(OFF) inhibitors, RAS(OFF) degraders and other RAS inhibitor types

[0421] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more RAS(OFF) inhibitors. Numerous mutant-selective and pan-KRAS inhibitors have been disclosed and are known in the art. A RAS(OFF) inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in its inactive state (GDP bound state), preventing its activation and downstream signaling.

[0422] In some embodiments, a RAS(OFF) inhibitor is a KRAS(OFF) inhibitor that has a molecular weight of under 700 Da. In some embodiments, the KRAS(OFF) inhibitor is specific for a KRAS3120mutation. KRASG12C(OFF) inhibitors use a covalent binding group that allows them to selectively target the KRASG12Cmutant protein, and many such inhibitors comprise a pyrimidine core. KRASG12C(OFF) inhibitors all target the same cysteine residue in the KRASG12Cmutant protein, leading to a conformational change that locks the protein in an inactive state. KRASG12C(OFF) inhibitors include, but are not limited to, adagrasib (MRTX849), divarasib (RG6330 / GDC-6036), fulzerasib (IBI351 / GFH925), garsorasib (D-1553), glecirasib (JAB-21822), olomorasib (LY3537982), opnurasib (JDQ443), sotorasib (AMG 510), ARS-853, ARS-1620, BI-0474, Bl 1823911, BPI-421286, D3S-001, ERAS-3490, GEC255, GH35, HBI-2438, HS-10370, JAB-21000, JAB-21822, JMKX001899, JNJ-74699157 (ARS-3248), MK-1084, SK-17, and YL-15293, HRS-7058. In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is MRTX849. In some embodiments, the KRAS(OFF) inhibitor is GDC-6036. A RAS(OFF) inhibitor may be an antibody-drug conjugate. See also

[0423] doi.org / 10.1021 / acs.jmedchem.4c02929. PATENT

[0424] ATTORNEY DOCKET NO.: 51432-080WO5

[0425] In some embodiments, a KRAS(OFF) inhibitor is specific for a KRAS3120mutation. Non-limiting examples of KRASG12D(OFF) inhibitors include AST2169, BPI-501836, DN022150, ERAS-4693, ERAS-5024, GDC-7035 (RG6620), HBW-012-D, HBW-012-E, HBW-012336, HRS-4642, HS-10529, INCB186748, JAB-22000, KD-8, KRB-456, LY3962673, MRTX282, MRTX1133, Q2a, QLC1101, RNK08954, SHR1127, TH-Z827, TH-Z835, TSN1611, VRTX153, HJ-119, JR-6000, NKT-G12D, FWD-K02, JAB-BX600, EB-TM1, ABSK141, BPI-2491, HRS-6093, and HRS-7172.

[0426] In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG12Vmutation (e.g., JAB-23000, QTX3544). In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRAS21130mutation.

[0427] In some embodiments, reference to the term RAS(OFF) inhibitor includes any such RAS(OFF) inhibitor disclosed in any one of the following patent applications: WO 2025209490, WO 2025202022, WO 2025201480, WO 2025199170, WO 2025194340, WO 2025194134, WO 2025194057, WO 2025194054, WO 2025190342, WO 2025188668, WO 2025179058, WO 2025170938, WO 2025168072, WO 2025167948, WO 2025165972, WO 2025162091, WO 2025157289, WO 2025157260, WO 2025157246, WO 2025157162, WO 2025153038, WO 2025151738, WO 2025151594, WO 2025148979, WO 2025146194, WO 2025136346, WO 2025132549, WO 2025130912, WO 2025129002, WO 2025124415, WO 2025123318, WO 2025123007, WO 2025122619, WO 2025117828, WO 2025111586, WO 2025111582, WO 2025108443, WO 2025106905, WO 2025106901, WO 2025101776, WO 2025096984, WO 2025096957, WO 2025096738, WO 2025092986, WO 2025092798, WO 2025085748, WO 2025085580, WO 2025080653, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025072649, WO 2025072457, WO 2025072451, WO 2025067459, WO 2025067453, WO 2025064848, WO 2025064542, WO 2025061125, WO 2025059366, WO 2025059040, WO 2025054530, WO 2025054347, WO 2025054270, WO 2025053850, WO 2025051242, WO 2025045141, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025049274, WO 2025040767, WO 2025038936, WO 2025036475, WO 2025036470, WO 2025034883, WO 2025034849, WO 2025026903, WO 2025019688, WO 2025018418, WO 2025016899, WO 2025016432, WO 2025011443, WO 2025010415, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2025002430, WO 2025002302, WO 2024259169, WO 2024254404, WO 2024254334, WO 2024255795, WO 2024246099, WO 2024243025, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024233776, WO 2024230734, WO 2024230707, WO 2024229447, WO 2024229444, WO 2024229442, WO 2024229317, WO 2024227091, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215862, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024208305, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024197503, WO 2024193698, WO 2024192424, WO 2024179546, WO 2024178313, WO 2024178304, WO 2024173842, WO 2024167922, WO 2024160225, WO 2024159471, WO 2024159470, WO 2024158778, WO 2024158242, WO 2024153119, WO 2024153116, WO 2024138486, WO 2024138206, WO 2024138052, WO 2024131829, WO 2024125642, WO 2024125600, WO 2024123913, WO 2024123102, WO 2024120433, WO 2024120419, WO 2024119277, WO 2024118926, WO 2024109233, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024097559, WO 2024091409, WO 2024088273, WO 2024085661, WO 2024083258, WO 2024083256, WO 2024083246, WO 2024083168, WO 2024078555, WO 2024076674, WO 2024076672, WO 2024076670, PATENT

[0428] ATTORNEY DOCKET NO.: 51432-080WO5

[0429] WO 2024067714, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024061370, WO 2024061333, WO 2024061267, WO 2024056063, WO 2024055112, WO 2024054926, WO 2024054647, WO 2024054625, WO 2024051763, WO 2024051721, WO 2024050742, WO 2024050640, WO 2024046406, WO 2024046370, WO 2024045066, WO 2024044667, WO 2024044649, WO 2024044334, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024041573, WO 2024040131, WO 2024040109, WO 2024040080, WO 2024036270, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024029613, WO 2024022507, WO 2024022444, WO 2024020159, WO 2024019103, WO 2024017859, WO 2024017392, WO 2024015731, WO 2024015262, WO 2024012456, WO 2024009191, WO 2024008179, WO 2024008178, WO 2024008068, WO 2024006445, WO 2024006424, WO 2024002373, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023246914, WO 2023246903, WO 2023246777, WO 2023244713, WO 2023244615, WO 2023244604, WO 2023244600, WO 2023244599, WO 2023230190, WO 2023226630, WO 2023225302, WO 2023225252, WO 2023220421, WO 2023219941, WO 2023217148, WO 2023215802, WO 2023215801, WO 2023213269, WO 2023212548, WO 2023208005, WO 2023205719, WO 2023199180, WO 2023198191, WO 2023197984, WO 2023190748, WO 2023185864, WO 2023183755, WO 2023183585, WO 2023179703, WO 2023179629, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023171781, WO 2023159087, WO 2023159086, WO 2023154766, WO 2023152255, WO 2023151674, WO 2023151621, WO 2023150394, WO 2023150284, WO 2023143623, WO 2023143605, WO 2023143352, WO 2023143352, WO 2023143312, WO 2023141570, WO 2023141300, WO 2023138662, WO 2023138601, WO 2023138589, WO 2023138524, WO 2023133183, WO 2023133181, WO 2023130012, WO 2023125989, WO 2023125627, WO 2023122662, WO 2023122154, WO 2023120742, WO 2023119677, WO 2023117681, WO 2023116934, WO 2023116895, WO 2023114733, WO 2023105491, WO 2023104018, WO 2023103906, WO 2023103523, WO 2023101928, WO 2023099624, WO 2023099624, WO 2023099620, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023098832, WO 2023098425, WO 2023097227, WO 2023081840, WO 2023081476, WO 2023078424, WO 2023077441, WO 2023072297, WO 2023072188, WO 2023066371, WO 2023064857, WO 2023061463, WO 2023061294, WO 2023057985, WO 2023056951, WO 2023056421, WO 2023051586, WO 2023049697, WO 2023046135, WO 2023045960, WO 2023041059, WO 2023041059, WO 2023040989, WO 2023040513, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023030495, WO 2023030517, WO 2023030685, WO 2023030687, WO 2023034290, WO 2023036282, WO 2023039240, WO 203020347, WO 2023025116, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023040989, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO 2023004102, WO 2023003417, WO PATENT

[0430] ATTORNEY DOCKET NO.: 51432-080WO5

[0431] 2023001141, WO 2023001123, WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO 2022216762 (e.g., Compound 44 or Compound 66a), WO 2022212894, WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO 2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO 2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO 2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO

[0432] 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO

[0433] 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, KR 20250100539, KR102819454, KR 20240159370, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, JP 2025100453, CN 120647614, CN 120607543, CN 120590414, CN 120574243, CN 120574242, CN 120535536, CN 120535527, CN 120441596, CN 120230123, CN 119607214, CN 119930639, CN 119909188, CN 119751476, CN 119733053, CN 119684316, CN 119684315, CN 119684314, CN 119661556, CN 119661555, CN 119661539, CN 119606974, CN 119528902, CN 119528810, CN 119504612, CN 119490514, CN 119490512, CN 119462648, CN 119371353, CN 119350242, CN 119264124, CN 119241566, CN 119060049, CN 119060066, CN 119019382, CN 118994158, CN 118994031, CN 118806919, CN 118791505, CN 118772176, CN 118754899, CN 118745175, CN 118666870, CN118666869, CN 118580238, CN 118307563, CN 118221700, CN 118221699, CN PATENT

[0434] ATTORNEY DOCKET NO.: 51432-080WO5

[0435] 118221698, ON 118221685, ON 118126064, ON 118078802, ON 118078801, ON 118005656, ON 117986263, ON 117986263, ON 117946135, ON 117924327, ON 117903117, ON 117800990, ON 117800989, ON 117800976, ON 117736226, ON 117683051, ON 117645627, ON 117624194, ON 117624190, ON 117586280, ON 117486901, ON 117466917, ON 117462688, ON 117362315, ON 117327102, ON 117327094, ON 117327074, ON 117285590, ON 117263959, ON 117247382, ON 117186095, ON 117164605, ON 116969977, ON 116925075, ON 116891489, ON 116731045, ON 116731044, ON 116554208, ON 116514846, ON 116478184, ON 116478141, ON 116410145, ON 116375742, ON 116354988, ON 116332948, ON 116332938, ON 116327956, ON 116262759, ON 116217592, ON 116199703, ON 116162099, ON 116143806, ON 116143805, ON 116120315, ON 116102559, ON 115960105, ON 115894520, ON 115872979, ON 115850267, ON 115785199, ON 115785124, ON 115724842, ON 115724842, ON 115721720, ON 115716840, ON 115703775, ON 115611923, ON 115611898, ON 115583937, ON 115572278, ON 115557949, ON 115521312, ON 115504976, ON 115490709, ON 115466272, ON 115433183, ON 115433179, ON 115403575, ON 115385938, ON 115385937, ON 115385912, ON 115381786, ON 115368383, ON 115368382, ON 115368381, ON 115353506, ON 115322158, ON 115304623, ON 115304602, ON 115197245, ON 115181106, ON 114989195, ON 114989166, ON 114989147, ON 114920741, ON 114920739, ON 114907387, ON 114874234, ON 114874201, ON 114716436, ON 114716435, ON 114685532, ON 114685460, ON 114591319, ON 114539293, ON 114539286, ON 114539246, ON 114437107, ON 114437084, ON 114409653, ON 114380827, ON 114195804, ON 114195788, ON 114437107, ON 114409653, ON 114380827, ON 114195804, ON 114057776, ON 114057744, ON 114057743, ON 113999226, ON 113980032, ON 113980014, ON 113960193, ON 113929676, ON 113754653, ON 113683616, ON 113563323, ON 113527299, ON 113527294, ON 113527293, ON 113493440, ON 113429405, ON 113321654, ON 113248521, ON 113087700, ON 113024544, ON 113004269, ON 112920183, ON 112778284, ON 112390818, ON 112390788, ON 112300196, ON 112300194, ON 112300173, ON 112225734, ON 112142735, ON 112110918, ON 112094269, ON 112047937, ON 109574871, US 12331063, US 2025115603, US 2025114346, US 2025114339, US 20240358702, US 2024270736, EP 4574151, or EP 4389751, each of which is incorporated herein by reference in its entirety, including the RAS compound structures disclosed therein which are specifically incorporated herein by reference.

[0436] In some embodiments, reference to the term RAS(OFF) inhibitor refers to a pan-KRAS inhibitor, such as selected from one disclosed in any of the following: WO 2025194057, WO 2025194054, WO 2025165972, WO 2025153038, WO 2025151594, WO 2025136346, WO 2025130912, WO 2025129002, WO 2025123007, WO 2025117828, WO 2025106905, WO 2025106901, WO 2025101776, WO 2025096738, WO 2025092798, WO 2025085748, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025064848, WO 2025059366, WO 2025059040, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025045141, WO 2025038936, WO 2025026903, WO 2025016899, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2024255795, WO 2024254404, WO 2024246099, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024230734, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024192424, WO 2024178313, WO 2024178304, WO 2024173842, WO2024153180, WO PATENT

[0437] ATTORNEY DOCKET NO.: 51432-080WO5

[0438] 2024119277, WO 2024120433, WO 2024115890, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024085661, WO 2024083246, WO 2024083168, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024051852, WO 2024051763, WO 2024046370, WO 2024044667, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024040131, WO 2024040109, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024015262, WO 2024009191, WO 2024008068, WO 2024002373, WO 2023287896, WO 2023274324, WO 2023246914 (e.g., compound 14), WO 2023246777, WO 2023230190, WO 2023215802, WO 2023215801, WO 2023197984, WO 2023190748, WO 2023183585, WO 2023179703, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023154766, WO 2023143352, WO 2023143312, WO 2023138589, WO 2023133183, WO 2023122662, WO 2023114733, WO 2023099624, WO 2023099623, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023097227, WO 2023064857, WO 2023056421, WO 2023049697, WO 2023046135, WO 2023039240, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023001123, WO 2022271823, WO 2022261210, WO 2022258974, WO 2022256459, WO 2022250170, WO 2022248885, WO 2022228543, WO 2022216762, WO 2022072783, WO 2016161361, KR 20250100539, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, JP 2025100453, ON 120607543, ON 120535536, ON 120441596, ON 120365289, ON 119751476, ON 119661539, ON 119371353, ON 119019382, ON 118791505, ON 118221700, ON 118126064, ON 117924327, ON 117946135, ON 117800990, ON 117800989, ON 117683051, ON 117486901, ON 117263959, ON 116969977, ON 116332948, or US 12331063, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, combination comprising a pan-KRAS inhibitor therapy comprises ERAS-4001. In some embodiments, the pan-KRAS inhibitor is a pan-KRAS inhibitor in a patent application filed in the name of Medshine Discovery, Inc. In some embodiments, a combination comprising a pan-KRAS inhibitor therapy includes A2A-03, ABREV01, ADT-007, ABT-200, ADT-030, ADT-1004, BBP-454, BGB-53038, BI-2865, BI-2493, Bl 3706674, BRSD-143, ERAS-4, ERAS-254, ERAS-4001, HB-700 (G12X+G13D), HZ-V068, ID12241161, JAB-23400, LY4066434, OC211, PF-07985045, PF-07934040, PF-4040, QTX2024, QTX3034, RSC-1255, SIL204, SYNB021225, YL-17231, ZG2001, WEF-001.

[0439] In some embodiments, a RAS inhibitor binds to the OFF form as well as the ON form. Nonlimiting examples of such inhibitors include, e.g., pan-KRAS: ALTA3263, AMG 410, BBO-11818, HBW-012462, HBW-016-K, HEC211909, JAB-23E73, JAB-23425, JAB-23E73; or a compound disclosed in Zheng, Q.; Shen, T.; Pampel, J.; Shokat, K. M.; Distal Covalent Targeting Suppresses Signaling of Oncogenic KRas(G13C) in Cancer Cells. ACS Chem. Biol. 2025, 20, 7, 1696-1706; G12C: BBO-8520, FMC-376; G12D: AZD0022, GFH375 (VS-7375), INCB161734, QTX3046, TSN1611, TH-Z835, TLN-372.

[0440] In some embodiments, a RAS inhibitor binds to the ON form of RAS but is not a tri-complex inhibitor, such as pan-KRAS inhibitors JTX-102 and JTX-105. Pan-KRAS(ON) inhibitors with a high selectivity for the ON form may be found, for example, in WO 2025193878.

[0441] In any embodiment employing a RAS(OFF) inhibitor herein, a RAS(OFF) degrader targeting the OFF state of RAS may be employed. These degraders are known in the art, such as ASP3082 (G12D) PATENT

[0442] ATTORNEY DOCKET NO.: 51432-080WO5

[0443] and ASP5834 (pan-KRAS). RAS degraders may be found, for example, in one or more of the following applications: WO 2025190158, WO 2025169901, WO 2025168124, WO 2025168051, WO 2025162250, WO 2025159142, WO 2025151765, WO 2025125630, WO 2025108479, WO 2025107579, WO 2025103476, WO 2025096855, WO 2025085815, WO 2025083472, WO 2025078984, WO 2025076044, WO 2025058008, WO 2025053850, WO 2025024732, WO 2025019823, WO 2025006783, WO 2025006753, WO 2024263586, WO 2024261257, WO 2024261256, WO 2024241248, WO 2024233838, WO 2024199266, WO 2024188281, WO 2024 / 59164, WO 2024152247, WO 2024149214, WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112, WO 2024054625, WO 2024050742, WO 2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO 2023215906, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, WO 2022260482, ON 120647627, ON 120535501, ON 120463820, ON 120441554, ON 120365263, ON 119219669, ON 119161349, ON 118955610, ON 118772249, ON 118725012, ON 118496502, ON 118496300, ON 118126040, ON 115785199, or US 2025213706, each of which is incorporated herein by reference in its entirety. Non-limiting examples of RAS degraders include: ASP3082 (KRAS G12D); ASP4396 (KRAS G12D); BPI-585725 (G12X and WT), LT-010366 (G12D); PT0253 (G12D), RD0255359 (KRAS G12C / D / V); RP03707 (G12D), JR-9000, 356A, SH1718, I PS-06061, HDB-82.

[0444] In some embodiments, the RAS(OFF) inhibitor is a peptide-based inhibitor. Peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. Non-limiting examples include the K-Ras-binding peptide (Krpep-2d), the Ras inhibitory peptide (Rasln) and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target the RAS protein by disrupting its interaction with its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motifs of RAS-interacting proteins or other RAS effectors, such as RAF or PI3K. By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and prevent the activation of downstream signaling pathways. See, e.g., WO 2025162428, WO 2025127968, WO 2025018418, WO 2024219480, WO 2024219446, WO 2024176153, WO 2024101402, WO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO 2022234852, WO 2022234851, WO 2022234639 and ON 120040551, each of which is incorporated herein by reference in its entirety.

[0445] Peptide-based RAS(OFF) inhibitors can be further classified into two main categories: those that target the RAS-effector interface, and those that target other regions of the RAS protein. Peptide-based inhibitors that target the RAS-effector interface are designed to bind to the switch regions of RAS that are critical for its interaction with downstream effectors, such as RAF or PI3K. These inhibitors typically contain amino acid residues that are similar to those found in the binding motifs of RAS-interacting proteins or effectors and are often designed to form hydrogen bonds or other interactions with key residues on the surface of RAS.

[0446] Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to disrupt other interactions that are critical for the activation or signaling of RAS. For example, PATENT

[0447] ATTORNEY DOCKET NO.: 51432-080WO5

[0448] some peptide-based inhibitors are designed to bind to the hypervariable region of RAS, which is thought to play a role in membrane localization and anchoring of the protein. By binding to this region, peptide-based inhibitors can prevent the proper localization of RAS to the plasma membrane, which is necessary for its activation and signaling.

[0449] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors and are often used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), which is found in many RAS-interacting proteins and is important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is critical for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction of RAS with this downstream effector. The RBD of PI3K contains several conserved amino acid residues (such as Arg-Arg-Trp) that are critical for binding to RAS, and these motifs have been used in the design of peptide-based inhibitors that target the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins such as RaIGDS and SOS, as well as sequences that mimic the structure of the switch regions of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for the desired target protein or interaction.

[0450] In some embodiments, the RAS(OFF) inhibitor is an antibody or antigenic binding peptide specific for RAS(OFF). Antibodies have been developed that bind to specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. For example, some antibodies have been developed that target the switch regions of RAS proteins, which are critical for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to the switch regions can prevent the conformational changes required for RAS activation and downstream signaling. Another approach involves the use of antibodies that target RAS-interacting proteins or downstream effectors, such as RAF or PI3K. Binding of these antibodies to their target proteins can disrupt the RAS-dependent signaling pathways and inhibit the growth and survival of cancer cells. Additionally, some antibodies have been developed that can induce the internalization and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling. For example, some antibodies have been developed that recognize the unique structure of mutant RAS proteins and target them for degradation via the ubiquitin-proteasome pathway. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser, and K27 (DARPin) (see, e.g., Khan et al, Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570). See also WO 2024136608 and WO 2024111590, each of which is incorporated herein by reference in its entirety.

[0451] Antibody-drug conjugates may also be constructed using RAS inhibitors (e.g., RAS(OFF) inhibitors), such as WO 2025212580 and WO 2024189481, which are incorporated herein by reference in their entirety, including the compound structures disclosed therein.

[0452] Vaccines may also be used in combination with RAS(ON) inhibitor therapy of the present invention. Non-limiting examples include: AFNT-111 (KRAS G12V), AFNT-211 (KRAS G12V), AFNT-212 (KRAS G12D), ELI-002 (KRAS G12 / 13X), HB-700, NT-112 (KRAS G12D), and TG01 (pan-KRAS). PATENT

[0453] ATTORNEY DOCKET NO.: 51432-080WO5

[0454] Other RAS modalities useful in combination with RAS(ON) inhibitor therapy of the present invention include: ADGN-123, ADGN-121 (gene editing peptide-RNA nanoparticles G12D); ADT-030 (Ras / B-catenin inhibitor); BBO-10203 (PI3Ka: RAS breaker); Bl 1701963 (Pan-KRAS: SOS1); mRNA-5671 (nucleic acid) and RO7673396 (RAS inhibitor), AZD0240 (TCR-T cell product targeting G12D), MDG2021 (TCR-T cell product targeting G12D), ADGN-121 (peptide-sgRNA nanoparticles), BION-302 (antibody based) LIB111 (antibody based), SIL-204 (ASO I siRNA-based).

[0455] ii. SOS1 inhibitors

[0456] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more SOS1 inhibitors. A SOS1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a SOS1 inhibitor is one or more of RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-1918455, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, reference to the term SOS1 inhibitor includes any such SOS1 inhibitor disclosed in any one of the following patent applications: WO 2025070947, WO 2025067316, WO 2025062157, WO 2025059046, WO 2025038785, WO 2025003694, WO 2025000265, WO 2024255827, WO 2024172632, WO 2024172631, WO 2024119028, WO 2024102952, WO 2024083257, WO 2024083255, WO 2024079252, WO 2024075070, WO 2024067744, WO 2024035921, WO 2024027762, WO 2024008185, WO 2023250165, WO 2023215257, WO 2023215256, WO 2023180345, WO 2023109929, WO 2023059597, WO 2023041049, WO 2023029833, WO 2023022497, WO 2022184116, WO 2022171184, WO 2022170952, WO 2022170917, WO 2022170802, WO 2022161461, WO 2022157629, WO 2022139304, WO 2022121813, WO 2022028506, WO 2021228028, WO 2019122129, KR 20240128541, ON 119431234, ON 119039237, ON 119039234, ON 118812510, ON 117800922, CN117143175, ON 117143176, ON 116462669, ON 116444447, ON 115806560, ON 115677702, ON 115215847, ON 115028644, ON 114685488, and ON 111393519 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0457] Hi. SHP inhibitors

[0458] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more SHP inhibitors. A SHP inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 inhibitor is SB8091 or SB6299 aka DA-4511. In some embodiments, a SHP2 inhibitor is one or more of SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, ARRY-558, or BBP-398. In some embodiments, reference to the term SHP2 inhibitor includes any such SHP2 inhibitor disclosed in any one of the following patent applications: WO 2025075693, WO 2025019666, WO 2025011568, WO 2025011480, WO 2024258652, WO 2024193439, WO 2024175081, WO 2024147703, WO 2024125603, WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, WO 2022135568, WO PATENT

[0459] ATTORNEY DOCKET NO.: 51432-080WO5

[0460] 2022063190, WO 2022043865, WO 2022042331, WO 2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO 2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO 2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, ON 116332908, ON 119264153, ON 117069698, ON 117143107, ON 115677661, ON 115677660, ON 115611869, ON 115521305, ON 115490697, ON 115466273, ON 115394612, ON 115304613, ON 115304612, ON 115300513, ON 115197225, ON 114957162, ON 114920759, ON 114716448, ON 114671879, ON 114539223, ON 114524772, ON 114213417, ON 114195799, ON 114163457, ON 113896710, ON 113248521, ON 113248449, ON 113135924, ON 113024508, ON 112920131, ON 112823796, ON 112409334, ON 112402385, ON 112174935, 111848599, ON 111704611, ON 111393459, ON 111265529, ON 110143949, ON 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US 11001561, US 10988466, US 10954243, US 10934302, or US 10858359, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0461] iv. MEK inhibitors

[0462] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more MEK inhibitors. A MEK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MEK inhibitor is one or more of pimasertib, IMM-1 -104, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), atebimetinib and binimetinib (Mektovi®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from AE51 -Q58; AF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. In some embodiments, reference to the term MEK inhibitor includes any such MEK inhibitor disclosed in any one of the following patent applications: WO 2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO 2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO 2019076947, PATENT

[0463] ATTORNEY DOCKET NO.: 51432-080WO5

[0464] WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO 2011047238, WO 2007044515, US 2023032403, and ON 115813930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0465] v. RAF inhibitors

[0466] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more RAF inhibitors. A RAF inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, a RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with a RAS(ON) inhibitor therapy of the present disclosure include, for example, VS-6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may comprise a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E. In some embodiments, reference to the term RAF inhibitor includes any such RAF inhibitor disclosed in any one of the following patent applications: WO 2023076991, WO 2022226626, WO 2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO 2017212442, WO 2015075483, WO 2013134243, WO 2013134298, WO 2011047238, WO 2011025965, WO 2011025947, WO

[0467] 2011025951, WO 2011025940, WO 2011025938, WO 2010065893, WO 2009016460, WO 2009130015, WO 2009111278, WO 2009111279, WO 2008028141, and WO 2006024834, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0468] vi. ERK inhibitors

[0469] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more ERK inhibitors. An ERK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ERK inhibitor is an ERK1 / 2 inhibitor, such as ERAS-007. In some embodiments, an ERK inhibitor is an ERK 5 inhibitor. In some embodiments, an ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, reference to the term ERK inhibitor includes any such ERK inhibitor disclosed in any one of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO

[0470] 2021110169, WO 2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO 2020107987, WO 2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WO 2016106029, WO 2016106009, WO 2015051341, WO 2014124230, WO 2014052563, WO 2011041152, WO 200910550, WO 2008153858, ON 114315837, ON 115057860, ON 107973783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0471] vii. MAPK inhibitors

[0472] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Mitogen-Activated Protein PATENT

[0473] ATTORNEY DOCKET NO.: 51432-080WO5

[0474] Kinase (MAPK) inhibitors. A MAPK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MAPK inhibitor is a p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of Tilpisertib (GS-4875) and neflamapidmod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any one of the following patent applications: WO 2016029263, ON 114767674, ON 115850179, and ON 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0475] In some embodiments, a therapeutic agent that may be combined with a RAS(ON) inhibitor therapy of the present disclosure is an inhibitor of MAP2K4. A non-limiting example of a MAP2K4 inhibitor useful according to the disclosure is HRX-0233.

[0476] c) Kinase Inhibitors

[0477] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play a crucial role in various cellular processes such as cell signaling, growth, and differentiation. Kinase inhibitors known in the art have been developed as a treatment for various types of cancer in addition to therapies for conditions such as neurodegenerative diseases, autoimmune disorders, and inflammation.

[0478] i. PKA inhibitors

[0479] In some embodiments, compositions and methods described herein may include one or more Protein Kinase A (PKA) inhibitors. A PKA inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any one of the following patent applications: ON 106620678 and ON 114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ii. FAK inhibitors

[0480] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Focal Adhesion Kinase (FAK) inhibitors. A FAK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a FAK inhibitor is one or more of BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, reference to the term FAK inhibitor includes any such FAK inhibitor disclosed in any one of the following patent applications: WO 2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO 2013134353, WO 2012110774, WO 2010062578, ON 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0481] Hi. ROCK inhibitors

[0482] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Rho-associated, coiled-coil PATENT

[0483] ATTORNEY DOCKET NO.: 51432-080WO5

[0484] containing protein kinase (ROCK) inhibitors. A ROCK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a ROCK inhibitor is GSK269962A. In some embodiments, reference to the term ROCK inhibitor includes any such ROCK inhibitor disclosed in any one of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO 2021093795, WO 2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO 2019179525, WO 2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO 2018009625, WO 2018009622, WO 2017123860, WO 2017205709, WO 2016112236, WO 2014068035, WO 2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN 108129453, CN 108191821, CN 110917352, CN 108558823, CN 108047193, CN 107973777, CN 108047197, CN 108129448, CN 115869304, and GB202214708, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0485] iv. MSK1 inhibitors

[0486] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Mitogen- and stress-activated kinase (MSK1) inhibitors. A MSK1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MSK1 inhibitor is one or more of SB-747651 A, SB 747651 A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0487] v. RSK inhibitors

[0488] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more ribosomal S6 kinase (RSK) inhibitors. A RSK1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a RSK inhibitor is one or more of BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, a RSK inhibitor is PMD-026. In some embodiments, reference to the term RSK inhibitor includes any such RSK inhibitor disclosed in any one of the following patent applications: WO 2021249558, WO 2020165646, WO 2017141116, and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0489] vi. ALK inhibitors

[0490] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Anaplastic Lymphoma Kinase (ALK) inhibitors. An ALK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ALK inhibitor is one or more of Crizotinib (Xalkori), Ceritinib (Zykadia), Alectinib (Alecensa), Brigatinib (Alunbrig), Lorlatinib (Lorbrena), Ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (Ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of WG05016894. In some embodiments, reference to the term ALK inhibitor includes any such ALK inhibitor disclosed in PATENT

[0491] ATTORNEY DOCKET NO.: 51432-080WO5

[0492] any one of the following patent applications: WO 2019142095, WO 2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO 2016192132, WO 2014100431, WO 2012082972, ON 111138492, ON 110526914, ON 109836415, ON 105801603, ON 107987056, and ON 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0493] d) Receptor tyrosine kinase inhibitors

[0494] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more receptor tyrosine kinase inhibitors. A receptor tyrosine kinase (RTK) inhibitor is a type of molecule (e.g., small molecule, antibody, and nucleic acid) that binds to and blocks the activity of receptor tyrosine kinases or their ligands. RTKs are proteins found on the surface of cells that play a critical role in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0495] i. EGFR inhibitors

[0496] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more EGFR inhibitors. An EGFR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. In some embodiments, the antibody-based EGFR inhibitor is a bispecific antibody. In some embodiments, the bispecific is selective for EGFR and MET. In some embodiments, the bispecific is amivantamab. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res.1999, 59:1236-1243. The EGFR inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0497] Small molecule antagonists of EGFR include gefitinib (Iressa®), Lazertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, an EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. An EGFR inhibitor may be ERAS-801. In some embodiments, an EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, PATENT

[0498] ATTORNEY DOCKET NO.: 51432-080WO5

[0499] lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, reference to the term EGFR inhibitor includes any such EGFR inhibitor disclosed in any one of the following patent applications: WO 2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, WO 2021073498, WO 2021238827, WO 2020254547, WO 2020216371, WO 2020147838, WO 2020207483, WO 2020254572, WO 2020001350, WO 2021001351, WO 2019164948, WO 2019218958, WO 2019046775, WO 2019015655, WO 2018121758, WO 2018218963, WO 2017220007, WO 2017205459, WO 2017161937, WO 2016192609, WO 199633980, WO 199630347, WO 199730034, WO 199730044, WO 199738994, WO 199749688, WO 199802434, WO 199738983, WO 199519774, WO 199519970, WO 199713771, WO 199802437, WO 199802438, WO 199732881, WO 199833798, WO 199732880, WO 199732880, WO 199702266, WO 199727199, WO 199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO 199935132, WO 199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, ON 115960018, ON 110283162, ON 114044774, CN111973601, ON 111973602, and CN113896744, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0500] ii. HER2 inhibitors

[0501] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more HER2 inhibitors. A HER2 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an HER2 inhibitor is one or more of tucatinib, rastuzumab (Herceptin™), pertuzumab (Perjeta™), lapatinib (Tykerb™), ado-trastuzumab emtansine (Kadcyla™), and neratinib (Nerlynx™). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (Cl 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327. In some embodiments, reference to the term HER2 inhibitor includes any such HER2 inhibitor disclosed in any one of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO 2013561183, and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0502] iii. MET inhibitors

[0503] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more MET inhibitors. A MET inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, the MET inhibitor is an anti-MET antibody-drug-conjugate such as MYTX-011, TR1801-ADC, ABBV-399, and SHR-A1403. In some embodiments, a MET inhibitor is one or more of Crizotinib (Xalkori™), Cabozantinib PATENT

[0504] ATTORNEY DOCKET NO.: 51432-080WO5

[0505] (Cometriq, Cabometyx™), Capmatinib (Tabrecta™), Tepotinib (Tepmetko™), Savolitinib (Volitinib™), Onartuzumab (MetMab™), Foretinib (GSK1363089), MGCD-265 (Amuvatinib), SU11274, and SU5416. In some embodiments, reference to the term MET inhibitor includes any such MET inhibitor disclosed in any one of the following patent applications: WO 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO 2008051547, WO 2007130468, US 2012237524, ON 103497177, ON 107311983, ON 107382968, ON 110218191, and TW201331206, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0506] iv. AXL inhibitors

[0507] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more AXL inhibitors. An AXL inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. AXL is a receptor tyrosine kinase that belongs to the TAM family of receptors, which also includes TYRO3 and MERTK. In some embodiments, an AXL inhibitor is one or more of bemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, reference to the term AXL inhibitor includes any such AXL inhibitor disclosed in any one of the following patent applications: WO 2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO 2010083465, ON 115073367, and JP 2022171109, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0508] v) IGFR inhibitors

[0509] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more insulin-like growth factor receptor 1 (IGF-1 R) inhibitors. An IGFR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. IGFR inhibitors have been developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, an IGFR inhibitor is one or more of linsitinib, AXL1717, OSI-906 (Linsitinib), BMS-754807, Bl 836845, AZ12253801, PQIP (Pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, reference to the term IGFR inhibitor includes any such IGFR inhibitor disclosed in any one of the following patent applications: WO 2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO 2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO 2016173682, WO 2015162291, WO 2015162292, WO 2010066868, WO 2006069202, and ON 112125916, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0510] ATTORNEY DOCKET NO.: 51432-080WO5

[0511] vi. RET inhibitors

[0512] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Rearranged during transfection (RET) inhibitors. An RET inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. RET plays a critical role in various cellular processes, including cell growth, differentiation, survival, and migration. RET is activated by binding of its ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, a RET inhibitor is one or more of pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, reference to the term RET inhibitor includes any such RET inhibitor disclosed in any one of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO

[0513] 2014050781, ON 113943285, ON 113683610, ON 113683611, ON 113620944, ON 113620945, ON 113527291, ON 113527292, ON 113527290, ON 113135896, ON 111057075, CN111233899, and CN111362923, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0514] vii. ROS1 inhibitors

[0515] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more c-ros oncogene 1 (ROS1) inhibitors. A ROS1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. ROS1 is a receptor tyrosine kinase that belongs to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, a ROS1 inhibitor is one or more of taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any one of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0516] viii. PDGFR inhibitors

[0517] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. A PDGFR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. PDGFR is a family of receptor tyrosine kinases that consists of two members, PDGFRa and PDGFRp. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), which leads to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, a PDGFR inhibitor is one or more of CP-673451, imatinib, nintedanib (Ofev™), sunitinib (Sutent™), pazopanib (Votrient™), regorafenib (Stivarga™), and dasatinib

[0518] (Sprycel™). PATENT

[0519] ATTORNEY DOCKET NO.: 51432-080WO5

[0520] ix. FGF inhibitors

[0521] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with fibroblast growth factor (FGF) inhibitors. An FGF inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. FGFRs are a family of receptor tyrosine kinases that consists of four members, FGFR1-4. FGFRs are activated by binding to their ligands, fibroblast growth factors (FGFs), which leads to the activation of downstream signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some embodiments, an FGFR inhibitor is one or more of futibatinib (TAK-659), erdafitinib (Balversa™), infigratinib (Truseltiq™), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, reference to the term FGFR inhibitor includes any such FGFR inhibitor disclosed in any one of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO 2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO 2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO 2018028438, WO 2018153373, WO 2018121650, WO 2018010514, WO 2017028816, WO 2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO 2013179033, WO 2013087578, WO 2012047699, ON 105906630, ON 115869315, ON 115141176, ON 115043832, and ON 115028634, each of which is incorporated herein by reference in its entirety. In some embodiments, the FGF pathway inhibitor targets an FGF ligand. Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include, FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG 1, designed to sequester FGF ligands and inhibit FGF signaling, and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0522] x. VEGF inhibitors

[0523] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target the signaling pathway mediated by VEGF and its receptors. VEGF plays a critical role in angiogenesis, the process of forming new blood vessels from existing ones, and it is overexpressed in many types of cancer, making it an attractive target for cancer therapy. A VEGF inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, the VEGF inhibitor is an antibody or antigen binding regions that specifically bind VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto). In some embodiments, the VEGF inhibitor is one or more of bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib. PATENT

[0524] ATTORNEY DOCKET NO.: 51432-080WO5

[0525] e) PI3K / mTOR pathway inhibitors

[0526] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a critical intracellular pathway that regulates a wide range of cellular processes including cell growth, proliferation, metabolism, and survival. The pathway is initiated when growth factors, such as insulin or IGF- 1, bind to cell surface receptors and activate phosphoinositide 3-kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates a variety of downstream targets including the tuberous sclerosis complex (TSC1 / TSC2), leading to the activation of mTOR (mammalian target of rapamycin) complex 1 (mTORC1). Activated mTORC1 promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).

[0527] i. PI3K inhibitors

[0528] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more PI3K inhibitors. A PI3K inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. A PI3K inhibitor useful in a combination of the disclosure may be a PI3Ka: RAS breaker, such as BBO-10203. PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO 2006044453; 4-[2-(1 H-lndazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO 2009036082 and WO 2009055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1 -yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO 2006122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1 -methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2, 4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrirnidin-4-one (available from Axon Medchem); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib. In some embodiments, reference to the term PI3K inhibitor includes any such PI3K inhibitor disclosed in any one of the following patent applications WO 2025072451 A1, WO 2025061125 A1, WO 2025051235 A1, WO 2025045106 A1, WO 2025040167 A1, WO 2025036439 A1, WO 2025038698 A1, WO 2025038395 A1, WO 2025034858 A1, WO 2025034849 A1, WO 2025029683 A1, WO 2025016314 A1, WO 2025003330 A1, WO 2025007074 A1, WO 2025002179 A1, WO PATENT

[0529] ATTORNEY DOCKET NO.: 51432-080WO5

[0530] 2024260464 A1, WO 2024229121 A1, WO 2024222894 A1, WO 2024215799 A1, WO 2024192309 A1, WO 2024183806 A1, WO 2024182404 A1, WO 2024182447 A1, each of which is incorporated herein by reference in its entirety.

[0531] ii. AKT inhibitors

[0532] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more AKT inhibitors. An AKT inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. AKT inhibitors include, but are not limited to, ipatasertib, GSK-2141795, Akt-1 -1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1 -1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-carbinol and derivatives thereof (e.g., U. S. Pat. No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9). The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; and GSK2126458.

[0533] iii. mTOR inhibitors

[0534] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more mTOR inhibitors. A mTOR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO 199409010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO 199802441 and WO 200114387, e.g. AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in WO 2005005434; derivatives disclosed in U. S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO 1994090101, WO 199205179, WO 1993111130, WO 199402136, WO 199402485, WO 199514023, WO 199402136, WO 199516691, WO 199641807, WO 199641807, and WO 2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO 2005016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO 2018204416, WO 2019212990 and WO 2019212991), such as RMC-5552.

[0535] iv. MNK inhibitors

[0536] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more mitogen-activated protein PATENT

[0537] ATTORNEY DOCKET NO.: 51432-080WO5

[0538] kinase-interacting kinase (MNK) inhibitors. A MNK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in the regulation of cellular proliferation, differentiation, and survival. MNKs phosphorylate elF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and oncogenesis. In some embodiments, a MNK inhibitor is one or more tomivosertib (eFT508), CGP57380, and SEL201. In some embodiments, reference to the term MNK inhibitor includes any such MNK inhibitor disclosed in any one of the following patent applications: WO 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO 2015200481, and CN115583942, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0539] v. elF4 inhibitors

[0540] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more eukaryotic initiation factor 4A (elF4A) inhibitors. An elF4A inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. elF4A is a critical component of the eukaryotic translation initiation complex, where it functions as an RNA helicase to unwind the secondary structure of mRNA and facilitate ribosome binding. elF4A is required for the translation of many cancer-associated genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, an elF4A inhibitor is one or more zotatifin (eFT226), silvestrol, pateamine A, and rocaglates. In some embodiments, reference to the term elF4A inhibitor includes any such elF4A inhibitor disclosed in any one of the following patent applications: WO 2023034813, WO 2021195128, and WO 2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0541] In some embodiments, compositions and methods described herein may include one or more eukaryotic initiation factor 4G (elF4G) inhibitors. An elF4G inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. elF4G family includes several proteins that are involved in the initiation of protein translation. elF4G serves as a scaffold for other proteins, including elF4E and elF4A, to form the elF4F complex, which is responsible for binding to the 5’ cap of mRNA and unwinding the secondary structure of the mRNA to allow ribosomal scanning and translation initiation. In some embodiments, an elF4G inhibitor is one or more pateamine A, and hippuristanol.

[0542] f) DNA Damage Response Inhibitors

[0543] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a critical cellular pathway that is activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing the development of cancer. However, cancer cells often have defects in the DDR pathway, which makes them more sensitive to DDR inhibitors. DDR inhibitors PATENT

[0544] ATTORNEY DOCKET NO.: 51432-080WO5

[0545] have shown promise in preclinical studies as potential cancer therapeutics, particularly in combination with other agents.

[0546] i. Wee1 inhibitors

[0547] In some embodiments, compositions and methods described herein may include one or more Wee1 inhibitors. A Wee1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. Wee1 is a kinase that plays a critical role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing the progression of cells through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and has been implicated in tumor growth and survival. In some embodiments, a Wee1 inhibitor is one or more of imp7068, adavosertib, or ZNL-02-096. In some embodiments, reference to the term Wee1 inhibitor includes any such Wee1 inhibitor disclosed in any one of the following patent applications: WO 2022011391, WO 2022247641, WO 2021043152, WO 2020221358, WO 2020083404, WO 2020192581, WO 2019085933, WO 2018133829, WO 2015115355, WO 2015183776, WO 2014085216, and ON 114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0548] ii. CHK inhibitors

[0549] In some embodiments, compositions methods described herein may include one or more checkpoint kinase (CHK) inhibitors. A CHK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. CHK1 kinase is a critical regulator of the cell cycle and the DNA damage response pathway. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, a CHK inhibitor is a CHK2 inhibitor. In some embodiments, a CHK1 inhibitor is one or more BBI-355, rabusertib, LY2606368, LY2880070, GDC-0575, MK-8776, BEBT-260, and PEP07. In some embodiments, reference to the term CHK1 inhibitor includes any such CHK1 inhibitor disclosed in any one of the following patent applications: WO 2024196923, WO 2024211271, WO 2024211270, WO 2024118564, WO 2023230477, WO 2022251502, WO 2021113661, WO 2021104461, WO 2019012030, WO 2010118390, WO 2008067027, WO 2002070494, CN119661557, and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0550] iii. ATM inhibitors

[0551] In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia mutated (ATM) inhibitors. An ATM inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. ATM plays a role in regulating the replication stress response and maintaining genomic stability. In some embodiments, an ATM inhibitor is one or more lartesertib, AZD1390, AZD0156, KU-60019, M4076, M3541, WSD-0628, ZN-B-2262, SYH2051, and VE-821. In some embodiments, reference to the term ATM inhibitor includes any such ATM inhibitor disclosed in any one of the following patent applications: WO 2024189299, WO 2022058351, WO 2021197339, WO 2021098734, WO 2021260580, WO 2020193660, WO 2020063855, WO 2016155884, WO 2007026157, WO 2006085067, US 2016113935, ON 116440082, ON 117180432 and ON 115105596 each of which is incorporated herein by PATENT

[0552] ATTORNEY DOCKET NO.: 51432-080WO5

[0553] reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0554] iv. ATR inhibitors

[0555] In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia and Rad3-related (ATR) inhibitors. An ATR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ATR inhibitor is one or more berzosertib, gartisertib, camonsertib, ceralaertib, VE-821, RP-3500, AZ20, VX-970, abd110, VX-803, and elimusertib (BAY 1895344). In some embodiments, reference to the term ATR inhibitor includes any such ATR inhibitor disclosed in any one of the following patent applications: WO 2025019344, WO 2025019346, WO 2023138343, WO 2023126823, WO 2023109883, WO 2023016529, WO 2022237875, WO 2022268025, WO 2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO 2019154365, WO 2019036641, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO 2007015632, and CN113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0556] v. PARP inhibitors

[0557] In some embodiments, compositions and methods described herein may include one or more Poly(ADP-ribose) polymerase (PARP) inhibitors. A PARP inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. There are 17 PARP (aka tankyrase) family members that have been identified. PARP enzymes play a critical role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, a PARP inhibitor is one or more olaparib, rucaparib, niraparib, and veliparib (ABT-888). In some embodiments, reference to the term PARP inhibitor includes any such PARP inhibitor disclosed in any one of the following patent applications: WO 2025024581, WO 2025037273, WO 2025061057, WO 2024256377, WO 2024255782, WO 2023051812, WO 2023051807, WO 2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO 2022000946, WO 2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO 2020142583, WO 2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO 2018125961, WO 2018205938, WO 2018192576, WO 2018218025, WO 2017032289, WO 2017177838, WO 2017029601, WO 2017088723, WO 2016155655, WO 2015154630, WO 2013097225, WO 2012130166, WO 2011006794, WO 2009046205, WO 2009063244, WO 2008084261, WO 2007138351, WO 2006110816, WO 2005053662, WO 2005012524, CN113698356, ON 113603647, ON 115073544, ON 108938634, ON 104887680, ON 110343088, ON 108976236, ON 117069731, ON 119185316, ON 119112794, and ON 107629071, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0558] vi. DNA-PK inhibitors

[0559] In some embodiments, compositions and methods described herein may include one or more DNA-dependent protein kinase (DNA-PK) inhibitors. A DNA-PK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional PATENT

[0560] ATTORNEY DOCKET NO.: 51432-080WO5

[0561] therapeutic agent described herein. DNA-PK is a serine / threonine protein kinase that plays a crucial role in DNA repair and maintenance of genome stability. In some embodiments, a DNA-PK inhibitor is one or more NU7441, AZD7648, VX-984, peposertib (M3814), and CC-115. In some embodiments, reference to the term DNA-PK inhibitor includes any such DNA-PK inhibitor disclosed in any one of the following patent applications: WO 2025023957, WO 2023220418, WO 2023215991, WO 2023165603, WO 2022187965, WO 2021197159, WO 2021260583, WO 2021204111, WO 2021104277, WO 2021098813, WO 2021022078, WO 2020259613, WO 2019143678, WO 2019143675, WO 2019201283, WO 2015058031, WO 2014159690, WO 2012028233, WO 2009010761, WO 2006032869, WO 2006109084, ON 112574179, ON 112300132, ON 115322209, and ON 112300126, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0562] g) Cell Cycle Inhibitors

[0563] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, which is the process by which a cell divides and replicates its DNA. Non-limiting examples cell cycle proteins include cyclin-dependent kinase (CDK), aurora kinase, and polo-like kinase (PLK). CDKs are a family of kinases that are involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, leading to mitotic arrest and cell death. PLKs are a family of serine / threonine kinases that are involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis.

[0564] i. CDK inhibitors

[0565] In certain embodiments, a cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4 and CDK6, while other CDKs such as CDK7, CDK8 and CDK9 are critical to transcription. CDK binding to cyclins forms heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiates events required for cell-cycle transcription and progression. In some embodiments, a CDK inhibitor is a CDK2 inhibitor. In some embodiments, a CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, a CDK inhibitor is a CDK7 inhibitor. In some embodiments, a CDK inhibitor is a CDK9 inhibitor. In some embodiments, a CDK inhibitor is one or more palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, a CDK inhibitor is one or more of tagtociclib (PF-07104091), seliciclib, voruciclib (P1446A-05), BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573.

[0566] In some embodiments, reference to the term CDK inhibitor includes any such CDK inhibitor disclosed in any one of the following patent applications: WO 2025040170, WO 2025060620, WO 2024238574, WO 2024027825, WO 2024048541, WO 2022166793, WO 2022187611, WO 2022130304, WO 2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO 2020093011, WO 2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO 2017177836, WO 2017172826, WO 2016193939, WO 2016014904, WO 2016015598, WO PATENT

[0567] ATTORNEY DOCKET NO.: 51432-080WO5

[0568] 2016015605, WO 2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO

[0569] 2010125004, WO 2007139732, WO 2006024945, ON 114478529, ON 108794496, ON 105294737, CN107652284, KR 20180106188, and US 2017152269, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0570] ii. Aurora kinase inhibitors

[0571] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more aurora kinase inhibitors. An aurora kinase inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating cell division and maintaining genomic stability. The Aurora kinase family consists of three members: Aurora A, Aurora B, and Aurora C. In some embodiments, an aurora kinase inhibitor is one or more palbociclib, ribociclib, and abemaciclib. In some embodiments, an aurora kinase inhibitor is one or more of alisertib, danusertib, barasertib, and MLN8237. In some embodiments, reference to the term aurora kinase inhibitor includes any such aurora kinase inhibitor disclosed in any one of the following patent applications: WO 2021110009, WO 2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO 2013143466, WO 2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO 2008001886, WO 2007095124, WO 2007003596, WO 2006129064, ON 114276227, ON 108078991, ON 106543155, ON 104211692, and ON 104098551, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0572] Hi. PLK inhibitors

[0573] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more polo-like kinase (PLK) inhibitors. A PLK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. PLKs are a family of serine / threonine kinases that play a crucial role in regulating cell division, DNA damage response, mitotic progression, and consists of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, a PLK inhibitor is one or more of volasertib, onvansertib, Bl 2536, and GSK461364. In some embodiments, reference to the term PLK inhibitor includes any such PLK inhibitor disclosed in any one of the following patent applications: WO 2011012534 A1, WO 2010065134, WO 2009130453, WO 2009042806, WO 2004043936, WO 2007030361, WO 2006021547, ON 115804777, and EP 2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0574] iv. Kinesin superfamily of microtubule motor protein inhibitors

[0575] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Kinesin spindle protein (KSP) inhibitors. In some embodiments, compositions described herein may include one or more Kinesin family (KIF) inhibitors. In some embodiments, a KSP inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent PATENT

[0576] ATTORNEY DOCKET NO.: 51432-080WO5

[0577] described herein. KSP and KIF are a subset of the kinesin superfamily of microtubule motor proteins. KSP, also known as Eg5, is a member of the kinesin superfamily of motor proteins that plays a critical role in mitotic spindle formation and cell division. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, a KSP inhibitor is one or more of SB743921, monastrol, S-Trityl-L-cysteine (STLC), and filanesib (ARRY-520). In some embodiments, a KIF inhibitor is an inhibitor of a Kinesin-8 family microtubule motor protein. In some embodiments, the kinesin-8 family protein is KIF18A. In some embodiments, a KIF inhibitor is one or more of AMG650, BTB-1, K03861, and SJ000291942. In some embodiments, reference to the term kinesin superfamily of microtubule motor protein inhibitor includes any such kinesin superfamily of microtubule motor protein inhibitor disclosed in any one of the following patent applications: WO 2015114854, WO 2015114855, WO 2010084186, WO 2006101761, WO 2006110390, WO 2006044825, WO 2006078574, WO 2005060654, WO 2004092147, WO 2004037171, WO 2004058700, WO 2003050064, WO 2003105855, WO 2022037665, WO 2018114804, WO 2017162663, WO 2016207089, WO 2012073375, JP 2014162787, JP 2019189590, JP2013166713, and KR 20220145566, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0578] v. DYRK1 inhibitors

[0579] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Dual-specificity tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. A DYRK1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. DYRK1 is a member of the DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays essential roles in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional control. In some embodiments, a DYRK1 inhibitor is one or more of harmine, INDY, D4476, and AZ191. In some embodiments, reference to the term DYRK1 inhibitor includes any such DYRK1 inhibitor disclosed in any one of the following patent applications: WO 2023277331 A1, WO 2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0580] h) Anti-Apoptotic Protein Inhibitors

[0581] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more anti-apoptotic protein inhibitors. In some embodiments, an anti-apoptotic protein inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. Anti-apoptotic inhibitors target proteins that play a role in preventing apoptosis, a form of programmed cell death. Apoptosis is a critical mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit the apoptotic pathway, thereby preventing cell death. There are several known classes of anti-apoptotic inhibitors, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors work by binding to specific anti-apoptotic proteins and preventing their activity, thereby promoting cell death in cancer cells. In some embodiments, compositions described herein may include one or more anti-apoptotic protein PATENT

[0582] ATTORNEY DOCKET NO.: 51432-080WO5

[0583] inhibitors. An anti-apoptotic protein inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. In some embodiments, the anti-apoptotic protein inhibitor includes a MCL-1 inhibitor. Non-limiting examples of MCL-1 inhibitors include, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. In some embodiments, the anti-apoptotic protein inhibitor includes a BCL protein inhibitor. Examples of BCL protein inhibitors include but are not limited to Venetoclax (Venclexta), Navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0584] i) Autophagy Inhibitors

[0585] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more autophagy inhibitors. In some embodiments, an autophagy inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. Autophagy inhibitors include, but are not limited to chloroquine, 3- methyladenine, hydroxychloroquine (Plaquenil™), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagysuppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[0586] a) ULK inhibitors

[0587] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Unc-51 -like kinase (ULK) inhibitors. An ULK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, an ULK inhibitor is one or more of ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and Dorsomorphin.

[0588] b) VPS inhibitors

[0589] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Vacuolar protein sorting protein (VPS) inhibitors. A VPS inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. VPS (proteins are a family of proteins that play a critical role in the process of autophagy by regulating the formation and function of autophagosomes, structures that engulf and transport cellular components to lysosomes for degradation. Dysregulation of VPS proteins has been implicated in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. In some embodiments, a VPS inhibitor is a VPS34 inhibitor. In some embodiments, a VPS inhibitor is one or more of PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058. PATENT

[0590] ATTORNEY DOCKET NO.: 51432-080WO5

[0591] c) Macropinocytosis inhibitors

[0592] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more macropinocytosis inhibitors. A macropinocytosis inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the disclosure and / or any additional therapeutic agent described herein. Macropinocytosis inhibitors are compounds that can block or reduce the process of macropinocytosis. In some embodiments, a macropinocytosis inhibitor is one or more of EIPA (ethylisopropylamiloride), Wortmannin, Amiloride, Apilimod, Dyngo-4a, and Latrunculin B.

[0593] j) WNT / b-catenin Pathway Inhibitors

[0594] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more WNT / beta-catenin pathway inhibitors. In some embodiments, a WNT / beta-catenin pathway inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. The WNT / beta-catenin pathway is an important signaling pathway that plays a crucial role in development, tissue homeostasis, and disease. Dysregulation of this pathway has been implicated in various cancers, making it an attractive target for cancer therapy. WNT / beta-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors, i. b-catenin inhibitors

[0595] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure and one or more b-catenin inhibitors. A b-catenin inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. Beta-catenin is a protein that plays an important role in the WNT signaling pathway, which regulates various cellular processes including cell proliferation, differentiation, and migration. In normal cells, b-catenin levels are tightly regulated by a destruction complex, which marks beta-catenin for degradation. However, in many cancer cells, the destruction complex is impaired, leading to the accumulation of beta-catenin in the nucleus and the activation of target genes involved in tumor growth and metastasis. In some embodiments, a WNT / b-catenin inhibitor is one or more of FOG-001, OMP-131 R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, Niclosamide, OMP-18R5, GTSA-101, BNC101, DKN-01, Sulindac, Pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWP L6, C59, GNF-6231, GNF-1331, DK-520, DK-419, lgG-2919, Fz7-21, RHPD-P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, lgG-2919, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 tegavivant, foscenvivant, PNPB-29, ZW4864, SAH-BCL9, Carnosic acid, xStAx-VHL, NRX-252114, Septuximab vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, reference to the term b-catenin inhibitor includes any such b-catenin inhibitor disclosed in any one of the following patent applications: CN 104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0596] ATTORNEY DOCKET NO.: 51432-080WO5

[0597] ii. PORCN inhibitors

[0598] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Porcupine (PORCN) inhibitors. A PORCN inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. PORCN is a membranebound O-acyltransferase enzyme that plays a critical role in the WNT signaling pathway by mediating the palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WMT proteins. Inhibition of PORCN leads to reduced WNT signaling activity. In some embodiments, a PORCN inhibitor is one or more of LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291. iii. GSK3 inhibitors

[0599] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Glycogen synthase kinase (GSK3) inhibitors. A GSK3 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3a and GSK3p. These kinases are involved in numerous cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutics for various diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, a GSK3 inhibitor is one or more of Tideglusib, lad uviglusib, LiCI (Lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, reference to the term GSK3 inhibitor includes any such GSK3 inhibitor disclosed in any one of the following patent applications: WO 2017153834, WO 2014059383, WO 2010012398, WO 2009017455, WO 2003037891, ON 107151235, and ON 102258783, each of which is incorporated herein by reference in its entirety, including the RAS(ON) inhibitor therapy structures disclosed therein which are specifically incorporated herein by reference. iv. CLK inhibitors

[0600] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Cdc2-like kinase (CLK) inhibitors. A CLK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. LKs (Cdc2-like kinases) are a family of serine / threonine kinases that play a crucial role in pre-mRNA splicing, specifically in the regulation of alternative splicing. There are four members of the CLK family: CLK1, CLK2, CLK3, and CLK4. The CLK family of kinases have been shown to be involved in several diseases, including cancer, neurodegenerative disorders, and viral infections. In some embodiments, a CLK inhibitor is a CLK 2 inhibitor. In some embodiments, a CLK2 inhibitor is one or more of Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, reference to the term CLK inhibitor includes any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0601] k) JAK / STAT Pathway Inhibitors

[0602] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more JAK / STAT pathway inhibitors. In some embodiments, PATENT

[0603] ATTORNEY DOCKET NO.: 51432-080WO5

[0604] a JAK / STAT pathway inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune response, cell growth, and differentiation.

[0605] Dysregulation of this pathway has been linked to various diseases, including inflammatory disorders, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used for the treatment of these diseases. In some embodiments, a JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2 and / or JAK3. In some embodiments, a JAK inhibitor is one or more of Ruxolitinib (Jakafi®), Pacritinib, Fedratinib, Tofacitinib (Xeljanz®), Abrocitinib, Filgotinib, Oclacitinib, Peficitinib, Upadacitinib, Deucravacitinib, Delgocitinib, and Baricitinib (Olumiant®). In some embodiments, reference to the term JAK inhibitor includes any such JAK inhibitor disclosed in any one of the following patent applications: WO 2023011301, WO 2023201044, WO 2022143629, WO 2022251434, WO 2022067106, WO 2022033551, WO 2021244323, WO 2021238817, WO 2021238818, WO 2021178991, WO 2021136345, WO 2021190647, WO 2020219639, WO 2020182159, WO 2020155931, WO 2020038457, WO 2020219524, WO 2020173400, WO 2018204233, WO 2018204238, WO 2018169875, WO 2018117152, WO 2017215630, WO 2016070697, WO 2016027195, ON 117815195, CN117815367, and ON 115969796, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0606] In some embodiments, the JAK / STAT pathway inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT3 degrader is KT-333. In some embodiments, the STAT inhibitor is one or more of TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Stattic, S3I-201, OPB-31121, KT-333, and Napabucasin (BBI608). In some embodiments, reference to the term STAT inhibitor includes any such STAT inhibitor disclosed in any one of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO 2023133336, W02020206424, WO 2023107706, WO 2021150543, WO 2008151037, and ON 109288845, each of which is incorporated herein by reference in its entirety, including the RAS(ON) inhibitor therapy structures disclosed therein which are specifically incorporated herein by reference.

[0607] I) Epigenetic Modulators

[0608] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more epigenetic modulators. Epigenetic modulators are a class of therapeutics that target enzymes responsible for modifying the structure and function of chromatin, the complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play critical roles in gene expression and regulation by modifying the packaging of DNA and affecting how it is read and transcribed. Epigenetic modulators work by altering the activity of these enzymes, either by inhibiting or enhancing their function, to regulate gene expression in specific ways. By targeting specific epigenetic modifications, such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory disorders, and neurological disorders. PATENT

[0609] ATTORNEY DOCKET NO.: 51432-080WO5

[0610] i. HDAC inhibitors

[0611] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more histone deacetylase (HDAC) inhibitors. A HDAC inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. There are several classes of HDACs, including class I, class Ila, class lib, class III, and class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, while class Ila HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class lib HDACs consist of HDAC6 and HDAC10, and class III HDACs are known as sirtuins. HDAC inhibitors can target different classes of HDACs, and their specific effects on gene expression can vary depending on which HDACs they target. In some embodiments, a HDAC inhibitor is one or more of Vorinostat (Zolinza™), Romidepsin (Istodax™), Belinostat (Beleodaq™), Panobinostat (Farydak™), Entinostat (MS-275), Valproic acid (Depakene™), Trichostatin A (TSA), Sodium butyrate, and Mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and Panobinostat. In some embodiments, reference to the term HDAC inhibitor includes any such HDAC inhibitor disclosed in any one of the following patent applications: WO 2022110958, WO 2021252628, WO 2019204550, WO 2018178060, WO 2016126724, WO 2014143666, WO 2013041480, and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0612] ii. BET inhibitors

[0613] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more bromodomain and extraterminal protein (BET) inhibitors. A BET inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. BET (bromodomain and extra-terminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, leading to chromatin remodeling and gene expression regulation. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomains of BET proteins, inhibiting their binding to acetylated lysine residues on histones and leading to alterations in gene expression. BET inhibitors are useful in the treatment of cancer and other diseases characterized by dysregulated gene expression. In some embodiments, a BET inhibitor is one or more of JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, reference to the term BET inhibitor includes any such BET inhibitor disclosed in any one of the following patent applications: WO 2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO 2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO 2015011084, and ON 113264930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0614] iii. EZH2 inhibitors

[0615] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Enhancer of Zeste Homolog 2 (EZH2) inhibitors. An EZH2 inhibitor may be administered or formulated in combination with a RAS(ON) PATENT

[0616] ATTORNEY DOCKET NO.: 51432-080WO5

[0617] inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. EZH2 is a histone-lysine N-methyltransferase that is a member of the Polycomb repressive complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancers and is associated with tumor progression and poor prognosis. In some embodiments, an EZH2 inhibitor is one or more of Tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, reference to the term EZH2 inhibitor includes any such EZH2 inhibitor disclosed in any one of the following patent applications: WO 2023030299, WO 2022179584, WO 2020224607, WO 2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO 2018137639, WO 2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO 2013155317, WO 2013138361, and CN 114621191, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0618] iv. Co-REST inhibitors

[0619] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Co-REST inhibitors. A Co-REST inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. Co-REST is a transcriptional co-repressor protein that interacts with a variety of transcription factors to regulate gene expression. Co-REST acts by recruiting histone deacetylases (HDACs) to chromatin, leading to the repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for the treatment of various diseases, including neurodegenerative disorders and cancer. In some embodiments, a co-REST inhibitor is one or more of Nocodazole, NSC 1892, and Anacardic acid.

[0620] v. EP300

[0621] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more E1 A-binding protein p300 (EP300) inhibitors. An EP300 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. EP300 is a transcriptional co-activator involved in the regulation of numerous cellular processes, including chromatin remodeling, DNA damage response, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histone proteins, which leads to changes in chromatin structure and gene expression. EP300 activity has been implicated in diseases, such as cancer, cardiovascular and neurological disorders. In some embodiments, an EP300 inhibitor is one or more of C646, A-485, NU9056, and L002. In some embodiments, reference to the term EP300 inhibitor includes any such EP300 inhibitor disclosed in any one of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0622] vi. LSD1

[0623] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Lysine-specific demethylase 1 PATENT

[0624] ATTORNEY DOCKET NO.: 51432-080WO5

[0625] (LSD1) inhibitors. A LSD1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. LSD1 is an enzyme that plays a crucial role in regulating gene expression through histone modification. It specifically removes the methyl group from lysine 4 on histone 3, leading to gene repression.

[0626] Dysregulation of LSD1 has been associated with various diseases including cancer and neurodegenerative disorders. In some embodiments, a LSD1 inhibitor is one or more of GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, reference to the term LSD1 inhibitor includes any such LSD1 inhibitor disclosed in any one of the following patent applications: WO 2021095840, WO 2021175079, WO 2021058024, WO 2020047198, WO 2020052649, WO 2020015745, WO 2020052647, WO 2018137644, WO 2017184934, WO 2017027678, WO 2017116558, WO 2017149463, WO 2016161282, WO 2015123465, WO 2015123424, WO 2013057322, WO 2013057320, WO 2012135113, ON 114805261, ON 111072610 CN107174584, ON 110478352, ON 106432248, and ON 106045881, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0627] vii. PRMT5

[0628] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Protein arginine methyltransferase 5 (PRMT5) inhibitors. A PRMT5 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. PRMT5 is a member of the PRMT family, which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the nitrogen atoms of arginine residues in target proteins. PRMT5 is involved in various biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, a PRMT5 inhibitor is one or more of TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, reference to the term PRMT5 inhibitor includes any such PRMT5 inhibitor disclosed in any one of the following patent applications: WO 2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO 2021088992, WO 2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO 2019102494, WO 2019112719, WO 2019180631, WO 2018065365, WO 2017153186, WO 2017212385, WO 2017032840, WO 2016022605, WO2014100695, WO 2014145214, WO 2014100719, ON 111825656, ON 114558014, ON 11304554, and ON 112778275, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0629] viii. MAT2A

[0630] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. A MAT2A inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), which is an important cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression has been associated with various PATENT

[0631] ATTORNEY DOCKET NO.: 51432-080WO5

[0632] cancers. In some embodiments, a MAT2A inhibitor is one or more of cycloleucine and 2-hydroxy-4-methylthiobutanoic acid. In some embodiments, reference to the term MAT2A inhibitor includes any such MAT2A inhibitor disclosed in any one of the following patent applications: WO 2022256808, WO 2022256806, WO 2019191470, and ON 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0633] ix. DOT1L

[0634] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Disruptor of Telomeric silencing 1 -like (DOT 1 L) inhibitors. A DOT 1 L inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. DOT1L is a histone methyltransferase enzyme that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with transcriptional elongation and is important for the maintenance of gene expression programs. The DOT1L family includes enzymes that are involved in epigenetic regulation and transcriptional control, and their dysregulation has been linked to various diseases, including cancer. In some embodiments, a DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, reference to the term DOT1L inhibitor includes any such DOT 1 L inhibitor disclosed in any one of the following patent applications: WO 2016090271, WO 2014100662, and ON 108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0635] iix) UBA1

[0636] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more ubiquitin-activating enzyme inhibitors (e.g., a UBA1 inhibitor). A UBA1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. UBA1, also known as ubiquitin-activating enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for protein degradation and regulation. Ubiquitination involves the covalent attachment of ubiquitin molecules to target proteins, marking them for degradation by the proteasome or modulating their activity, localization, or interactions within the cell. Several inhibitors have been developed to modulate UBA1 activity, with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors include but are not limited to adenosine-based inhibitors which typically compete with ATP for binding to the active site of UBA1, thereby preventing the activation of ubiquitin (e.g., PYR-41 and MLN7243); covalent inhibitors which form irreversible bonds with specific amino acid residues in the active site of UBA1, leading to inhibition of its activity (e.g., TAK-243 (formerly known as MLN4924)); allosteric inhibitors which bind to sites on UBA1 distinct from the active site, inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors which are designed based on smaller molecular fragments that bind to UBA1. In some embodiments, a UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, reference to the term UBA1 inhibitor includes any such UBA1 inhibitor disclosed in any one of the following patent applications: WO 2016069393 A1, WO 2016069392 A1, and JP 2013237627 A2, each of which is PATENT

[0637] ATTORNEY DOCKET NO.: 51432-080WO5

[0638] incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0639] m) Ribonucleotide reductase inhibitors

[0640] Compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more ribonucleotide reductase inhibitors (RNRi). RNR inhibitors are a class of compounds that inhibit the enzyme ribonucleotide reductase, which is essential for DNA synthesis and repair. RNR catalyzes the conversion of ribonucleotides (RNA building blocks) into deoxyribonucleotides (DNA building blocks), providing the necessary precursors for DNA replication and repair in proliferating cells. By inhibiting RNR, these compounds effectively limit the production of deoxyribonucleotides, thereby preventing DNA synthesis and halting the proliferation of rapidly dividing cells, such as cancer cells.

[0641] RNR is composed of two subunits: the R1 large subunit (containing the catalytic site) and the R2 small subunit (containing a di-iron center critical for enzymatic activity). RRIs typically act by binding to either the active site on the R1 subunit or the iron-oxygen complex in the R2 subunit, leading to the inhibition of the enzyme's activity. In some embodiments, a RNR inhibitor is a nucleoside analog inhibitor, an iron chelator, or an allosteric inhibitor. In some embodiments, a RNR inhibitor useful according to the present disclosure include but are not limited to one or more of hydroxyurea, triapine, didox, GTI-2040, CPI-613 (devimistat), and clofarabine. In some embodiments, reference to the term RNR inhibitor includes any such RNR inhibitor disclosed in any one of the following patent applications: WO 2025049814, WO 2022059691, WO 2022059692, WO 2021034776, WO 2019106579, WO 2014205179, WO 2013105088, WO 199312782, US 5,071,835, US 5,405,850, US 4,814,432, and WO 199518815 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0642] n) Additional Therapeutic Agents Useful for Combination Therapy

[0643] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Farnesyl transferase inhibitors. A farnesyl transferase inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein.

[0644] Farnesyl transferase inhibitors (FTIs) are a class of drugs that target the farnesyl transferase enzyme, which plays a role in a process called protein prenylation. Protein prenylation is an important step in the process of activating certain proteins involved in signal transduction, cell growth, and differentiation. In some embodiments, a farnesyl transferase inhibitor is one or more of tipifarnib, lonafarnib, and rilapladib. In some embodiments, reference to the term farnesyl transferase inhibitor includes any such farnesyl transferase inhibitor disclosed in any one of the following patent applications: WO 2010057028, WO 2007042465, WO 200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO 199426723, ON 107312000, ON 107365310, KR 100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0645] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more casein kinase inhibitors. In PATENT

[0646] ATTORNEY DOCKET NO.: 51432-080WO5

[0647] some embodiments, a casein inhibitor is, SR-3029, a potent and ATP

[0648] competitive CK16 and CK1 e inhibitor.

[0649] In some embodiments, compositions and methods described herein may include one or more FLT3 inhibitors in combination with a RAS(ON) inhibitor therapy of the present disclosure disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis, the process by which blood cells are formed. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it controls cell proliferation, survival, and differentiation. In some embodiments, a FLT3 inhibitor includes, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib and quizartinib.

[0650] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more one or more TGFb pathway inhibitors. In some embodiments, compositions and methods described herein may include one or more TGFb inhibitors. A TGFb inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. TGFb (transforming growth factor beta) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune response. Dysregulation of the TGFb signaling pathway has been implicated in various diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, a TGFb inhibitor is one or more of galunisertib (LY2157299), and vactosertib (TEW-7197). In some embodiments, a TGFb inhibitor is one or more of Galunisertib, LY2157299, Fresolimumab, Lerdelimumab, Trabedersen, curcumin, resveratrol and small interfering RNA (siRNA) to silence TGFb receptor expression. In some embodiments, reference to the term TGFb inhibitor includes any such TGFb inhibitor disclosed in any one of the following patent applications: WO 2023043473, WO 2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO 2004024159, WO 200226935, WO 2002062753, WO 2002062776, and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0651] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more HSP90 inhibitors. A HSP90 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a critical role in regulating the folding, stability, and activity of a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, a HSP90 inhibitor is one or more of Geldanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, Radicicol and its derivatives (e.g., PU-H71), SNX-2112, Ganetespib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, reference to the term HSP90 inhibitor includes any such HSP90 inhibitor disclosed in any one of the following patent applications: WO 2021137665, WO 2018200534, WO 2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO 2013119985, WO 2012138894, WO 2011044394, WO 2009097578, WO 2008115719, ON 105237533, and ON 104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0652] ATTORNEY DOCKET NO.: 51432-080WO5

[0653] In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor therapy of the present disclosure in combination with one or more Glutathione peroxidase 4 (GPX4) inhibitors. A GPX4 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor therapy of the present disclosure and / or any additional therapeutic agent described herein. GPX4 is an antioxidant enzyme that plays a critical role in protecting cells against oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and acts as a regulator of ferroptosis, a form of regulated cell death driven by lipid peroxidation. In some embodiments, a GPX4 inhibitor is one or more of RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, reference to the term GPX4 inhibitor includes any such GPX4 inhibitor disclosed in any one ...

Claims

PATENTATTORNEY DOCKET NO.: 51432-080WO5Claims1. A method of treating a RAS G12D-mutant cancer in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

2. The method of claim 1, wherein Compound A is administered in a total daily dose from 100 mg to 400 mg, and wherein Compound B is administered in a total daily dose from 400 mg to 1400 mg.

3. The method of claim 1 or 2, wherein Compound A and Compound B are administered concurrently in the AM or concurrently in the PM.

4. The method of claim 1 or 2, wherein Compound A is administered in the AM and Compound B is administered in the PM or Compound B is administered in the AM and Compound A is administered in the PM.

5. The method of claim 1 or 2, wherein Compound A is administered in the AM and Compound B is administered twice daily or wherein Compound A is administered in the PM and Compound B is administered twice daily.

6. The method of any one of claims 1 to 5, wherein the cancer comprises a KRAS mutation.

7. The method of any one of claims 1 to 6, wherein the cancer is locally advanced or metastatic.PATENTATTORNEY DOCKET NO.: 51432-080WO58. The method of any one of claims 1 to 7, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

9. The method of claim 8, wherein the pancreatic cancer is pancreatic adenocarcinoma.

10. The method of claim 8, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

11. The method of claim 8, wherein the lung cancer is non-small cell lung cancer.

12. The method of claim 8, wherein the colorectal cancer is microsatellite stable, microsatellite instability- high, or microsatellite instability-low.

13. A method of treating a RAS G12D-mutant cancer in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) multi- selective inhibitor, a RAS(ON) G12D-selective inhibitor, and an immune checkpoint inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

14. The method of claim 13, wherein the immune checkpoint inhibitor is one or more of anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, anti-B7.1, anti-B7H3, anti-B7H4, anti-TIM3, anti-VISTA, anti-CD137, anti-0X40, anti-CD40, anti-CD27, anti-CCR4, anti-GITR, anti-NKG2D, and anti-KIR.PATENTATTORNEY DOCKET NO.: 51432-080WO515. The method of claim 14, wherein the anti-PD1 is one or more of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, and XmAb20717.

16. The method of any one of claims 13 to 15, wherein the immune checkpoint inhibitor is ivonescimab (SMT112).

17. The method of any one of claims 13 to 16, wherein the cancer comprises a KRAS mutation.

18. The method of any one of claims 13 to 17, wherein the cancer is locally advanced or metastatic.

19. The method of any one of claims 13 to 18, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

20. The method of claim 19, wherein the pancreatic cancer is pancreatic adenocarcinoma.

21. The method of claim 19, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

22. The method of claim 19, wherein the lung cancer is non-small cell lung cancer.

23. The method of claim 19, wherein the colorectal cancer is microsatellite stable, microsatellite instability-high, or microsatellite instability-low.

24. A method of treating a RAS G12D-mutant cancer in a human subject in need thereof, wherein the cancer comprises a RAS amplification, the method comprising, administering to the subject a therapeutically effective amount of RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:PATENTATTORNEY DOCKET NO.: 51432-080WO525. A method of treating a cancer comprising a RAS G12D amplification in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

26. A method of treating, delaying, or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, wherein the subject is afflicted with a cancer comprising a RAS G12D mutation, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:PATENTATTORNEY DOCKET NO.: 51432-080WO5and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

27. A method of treating a RAS G12D-mutant colorectal cancer in a subject in need thereof, the method comprising administering to the subject a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitorand wherein the RAS(ON) G12D-selective inhibitor is Compound B:PATENTATTORNEY DOCKET NO.: 51432-080WO528. A method of treating a RAS G12D-mutant cancer in a subject in need thereof, wherein the cancer is resistant to a RAS(ON) multi-selective inhibitor, the method comprising administering to the subject a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

29. A method of treating a G12D-mutant cancer in a subject in need thereof, wherein the cancer further comprises a RAS amplification, the method comprising administering to the subject a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:PATENTATTORNEY DOCKET NO.: 51432-080WO530. A method of treating a RAS G12D-mutant cancer in a subject in need thereof, the method comprising administering to the subject a RAS(ON) inhibitor therapy comprising a RAS(ON) multi-selective inhibitor and a RAS(ON) G12D-selective inhibitor, wherein the RAS(ON) inhibitor therapy modulates the tumor immune microenvironment, wherein the RAS(ON) multi-selective inhibitor is Compound A:and wherein the RAS(ON) G12D-selective inhibitor is Compound B:

31. The method of any one of claims 24 to 30, wherein the cancer is locally advanced or metastatic.

32. The method of any one of claims 24 to 31, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

33. The method of claim 32, wherein the pancreatic cancer is pancreatic adenocarcinoma.

34. The method of claim 32, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.PATENTATTORNEY DOCKET NO.: 51432-080WO535. The method of claim 32, wherein the lung cancer is non-small cell lung cancer.

36. The method of claim 32, wherein the colorectal cancer is microsatellite stable, microsatellite instability-high, or microsatellite instability-low.

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