Inhibiting mitogen-activated protein (MAP) / ERK kinase (MEK)1 and MEK2 and related methods of treatment

Abstract

Methods of treating cancer, including RAS-mutated cancers and certain RAF-mutated cancers, are provided, comprising the administration of a therapeutically effective amount of dual-MEK inhibitor with a short plasma half-life that inhibits both the phosphorylation of mitogen-activated protein kinase kinase 1 or 2 (pMEK) and the phosphorylation of mitogen-activated protein kinase 1 or 2 (pERK), wherein the dual-MEK inhibitor is administered to the patient in certain dose amounts that achieves a Cmax effective to inhibit pERK and pMEK and with an interval between consecutive doses that is at least about certain times the plasma half-life of the dual-MEK inhibitor.

Description

IMMU.028WO PATENTINHIBITING MITOGEN-ACTIVATED PROTEIN (MAP) / ERK KINASE (MEK)1 AND MEK2 AND RELATED METHODS OF TREATMENTINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This patent application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 690,489, filed September 4, 2024; U.S. Provisional Patent Application No. 63 / 693,481, filed September 11, 2024; U.S. Provisional Patent Application No. 63 / 707,934, filed October 16, 2024; U.S. Provisional Patent Application No. 63 / 718,226, filed November 8, 2024; U.S. Provisional Patent Application No. 63 / 690,485, filed September 4, 2024; U.S. Provisional Patent Application No. 63 / 693,465, filed September 11, 2024; U.S. Provisional Patent Application No. 63 / 742,365, filed lanuary 6, 2025; and U.S. Provisional Patent Application No. 63 / 823,526, filed lune 13, 2025; each of which are incorporated by reference herein in their entirety.TECHNICAL FIELD

[0002] The present disclosure relates to the fields of chemistry and medicine. More particularly, the present disclosure relates to methods of treatment of certain forms of cancer with MEK inhibitor therapies.BACKGROUND

[0003] Activating mutations of RAS and / or RAF in the MAPK pathway are observed in approximately 30% of all cancer patients, and inappropriate activation of this pathway is observed in up to 50% of all tumors and represents one of the most highly utilized signaling pathways in oncology. In aggressive solid tumors of the pancreas, skin, lungs and colon, mutations in RAS and / or RAF are even more common. Approximately 40% of lung cancers and approximately 95% of pancreatic cancers are due to RAS and / or RAF mutations, and approximately 50% of melanomas display activation mutations, mainly, in BRAF but also in ARAF and CRAF (RAFI). However, approved MEK inhibitors chronically inhibit the downstream signaling of RAS, often leading to high rates of adverse events by harming healthy normal cells which also rely on the MAPK pathway. This can result in significant toxicity, for example as a result of prolonged systemic circulation of prior MEK inhibitor therapies. ThereIMMU.028WO PATENT remains an unmet medical need for methods of treating certain forms of cancer activated through the MAPK pathway, including methods of treatment to cyclically disrupt the ERK and MEK.SUMMARY

[0004] Atebimetinib (Compound A) is a dual MEK1 / 2 inhibitor useful to inhibit the activation of ERK while preventing RAF-mediated pathway reactivation:atebimetinib (Compound A).

[0005] Atebimetinib binds to mitogen-activated protein kinase kinase, or MEK, and acts as a highly selective inhibitor of mitogen-activated protein kinase, or ERK, activation (i.e., phosphorylation), with a “Dual MEK” function that is designed to block the CRAF-bypass feedback to prevent MAPK pathway reactivation. Compound A is also designed to prevent RAF- mediated activation of MEK, such as CRAF-bypass, by engagement of the RAF activation loop on MEK, and at elevated levels further disrupt the kinase suppressor of RAS 1 and 2, or KSR.

[0006] In some embodiments, a method of treating a cancer harboring a RAS or RAF mutation in a patient in need thereof comprises administering atebimetinib (Compound A) or a pharmaceutically acceptable salt thereof to the patient in need thereof, at a dose providing 320 mg or 240 mg of atebimetinib once daily to the patient in need thereof for the treatment of the RAS or RAF mutated cancer. In some embodiments, a total of 320 mg of Compound A is orally administered (po) once daily (QD) to treat a cancer harboring a mutation in KRAS, NRAS, or HRAS, in a patient in need thereof.

[0007] In some embodiments, a method of treating pancreatic ductal adenocarcinoma (PDAC) comprises the steps of administering to a patient in need thereof: 240 mg or 320 mg of atebimetinib once per day, optionally in combination with chemotherapy, to treat the PDAC in the patient. In some embodiments, a method of treating pancreatic ductal adenocarcinoma (PDAC)IMMU.028WO PATENT harboring a RAS mutation such as a KRAS G12C, G12V, G12D or G12R mutation, comprises the steps of orally administering (po) to a patient in need thereof: 240 mg or 320 mg of atebimetinib once per day (QD), optionally in combination with chemotherapy, to treat the RAS mutated PDAC in the patient. In some embodiments, a method of treating PDAC harboring a RAS mutation such as KRAS G12A, G12S, Q6A or G13 mutations comprises administering to a patient in need thereof: 240 mg or 320 mg of atebimetinib once per day, optionally in combination with chemotherapy.

[0008] In some embodiments, a method of treating pancreatic ductal adenocarcinoma (PDAC) comprises (a) orally administering 240 mg or 320 mg of atebimetinib once per day to a patient in need thereof, in combination with (b) a chemotherapy consisting of: modified gemcitabine + nab-paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 min, followed immediately by gemcitabine 1000 mg / m2via IV infusion over 30 min. In some embodiments, a method of treating pancreatic ductal adenocarcinoma (PDAC) comprises (a) orally administering 240 mg or 320 mg of atebimetinib once per day to a patient in need thereof, in combination with (b) a chemotherapy consisting of: a modified FOLFIRINOX (mFFX) regimen where the mFFX regimen is administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows: (i) 85 mg / m2oxaliplatin via IV infusion (e.g., over 2 hours), (ii) optionally administering 400 mg / m2folinic acid (leucovorin) via IV infusion (e.g., over 2 hours), (iii) 150 mg / m2irinotecan or an equivalent amount of liposomal irinotecan via IV infusion (e.g., over 90 minutes), and (iv) 2400 mg / m2fluorouracil via continuous IV infusion (e.g., given over 46 hours beginning Day 1 and ending on Day 3).

[0009] In some embodiments, a method of treating non-small cell lung cancer (NSCLC) comprises administering 240 mg or 320 mg of atebimetinib once per day to a patient in need thereof to treat the NSCLC, optionally in combination with a G12C inhibitor (e.g., sotorasib or adagrasib) or an immune checkpoint inhibitor (ICI) such as an anti-PD-1, anti-PD-Ll or anti- CTLA-4 ICI. In some embodiments, a method of treating non-small cell lung cancer (NSCLC) harboring a KRAS mutation (e.g., a G12C, G12D, G12A, G12R, G12V, Q61, or G13 mutation), wherein the method comprises orally administering (po) 240 mg or 320 mg of atebimetinib once per day (QD) to a patient in need thereof to treat the KRAS mutated NSCLC, in combination withIMMU.028WO PATENT a G12C inhibitor (e.g., sotorasib or adagrasib) or an immune checkpoint inhibitor (ICT) such as an anti-PD-1, anti-PD-Ll or anti-CTLA-4 immunotherapeutic.

[0010] In some embodiments, a method of treating melanoma comprises administering 240 mg or 320 mg of atebimetinib once per day to a patient in need thereof to treat the melanoma, optionally in combination with an immune checkpoint inhibitor (ICI) such as an anti-PD-1, anti- PD-Ll or anti-CTLA-4 ICI. In some embodiments, a method of treating non-small cell lung cancer (NSCLC) harboring a RAF mutation (e.g., BRAF V600E or V600K mutation) or RAS mutation (e.g., a NRAS Q61R, Q61K, Q61H, G13R, G12D, or G13D mutation, or a HRAS Q61K mutation or a KRAS G12C, G12D, G12A, G12R, G12S, G12V, or Q61 mutation), wherein the method comprises orally administering (po) 240 mg or 320 mg of atebimetinib once per day (QD) to a patient in need thereof to treat the RAS or RAF mutated melanoma, in combination with a BRAF inhibitor (e.g., encorafenib) or an immune checkpoint inhibitor (ICI) such as an anti-PD-1, anti- PD-Ll or anti-CTLA-4 ICI. In some embodiments, a method of treating melanoma harboring a NRAS mutation such as NRAS Q61K, Q61H, GI3R, G13D, or a HRAS mutation such as HRAS Q61K, or a KRAS mutation such as G12A, G12S or a Q61 mutation comprises administering 240 mg or 320 mg of atebimetinib once per day to a patient in need thereof to treat the melanoma, optionally in combination with an immune checkpoint inhibitor (ICI) such as an anti-PD-1, anti- PD-Ll or anti-CTLA-4 ICI.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1A is a graph of overall survival (OS) probability by month in a human clinical trial of atebimetinib (320 mg QD) in the treatment of first line pancreatic (PDAC) patients, in combination with modified gemcitabine and nab-paclitaxel treatment, compared to third party published benchmark OS data obtained from different patients in the Phase 3 MP ACT clinical trial.

[0012] FIG. IB is a graph of the overall survival (OS) data from patients treated with atebimetinib in FIG. 1 A compared to third party published benchmark OS data obtained from other published clinical trial data.

[0013] FIG. 2A is a graph showing the progression free survival probability by month in a human clinical trial of atebimetinib (320 mg QD) in the treatment of first line pancreatic (PDAC) patients, in combination with modified gemcitabine and nab-paclitaxel treatment.IMMU.028WO PATENT

[0014] FIG. 2B is a graph showing the progression free survival (PFS) probability by month in a human clinical trial of atebimetinib (320 mg QD) combined with modified gemcitabine and nab-paclitaxel treatment in the treatment of first line pancreatic (PDAC) patients, as shown in FIG. 2A, compared to third party published benchmark PFS probability data obtained from different patients in the Phase 3 MP ACT clinical trial.

[0015] FIG. 2C is a graph of the progression free survival (PFS) data from patients treated with atebimetinib in FIG. 2A compared to third party published benchmark PFS probability data obtained from other published clinical trial data.

[0016] FIG. 3A is a graph showing PK / PD (pERK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) po (cycle 1, day 1).

[0017] FIG. 3B is a graph showing PK / PD (pMEK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) po (cycle 1, day 1).

[0018] FIG. 3C is a graph showing PK / PD (pERK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) po (cycle 1, day 15).

[0019] FIG. 3D is a graph showing PK / PD (pMEK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) po (cycle 1, day 15).

[0020] FIG. 4A is a graph showing plasma concentration (PK) for Compound A from patient 13 after receiving 240 mg Compound A administered orally (po) once daily (QD) at cycle 1, day 1 and at cycle 1, day 15.

[0021] FIG. 4B is a graph showing PK / PD (pERK) for Compound A from patient 13 after receiving 240 mg Compound A administered orally (po) once daily (QD) at cycle 1, day 1 and at cycle 1, day 15.

[0022] FIG. 5A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A.

[0023] FIG. 5B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A.

[0024] FIG. 5C is a graph showing ctDNA measurements for KRAS G12V from a patient in a Phase 1 clinical trial treated with Compound A.

[0025] FIG. 6A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A.IMMU.028WO PATENT

[0026] FIG. 6B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A.

[0027] FIG. 6C is a graph showing ctDNA measurements for KRAS G12D and NRAS G13D from a patient in a Phase 1 clinical trial treated with Compound A.

[0028] FIG. 7A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A.

[0029] FIG. 7B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A.

[0030] FIG. 7C is a graph showing ctDNA measurements for KRAS G12D from a patient in a Phase 1 clinical trial treated with Compound A.

[0031] FIG. 8A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A.

[0032] FIG. 8B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A.

[0033] FIG. 8C is a graph showing ctDNA measurements for KRAS G12D from a patient in a Phase 1 clinical trial treated with Compound A.

[0034] FIG. 9A is a graph of individual observed Compound A plasma concentrations versus time after dose (semi-logarithmic scale).

[0035] FIG. 9B is a graph of dose-normalized individual observed Compound A plasma concentrations versus time after dose after 240 or 320 mg (semi-logarithmic scale). Thick lines represent the GAM smooth of the data in each dose level.

[0036] FIG. 10A is a graph of individual observed (absolute value) versus time after dose (semi-logarithmic scale).

[0037] FIG. 10B is a graph of individual observed versus individual observed Compound A plasma concentrations (logarithmic scale).

[0038] FIG. 11 A is a graph of individual observed (absolute value) versus time after dose (semi-logarithmic scale).

[0039] FIG. 11B is a graph of individual observed versus individual observed Compound A plasma concentrations (logarithmic scale).

[0040] FIG. 12A is a schematic of Population PK modeling.IMMU.028WO PATENT

[0041] FIG. 12B is a graph of prediction-corrected visual predictive check of Compound A PK plasma concentrations vs time after Dose, C1D1; semi-logarithmic scale.

[0042] FIG. 12C is a graph of prediction-corrected visual predictive check of Compound A PK plasma concentrations vs time after Dose, C1D15; semi-logarithmic scale.

[0043] FIG. 13 A is a graph of prediction-corrected visual predictive check of p-ERK / t- ERK (left) versus time after Dose, at C1D1 (semi-logarithmic scale).

[0044] FIG. 13B is a graph of prediction-corrected visual predictive check of p-MEK / t- MEK (right) versus time after Dose, at CID 1 (semi-logarithmic scale).

[0045] FIG. 14 is a graph of populations simulations of Compound A plasma concentrations (ng / mL) versus time (h). Solid lines show the median concentration and shaded areas the 90% prediction interval. The dotted, dashed and solid black lines represent the IC50, IC80 and IC90, at 82.2 ng / mL, 329 ng / mL and 740 ng / mL, respectively.

[0046] FIG. 15 is a graph of populations simulations of phospho:total ERK (% baseline) versus time (h) on a linear scale for the different dose groups. Solid lines are colored by treatment group. The dashed black line represents 20% of maximum reduction.DETAILED DESCRIPTION

[0047] Atebimetinib (Compound A) was designed to have high oral bioavailability and a short half-life with a near-zero drug trough, to achieve Deep Cyclic Inhibition (DCI) of the MAPK pathway via features including a unique pharmacokinetic (PK) profile with high peak plasma drug levels and a near zero, daily drug trough:atebimetinib (Compound A).

[0048] Atebimetinib (Compound A) acts as a potent, dual-MEK inhibitor that uniquely inhibits both MEK and ERK enzymes. Without being limited to any particular theory, it is notedIMMU.028WO PATENT that the inhibition mechanism of Compound A is theorized to involve allosteric inhibition of MEK by targeting a site adjacent to the ATP binding pocket, which in turn inhibits ERK downstream. This compound exhibits a short plasma half-life and achieves a nearly zero steady-state trough concentration, facilitating deep, cyclic inhibition of the MAPK pathway. Compound A is chemically defined with a molecular weight of 506.55 g / mol and a molecular formula of C23H27FN4O6S, and can be chemically named as 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate. The method for synthesizing Compound A is detailed in Example E

[0049] In preclinical studies, Compound A inhibited MEK and ERK across a wide range of human and murine solid tumor models, including those with activating mutations in KRAS, NRAS, HRAS and BRAF. In addition, in head-to-head preclinical studies, Compound A was evaluated in murine-based KRAS, NRAS, and BRAF mutant solid tumor models representing lung, colon, pancreas and skin cancer, and observed tumor stasis or regression with insignificant body weight loss, or BWL, when compared to certain FDA-approved MEK inhibitors at reported human dose equivalent dose and schedules. For example, in head-to-head preclinical studies, Compound A was evaluated in murine-based KRAS, NRAS, and BRAF mutant solid tumor models representing lung (i.e., A549), colon (i.e., Colon-26), pancreas (i.e., MIA PaCa-2 and CAP AN-2) and skin cancer (i.e., A375 and SK-MEL-2), and observed superior antitumor activity with insignificant body weight loss, or BWL, when compared to certain FDA-approved MEK inhibitors and superior to non-inferior antitumor activity when compared to certain FDA-approved KRAS-G12C and BRAF inhibitors at reported human dose equivalent dose and schedules.

[0050] In primary pharmacodynamic assays, Compound A inhibited pERK across multiple tumor cells with half maximal inhibitory concentrations (ICso) values ranging from 24.2 nM to 83.2 nM, with the most sensitive models being predominantly melanoma and pancreatic cancer cell lines that harbor activating MAPK pathway mutations in K isomer of rat sarcoma (KRAS), N isomer of rat sarcoma (NRAS), H isomer of rat sarcoma (HRAS), BRAF, neurofibromatosis type 1 (NF 1), and / or kinase suppressor of Ras (KSR). Corresponding reductions in pMEK were observed with treatment of cells with 100 nM Compound A, confirming that Compound A was not sensitive to the MAPK pathway feedback reactivation events in RAS mutant models, such as CRAF-bypass.IMMU.028WO PATENT

[0051] Compound A has been evaluated in a wide range of human and murine solid tumor models, including those with activating MAPK pathway mutations in KRAS, NRAS, HRAS, BRAF, NF1, and KSR. Among others, Compound A was investigated in MIA PaCa-2 (KRASG12CPDAC), Capan-2 (KRASG12VPDAC), SK-MEL-2 (NRASQ61Rmelanoma), A549 (KRASG12SNSCLC) and Colon-26 (KRASG12DCRC) mouse tumor models at various dose ranges. Significant tumor reduction was observed at all doses and in all models, lending evidence that Compound A activity is not dependent upon specific RAS mutations or RAS paralogues.

[0052] In head-to-head nonclinical studies, Compound A was compared to certain current FDA-approved MEK, BRAF and KRASG12Cinhibitors in KRAS-, NRAS-, and BRAF- mutated solid tumor rodent models representing lung, colon, pancreas, and skin cancers; in each study, it demonstrated tumor stasis or regression while maintaining body weight. For instance, Compound A (100 and 150 mg / kg BID) was compared to the commercially available KRAS inhibitors sotorasib (30 and 100 mg / kg QD) and adagrasib (30 and 100 mg / kg QD) in the Capan- 2 (KRASG12D) model, with Compound A showing efficacy in a non-KRASG12Cmodel. In the KRASG12CMIA Paca-2 pancreatic model, similar tumor growth inhibition was observed between Compound A and sotorasib, and tumor regressions with improved durability of response (DoR) were demonstrated when Compound A and sotorasib were used in combination.

[0053] The oral administration of 320 mg of atebimetinib QD to pancreatic cancer patients was evaluated in Phase 1 and a Phase 2a human clinical trial, in combination with a modified gemcitabine + nab-paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 minutes, followed immediately by gemcitabine 1,000 mg / m2via IV infusion over 30 minutes. Results are discussed below.

[0054] A 94% overall survival (OS) was observed at 6 months in first-line (IL) pancreatic cancer patients treated with 320 mg of atebimetinib in combination with modified gemcitabine / nab-paclitaxel (mGnP) as disclosed in the Examples below (N=34). FIG. 1A is a graph of overall survival (OS) probability by month in a human clinical trial of atebimetinib (320 mg QD) in the treatment of first line pancreatic (PDAC) patients, in combination with modified gemcitabine and nab-paclitaxel treatment, compared to third party published benchmark OS data obtained from different patients in the Phase 3 MP ACT clinical trial. The data in FIG. 1A shows an 8-month OS of 94%, based on interim data collection from the 320mg intent-to-treat populationIMMU.028WO PATENT(N=34). This represents the primary Phase 2 population enrolled as part of the Simon two-stage design from the ongoing Phase l / 2a trial of atebimetinib. The benchmark 6-month OS for the standard of care treatment in this population (full dose and schedule GnP) is estimated as 67% and estimated at about 55% at 8-month OS data, based on the published results from the MP ACT study (Pivotal Ph3 Study MP ACT 2013 NEJM (PMID: 24131140) per 2024 JAMA Nichetti, et al. 7(l):e2350756). The median OS was not yet reached at the data cutoff date. FIG. IB is a graph of the overall survival (OS) data from patients treated with atebimetinib in FIG. 1A compared to third party published benchmark OS data obtained from other published clinical trial data. No head-to-head clinical trial has been conducted evaluating atebimetinib and other candidates or products. Differences exist between trial designs, subject characteristics and other factors, and caution should be exercised when comparing data across studies. The data shown in the lower line of FIG. IB is a Kaplan-Meier (KM) Plot of the Pivotal Ph3 Study MP ACT 2013 NEJM (PMID: 24131140) per 2024 JAMA Nichetti, et al. 7(l):e2350756, incorporated herein by reference in its entirety.

[0055] In addition, a 72% progression-free survival (PFS) was observed at 6 months in first-line (IL) pancreatic cancer patients treated with atebimetinib + mGnP at the 320 mg dose level (N=34). FIG. 2A is a graph showing the progression free survival probability by month in a human clinical trial of atebimetinib (320 mg QD) in the treatment of first line pancreatic (PDAC) patients, in combination with modified gemcitabine and nab-paclitaxel treatment, based on interim data collection from the 320mg intent-to-treat population (N=34). This represents the primary Phase 2 population enrolled as part of the Simon two-stage design from the ongoing Phase l / 2a trial of atebimetinib. The benchmark 6-month PFS for the standard of care treatment in this population (full dose and schedule GnP) is 44% and about 32% at 8-month PFS (extrapolated from reconstructed plots per 2024 JAMA Nichetti, et al. 7(l):e2350756]: (1.) MPACT 2013 NEJM (PMID: 24131140) N=431 [-32%]). FIG. 2B is a graph showing the progression free survival (PFS) probability by month in a human clinical trial of atebimetinib (320 mg QD) combined with modified gemcitabine and nab-paclitaxel treatment in the treatment of first line pancreatic (PDAC) patients, as shown in FIG. 2A, compared to third party published benchmark PFS probability data obtained from different patients in the Phase 3 MPACT clinical trial (2024 JAMA Nichetti, et al. 7(l):e2350756]: (1.) MPACT 2013 NEJM (PMID: 24131140), incorporated herein by reference in its entirety.). FIG. 2C is a graph of the progression free survival (PFS) data from patients treatedIMMU.028WO PATENT with atebimetinib in FIG. 2A compared to third party published benchmark PFS probability data obtained from other published clinical trial data. The 8 mo PFS benchmark data is extrapolated from reconstructed plots per 2024 JAMANichetti, et al. 7(1 ):e2350756] : (1.) MP ACT 2013 NEJM (PMID: 24131140) N=431 [~32%], (2.) PRODIGE 4 / ACCORD 11 2011 NEJM (PMID: 21561347) N=171 [~34%], (3.) NAPOLI 3 2023 LANCET (PMID: 37708904) N=383 [~44%], (4.) Ph2 - 2017 Ahn, et al. (PMID: 28203300) N=57 [-36%]. No head-to-head clinical trial has been conducted evaluating atebimetinib and other candidates or products in FIG. 1A, FIG. IB, FIG. 2B and FIG. 2C.

[0056] In addition, data was obtained from treating PDAC patients (N=6) with 240 mg atebimetinib QD and mGNP (1,000 mg / m2(Gem) + 125 mg / m2(nab-Pac) days 1 & 15, every 4 weeks), resulting in a median PFS of 7.1 months, and survival probability of about 20% at 8 months (estimated using a Cox proportional hazards regression model, with Kaplan-Meier methods were used to visualize time-to-event data). This data was based on interim data collection from the 240 mg (N=6) intent-to-treat populations, from an ongoing Phase l / 2a trial of atebimetinib.

[0057] The median PFS for the ongoing clinical trial with atebimetinib with mGnP has not yet reached at the data cutoff date. An overall response rate (ORR) of 39% and a disease control rate (DCR) of 81% were observed in response evaluable patients at both the 240 and 320 mg dose levels of atebimetinib + mGnP (N=36), including many patients with deepening, durable regressions and multiple examples of individual lesions rendered undetectable. Atebimetinib continued to demonstrate a markedly favorable tolerability profile in combination with mGnP. No Grade 3+ events were observed in a majority of the adverse event categories commonly observed with standard of care chemotherapy in first line pancreatic cancer.

[0058] The combination of atebimetinib and mGnP showed a markedly favorable tolerability profile. Safety data for the clinical trial of atebimetinib and mGnP described above is presented in Table 1 below, in comparison to data obtained from the following third party published pivotal trials: (1.) MP ACT 2013 NEJM (PMID: 24131140) N=431, (2.) PRODIGE 4 / ACCORD 11 2011 NEJM (PMID: 21561347) N=171, (3.) NAPOLI 3 2023 LANCET (PMID: 37708904) N=383, (4.) FFX pivotal study follow up (PMID: 27765912) (NR = not reported or not clearly reported). Not all pivotal trials reported on all AE’s or used fully consistent terminology.Table 1. Safety DataIMMU.028WO PATENT(a) = only AE groups in this atebi + mGnP arm (N=34) that reached > 10% Gr3 event level. ForAnemia, all Grade 3, not SAE’s, older patient population vs. historical benchmarksNeutropenia: Neutropenia, Neutrophil Count DecreasedSensory Neuropathy: Peripheral Sensory Neuropathy, Neuropathy PeripheralNo Gr 5 events; Patients received combination of 320mg atebi + mGnP (N=34)

[0059] To date, no other head-to-head clinical trial has been conducted evaluating atebimetinib and other candidates or products.Methods of Treating Cancer Harboring RAS and / or RAF Mutation(s)

[0060] In some embodiments, atebimetinib (Compound A) is administered to treat a cancer harboring a RAF or RAS mutation at a dose that provides Deep Cyclic Inhibition (DCI) of the MAPK pathway. In some embodiments, methods of administering atebimetinib provide a short-lived dual MEK inhibitor (MEKi) that is resistant to CRAF -bypass and has a unique pulsatile pharmacokinetic and pharmacodynamic mechanism (e.g., DCI MEKi). For example, in someIMMU.028WO PATENT embodiments, methods of treating a cancer can comprise administering a dose of atebimetinib at a dose and dose interval (e.g., 240-320 mg QD that exhibits high Cmax and near-zero drug trough, approximating a 2h plasma half-life and >90% inhibition of pERK) and provides adequate antitumor activity while not exceeding the MTD (e.g. Cmax levels over 2,000 ng / mL for ~1 pM drug free fraction, a median plasma half-life of about 2 hours, with -90% pharmacodynamic inhibition ofpERK).

[0061] In some embodiments, the cancer has a RAS mutation that is a KRAS G12D or G12V mutation or a NRAS Q61L or Q61K mutation. In some embodiments, the cancer has a KRAS G12D mutation. In some embodiments, the cancer has a KRAS G12V mutation. In some embodiments, the cancer has a NRAS Q61L mutation. In some embodiments, the cancer has a NRAS Q61K mutation.

[0062] In some embodiments, the cancer is selected from the group consisting of: NRAS-mutated melanoma, KRAS-mutated PDAC, KRAS-mutated NSCLC and KRAS-mutated, and APC-wildtype CRC. In some embodiments, the cancer is NRAS-mutated melanoma. In some embodiments, the cancer is KRAS-mutated PDAC. In some embodiments, the cancer is KRAS- mutated NSCLC. In some embodiments, the cancer is KRAS-mutated CRC. In some embodiments, the cancer is APC-wildtype CRC. In some embodiments, the cancer is pancreatic cancer with a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer with a G12D mutation. In some embodiments, the cancer is pancreatic cancer with a G12V mutation. In some embodiments, the cancer is colorectal cancer with a NRAS Q61L mutation. In some embodiments, the cancer is colorectal cancer with a NRAS Q61K mutation. In some embodiments, the cancer is colorectal cancer with a KRAS G12D mutation. In some embodiments, the cancer is melanoma with a NRAS Q61R mutation. In some embodiments, the cancer is melanoma with a KRAS G12S mutation. In some embodiments, the cancer melanoma with a BRAF V600E mutation. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) with a KRAS G12S mutation.

[0063] In some embodiments, patients are selected for treatment with Compound A based on the presence of RAS mutation such as a KRAS G12C mutation in plasma or tumor specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Additional information on FDA-approved tests for the detection of a KRAS G12C mutation is available at:IMMU.028WO PATENT https: / / www.fda.gov / CompanionDiagnostics. FDA approved diagnostics for identifying patients with a RAS-mutated cancer include the companion diagnostics provided in Table 2 below.Table 2IMMU.028WO PATENT

[0064] In some embodiments, RAS mutations can be detected by next generation sequencing (NGS) techniques. For example, molecular diagnostics of HRAS / KRAS and NRAS targeted gene panels can be obtained by NGS techniques. Next generation sequencing of amplification products can be performed on the Ion Torrent Personal Genome Machine and analyzed with the Torrent Suite Software. Reference DNA sequences used for these genes can be found at https: / / www.ncbi.nlm.nih.gov / refseq / rsg / . This mutation panel is designed to detect targeted mutations only. Confirmation of these mutations is performed by traditional or real time PCR followed by Sanger sequencing, fluorescent melting curve analysis and / or pyrosequencing (CPT codes: 81210 (BRAF), 81275 (KRAS codons 12 and 13 in exon 2), 81276 (KRAS codon 61 in exon 3), 81403 (HRAS), 81311 (NRAS)).Pharmaceutical Compositions

[0065] In some embodiments, Compound A may be formulated as a pharmaceutical composition using a pharmaceutically acceptable excipients and administered by a variety of routes. In some embodiments, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy, L. V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012). In a particular embodiment, the pharmaceutical composition comprises 4- ((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H- chromen-7-yl dimethylcarbamate or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0066] In certain embodiments, the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprisesIMMU.028WO PATENT an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier. The pharmaceutical composition can be a medicament.

[0067] Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, parenteral administration (e.g., intravenously, subcutaneously, or intramuscularly), oral administration (for example, tablets, and capsules); absorption through the oral mucosa (e.g., sublingually) or transdermally (for example as a patch applied to the skin) or topically (for example, as a cream, ointment or spray applied to the skin).

[0068] In certain embodiments, the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can be a medicament.

[0069] In some embodiments, pharmaceutical compositions comprising Compound A or pharmaceutically acceptable salts thereof can be formulated for oral administration. For example, a compound provided herein can be combined with suitable compendial excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of Compound A. The drug product can be prepared by first manufacturing Compound A as an active pharmaceutical ingredient (API), followed by roller compaction / milling with intragranular excipients and blending with extra granular excipients. A Drug Product can contain Compound A as the API and excipient components in a tablet in a desired dosage strength of Compound A. The blended material can be compressed to form tablets and then film coated. The excipients can be selected from materials appropriate for inclusion in a pharmaceutical composition for an intended purpose and route of delivery including providing a desired manufacturing and stability properties and / or desired in vivo characteristics or other properties to the pharmaceutical composition. In some embodiments, the pharmaceutical composition can include Compound A as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder or disintegrantIMMU.028WO PATENT(e g., a cross-linked polymer), a glidant (e.g., colloidal silicon dioxide) and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition can comprise a material such as an extended release or disintegrant involved in carrying or transporting the API pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject, including materials to desirable control the absorption of the API in the intestine.

[0070] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. For use in the methods of this disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (or, for example, 0.5 to 90%) of an active ingredient in combination with a pharmaceutically acceptable carrier.

[0071] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0072] To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using suitable excipients. The pharmaceutical compositions according to the present disclosure may contain conventional pharmaceutical carriers and / or auxiliary agents. In some embodiments, he pharmaceutical compositions according to the present disclosure may contain conventional carrier agentsIMMU.028WO PATENT including a binder, a lubricant and / or a glidant selected from those products and materials generally used in pharmaceutical industry for preparation of pharmaceutical compositions for an intended route of administration.

[0073] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0074] In some embodiments, an oral dosage form of Compound A is provided, such as the oral dosage form disclosed in Example 2. In some embodiments, an oral dosage form such as a tablet or capsule can contain Compound A or a pharmaceutically acceptable salt thereof as the API and one or more excipients such as a dry binder, tablet disintegrant, an absorbent, fdler or diluent, a lubricant, anti-adherent, binder, thickening agent, viscosity-increasing agent, coating agent and film former. In some embodiments, an oral dosage form such as a tablet or capsule can contain 20 mg to 160 mg of Compound A or a pharmaceutically acceptable salt thereof as the API and one or more intra-granulation excipients such as a dry binder, tablet disintegrant, an absorbent, filler or diluent, a lubricant, anti-adherent, binder, thickening agent, viscosity-increasing agent, coating agent and film former. In some embodiments, an oral dosage form such as a tablet or capsule can contain 20 mg, 120 mg or 160 mg of Compound A or a pharmaceutically acceptable salt thereof as the API and one or more intra-granulation excipients such as a dry binder, tablet disintegrant, an absorbent, filler or diluent, a lubricant, anti-adherent, binder, thickening agent, viscosity-increasing agent, coating agent and film former and one or more extra granulation excipients such as additional Compound A API granulate and a lubricant or film forming agent.

[0075] In some embodiments, an oral dosage form such as a tablet or capsule can contain 20 mg, 120 mg or 160 mg of Compound A or a pharmaceutically acceptable salt thereof as the API and one or more intra-granulation excipients such as microcrystalline cellulose, crospovidone Type A, and hydroxypropyl cellulose, and one or more extra-granulation excipients such as API granulate of Compound A and magnesium stearate. In some embodiments, an oral dosage form such as a tablet or capsule can contain about 20% w / w of Compound A or a pharmaceutically acceptable salt thereof as the API and about 60-70% w / w microcrystallineIMMU.028WO PATENT cellulose, about 5% w / w crospovidone Type A, and about 10% w / w hydroxypropyl cellulose, and one or more extra-granulation excipients such as API granulate of Compound A (95-99.5% w / w) and magnesium stearate (0.5-5% w / w).

[0076] Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modem Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).Combination Therapies

[0077] In some methods of treatment, atebimetinib (Compound A) is administered in combination with approved anti-cancer agents, and atebimetinib is administered once-daily at the dose that optimally displays DCI, while the combination agents will be administered in commonly used modified regimens that maintain effectiveness while reducing chemotherapy-related toxicities. Combination treatment continues until PD (radiographic or clinical) or other treatment discontinuation criteria are met. Individual components of the chemotherapy regimens can be discontinued if necessary to manage toxicities known to be associated with the agent(s). Likewise, if the entire chemotherapy regimen must be discontinued due to intolerability, participants may continue to receive Compound A as monotherapy until PD or other treatment discontinuation criteria are met. Similarly, participants who achieve a disease response of sufficient depth and duration that may warrant cessation of the approved agents may continue to receive maintenance Compound A until PD or other treatment discontinuation criteria are met. Other recognized maintenance regimens in combination with Compound A may be allowed with approval from the Sponsor MM.

[0078] In some embodiments, methods of treatment comprise the administration of Compound A in combination with gemcitabine for the treatment of pancreatic adenocarcinoma or other forms of cancer in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, a gemcitabine-based regimen in Table 3.IMMU.028WO PATENTTable 3. Chemotherapy Regimen combinations with Compound AIMMU.028WO PATENT

[0079] In some embodiments, methods of treatment comprise the administration of Compound A in combination with oxaliplatin and / or fluorouracil for the treatment of pancreatic adenocarcinoma or other forms of cancer in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, a fluoropyrimidine-based regimen in Table 4A, a FOLFIRINOX regimen in Table 4B or Table 4C.Table 4A. Chemotherapy Regimen combinations with Compound AIMMU.028WO PATENT

[0080] In this example, methods of treatment comprise the administration of Compound A in combination with oxaliplatin and / or fluorouracil for the treatment of pancreatic adenocarcinoma in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, a fluoropyrimidine-based regimen in Table 4A, a FOLFIRINOX regimen in Table 4B or Table 4C.Table 4B. FOLFIRINOX (irinotecan, oxaliplatin and fluorouracil) in combination with CompoundA (e.g., 320 mg QD PO or 240 mg QD PO)IMMU.028WO PATENT

[0081] An example of a modified FOLFIRINOX dosing schedule is provided in Table 17C. Oxaliplatin is administered in 250mL glucose 5% over 2 hours. This is infused concurrently with calcium folinate in 250mL glucose 5% over 2 hours. The line should then be flushed with glucose 5%.Table 4C. modified FOLFIRINOX (14 day cycle frequency, for up to 12 cycles) in combination with Compound A (e.g., 320 mg QD PO or 240 mg QD PO)

[0082] In some embodiments, methods of treatment comprise the administration of Compound A in combination with chemoradiation for the treatment of pancreatic adenocarcinoma in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, chemoradiation-based regimen in Table 5.Table 5. Chemoradiation Regimen combinations with Compound AIMMU.028WO PATENT

[0083] In this example, methods of treatment comprise the administration of Compound A in combination with chemoradiation for the treatment of pancreatic adenocarcinoma in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, chemoradiation-based regimen in Table 6.Table 6. Chemoradiation Regimen combinations with Compound AIMMU.028WO PATENT

[0084] In some embodiments, Compound A is administered to treat a cancer such as melanoma that has been previously treated with one or more immune checkpoint inhibitor. In some embodiments, Compound A is administered in combination with one or more immune checkpoint inhibitor to treat a cancer such as melanoma.

[0085] A review describing immune checkpoint pathways and the blockade of such pathways with immune checkpoint inhibitor compounds is provided by Pardoll in Nature Reviews Cancer (April 2012), pages 252-264, which is incorporated herein by reference in its entirety. Immune check point inhibitor compounds display anti-tumor activity by blocking one or more of the endogenous immune checkpoint pathways that downregulate an anti-IMMU.028WO PATENT tumor immune response. The inhibition or blockade of an immune checkpoint pathway typically involves inhibiting a checkpoint receptor and ligand interaction with an immune checkpoint inhibitor compound to reduce or eliminate the down regulation signal and resulting diminishment of the anti-tumor response.

[0086] The term “immune checkpoint inhibitor” or “ICI,” as used herein, refers to a molecule (e.g., small molecule, peptide, polypeptide, protein, antibody, antibody fragment and the like) that acts as an inhibitor (antagonist) of an immune checkpoint pathway. Inhibition of a pathway can include blockade of the pathway through binding to a receptor or signaling molecule that is part of the immune checkpoint pathway.

[0087] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound inhibits the signaling interaction between an immune checkpoint receptor and the corresponding ligand of the immune checkpoint receptor. The immune checkpoint inhibitor compound can act by blocking activation of the immune checkpoint pathway by inhibition (antagonism) of an immune checkpoint receptor (some examples of receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or by inhibition of a ligand of an immune checkpoint receptor (some examples of ligands include PD- L1 and PD-L2). In such embodiments, the effect of the immune checkpoint inhibitor compound is to reduce or eliminate down regulation of certain aspects of the immune system anti-tumor response in the tumor microenvironment.

[0088] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor compound is an antibody. In some embodiments, the antibody is a monoclonal antibody, specifically a human or a humanized monoclonal antibody. In some embodiments, the one or more immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a binding ligand of PD-L1. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the one or more immune checkpoint inhibitor as described herein includes a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitorIMMU.028WO PATENT is different from the second immune checkpoint inhibitor. In some embodiments, the first and the second immune checkpoint inhibitor are independently an inhibitor of PD-1, PD-L1 or CTLA-4. In some embodiments, the first immune checkpoint inhibitor is a PD-1 inhibitor, and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0089] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, relatlimab, durvalumab, or any combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor may include an anti-PD-1 HuMAbs can be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A11, 7D3 and 5F4, all of which are described in U.S. Pat. No. 8,008,449, which is incorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAbs can be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, all of which are described in U.S. Pat. No. 7,943,743, which is incorporated herein by reference in its entirety.

[0090] In some embodiments, atebimetinib is administered in combination with an anti-PD-1 antibody such as pembrolizumab. In some embodiments, a method of treatment comprises administering atebimetinib or a pharmaceutically acceptable salt thereof once daily (QD) at a dose providing 240 mg or 320 mg of atebimetinib for 21 days followed by administering 400 mg of pembrolizumab via IV infusion over 30 minutes once every six weeks (q6w) in combination with continued once daily dosing of the same dose of atebimetinib once daily. In some embodiments, a method of treatment comprises administering atebimetinib or a pharmaceutically acceptable salt thereof once daily (QD) at a dose providing 240 mg or 320 mg of atebimetinib in combination with 400 mg of pembrolizumab via IV infusion over 30 minutes once every six weeks (q6w) starting concurrently.

[0091] In some embodiments, atebimetinib is administered in combination with a kinase inhibitor that targets BRAF V600E, such as dabrafenib. In some embodiments, the atebimetinib is administered once daily in combination with 150 mg of dabrafenib twice per day (BID).Additional Embodiments

[0092] Accordingly, some aspects described herein relate to the following numbered alternatives:IMMU.028WO PATENT

[0093] 1 A method of treating pancreatic ductal adenocarcinoma (PDAC) comprising the steps of administering to a patient in need thereof: oral administration of 240 mg of Compound A once per day, in combination with a modified gemcitabine + nab-paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 minutes, followed immediately by gemcitabine 1000 mg / m2via IV infusion over 30 minutes.

[0094] 2 A use of 240 mg of Compound A administered once per day to treat pancreatic ductal adenocarcinoma (PDAC), in combination with a modified gemcitabine + nab- paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 minutes, followed immediately by gemcitabine 1000 mg / m2via IV infusion over 30 minutes.

[0095] 3 A method of treating pancreatic ductal adenocarcinoma (PDAC) comprising the steps of administering to a patient in need thereof: oral administration of 320 mg of Compound A once per day, in combination with a modified gemcitabine + nab-paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 min, followed immediately by gemcitabine 1000 mg / m2via IV infusion over 30 min.

[0096] 4 A use of 320 mg of Compound A once per day to treat pancreatic ductal adenocarcinoma (PDAC), in combination with a modified gemcitabine + nab-paclitaxel (mGnP) regimen where the mGnP regimen is administered on Day 1 and Day 15 of each 28-day cycle as follows: nab-paclitaxel 125 mg / m2via IV infusion over 30 min, followed immediately by gemcitabine 1000 mg / m2via IV infusion over 30 min.

[0097] 5 A method of treating pancreatic ductal adenocarcinoma (PDAC) comprising the steps of administering to a patient in need thereof: oral administration of 240 mg of Compound A once per day, in combination with a modified FOLFIRINOX (mFFX) regimen where the mFFX regimen is administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows: oxaliplatin 85 mg / m2via IV infusion over 2 hours, folinic acid (leucovorin) 400 mg / m2via IV infusion over 2 hours, irinotecan 150 mg / m2via IV infusion over 90 minutes, and fluorouracil 2400 mg / m2continuous IV infusion given over 46 hours beginning Day 1 and ending on Day 3.

[0098] 6. A use of 240 mg of Compound A once per day to treat pancreatic ductal adenocarcinoma (PDAC), in combination with a modified FOLFIRINOX (mFFX) regimen whereIMMU.028WO PATENT the mFFX regimen is administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows: oxaliplatin 85 mg / m2via IV infusion over 2 hours, folinic acid (leucovorin) 400 mg / m2via IV infusion over 2 hours, irinotecan 150 mg / m2via IV infusion over 90 minutes, and fluorouracil 2400 mg / m2continuous IV infusion given over 46 hours beginning Day 1 and ending on Day 3.

[0099] 7. A method of treating pancreatic ductal adenocarcinoma (PDAC) comprising the steps of administering to a patient in need thereof: oral administration of 320 mg of Compound A once per day, in combination with a modified FOLFINOX (mFFX) regimen where the mFFX regimen is administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows: oxaliplatin 85 mg / m2via IV infusion over 2 hours, folinic acid (leucovorin) 400 mg / m2via IV infusion over 2 hours, irinotecan 150 mg / m2via IV infusion over 90 minutes, and fluorouracil 2400 mg / m2continuous IV infusion given over 46 hours beginning Day 1 and ending on Day 3.

[0100] 8. A use of 320 mg of Compound A once per day to treat pancreatic ductal adenocarcinoma (PDAC), in combination with a modified FOLFIRINOX (mFFX) regimen where the mFFX regimen is administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows: oxaliplatin 85 mg / m2via IV infusion over 2 hours, folinic acid (leucovorin) 400 mg / m2via IV infusion over 2 hours, irinotecan 150 mg / m2via IV infusion over 90 minutes, and fluorouracil 2400 mg / m2continuous IV infusion given over 46 hours beginning Day 1 and ending on Day 3.

[0101] 9 A method of treating RAS-mutant non-small cell lung cancer (NSCLC) comprising oral administration of 320 mg of Compound A once per day to the patient in need thereof as a monotherapy to treat the RAS-mutant NSCLC.

[0102] 10. A use of 320 mg of Compound A once per day as a monotherapy to treatRAS-mutant NSCLC in a patient in need thereof.

[0103] 11. A method of treating RAS-mutant non-small cell lung cancer (NSCLC) comprising oral administration of 320 mg of Compound A once per day to the patient in need thereof in combination with a KRAS G12C inhibitor to treat the RAS-mutant NSCLC.

[0104] 12. A use of 320 mg of Compound A once per day in combination with a KRASG12C inhibitor to treat RAS-mutant NSCLC in a patient in need thereof.IMMU.028WO PATENT

[0105] 13. A method of treating RAS-mutant non-small cell lung cancer (NSCLC) comprising oral administration of 320 mg of Compound A once per day to the patient in need thereof in combination with an ant-PD-1 immunotherapy to treat the RAS-mutant NSCLC.

[0106] 14. A use of 320 mg of Compound A once per day in combination with an anti-PD1 immunotherapy to treat RAS-mutant NSCLC in a patient in need thereof.

[0107] 15. A method of treating RAS-mutant non-small cell lung cancer (NSCLC) comprising oral administration of 320 mg of Compound A once per day to the patient in need thereof in combination with 350 mg cemiplimab administered once every 3 weeks to treat the RAS-mutant NSCLC.

[0108] 16. A use of 320 mg of Compound A once per day in combination with 350 mg cemiplimab administered once every 3 weeks to treat RAS-mutant NSCLC in a patient in need thereof.

[0109] 17. A method of treating BRAF mutant melanoma comprising the steps of administering to a patient in need thereof: oral administration of 320 mg of Compound A once per day (QD), in combination with or administration of 150 mg dabrafenib twice per day (BID).

[0110] 18. A use of 320 mg of Compound A administered once per day (QD) to treat a BRAF mutant melanoma in a patient in need thereof, in combination with or administration of 150 mg dabrafenib twice per day (BID).[OHl] 19. A method of treating melanoma after treatment with an immumo-oncology therapy, the method comprising the steps of administering to a patient in need thereof: oral administration of 320 mg of Compound A once per day, in combination with 400 mg pembrolizumab via IV infusion over 30 minutes once every 6 weeks.

[0112] 20. A use of 320 mg of Compound A administered once per day (QD) to treat melanoma in a patient in need thereof, in combination with 400 mg pembrolizumab via IV infusion over 30 minutes once every 6 weeks.IMMU.028WO PATENTEXAMPLE 1Synthesis of Compound A

[0113] Compound A was prepared in 1 step:

[0114] 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) was suspended in methanol. Dimethylamine 2M was added and the formed reaction mixture was stirred until full conversion was observed. After full conversion the reaction was concentrated under reduced pressure. IM HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na2COs. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SC>4, fdtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow solid.

[0115] Yield: Compound A was isolated as a light yellow solid (74% over 1 step). Analysis: LCMS (Method T): tR = 1.53 min; m / z calculated for [M-H]+= 507.2, found = 507.2; *H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 - 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).EXAMPLE 2Oral Dosage Form of Compound A

[0116] An oral dosage form of Compound A can be prepared by combining Compound A as the active pharmaceutical ingredient (API) with pharmaceutically acceptable excipients to form a tablet. The intra granulation excipients can include microcrystalline cellulose (e.g., CEOLUS UF-711), crospovidone Type A (e.g., Polyplasdone XL), hydroxypropyl Cellulose HPC-IMMU.028WO PATENTSL, hyroxypropyl cellulose-Low Substituted L-HPC LH-21, and purified water. The extra granulation excipients can include Compound A and magnesium stearate (e.g., hyqual vegetable source). For example, a tablet dosage form is described in the Table 7 below.Table 7EXAMPLE 3First-in-Human Clinical Trial of Compound A

[0117] Chronic inhibitors of MEK have been poorly tolerated, and limited mainly to RAF mutant disease. Compound A is a deep cyclic inhibitor of MEK in the MAPK pathway. Compound A is a novel, oral, dual MEK inhibitor with a unique PK profde, characterized by a high Cmax and a short half-life. The clinical trial is an open-label study designed to evaluate the safety, tolerability, clinical pharmacology, and preliminary efficacy of Compound A when dosed as monotherapy, once daily, in participants with advanced RAS mutant solid tumors, following at least one line of systemic, standard-of-care therapy.

[0118] This is a Phase l / 2a, multicenter, open-label, nonrandomized study to characterize the safety and anti -turn or activity of Compound A administered to participants withIMMU.028WO PATENTRAS-mutated or RAS / MAPK pathway activated advanced or metastatic solid tumors as monotherapy and in combination with approved agents. This study begins with Phase 1 Dose Exploration (including monotherapy dose escalation and dose expansion stages). The monotherapy dose exploration is composed of a dose escalation study followed by the accrual of dose expansion cohorts to generate more robust data on Compound A’ s safety, tolerability, PK / PD, and antitumor activity.

[0119] The dose escalation follows an mTPI-2 design. The mTPI-2 dose escalation scheme in this study allows for a minimum of 1 participant and up to 8 participants at each dose level to be evaluated. The evaluation period encompasses the first 21 days after the first administration of Compound A (i.e., the first 21 days of the first 28-day treatment cycle [Cycle 1]), during which safety and tolerability data for each evaluable participant are collected. These data, along with PK and PD data (if available) and cumulative safety and tolerability data collected, inform dose-escalation decisions within the prespecified planned dose range (40 mg to 960 mg). The initially planned cohort dose escalation levels include: 40, 80, 160, 240, and 320 mg QD.

[0120] Once adequate safety, PK, PD, and any efficacy data are available, select tolerable and pharmacologically active dose cohorts are expanded by or enrolled to approximately 20 participants to further evaluate safety, tolerability, PK, PD, and anti-tumor activity. Monotherapy dose escalation participants previously treated at a dose level selected as one of the expansion cohort doses may be counted towards the overall enrollment of that expansion cohort. A preferred dose of Compound A exhibits optimal pharmacological characteristics of deep cyclic inhibition (DCI; high Cmax and near-zero drug trough, approximating a 2h plasma half-life and >90% inhibition of pERK) and provides adequate anti-tumor activity while not exceeding the MTD (if reached during dose escalation).

[0121] Initial phase l / 2a clinical data (NCT05585320) demonstrate favorable initial safety along with PK and PD profiles that are consistent with preclinical modeling of deep cyclic inhibition (DCI), including Cmax levels over 2,000 ng / mL (~1 pM drug FF), a median plasma tl / 2 of 1.94 hours, and -90% pharmacodynamic inhibition of pERK.

[0122] The study population comprises male and female participants 18 years of age or older with advanced, unresectable, or metastatic RAS-mutated solid tumors who have received at least 1 prior line of systemic therapy for their advanced / metastatic disease. Patients for treatment can have any advanced, unresectable, or metastatic RAS-mutated solid tumors in Phase 1, whileIMMU.028WO PATENTPhase 2a will focus on tumor type cohorts: NRAS-mutated melanoma, KRAS-mutated PDAC, KRAS-mutated NSCLC and KRAS-mutated, APC-wildtype CRC.

[0123] The cohort dose escalation levels include oral administration of Compound A at doses of 40, 80, 160, 320 mg QD, for up to twelve 28-day cycles. Once daily administration will allow for more than 10 half-lives between doses. Timed serial PK samples are collected on CID 1 and CID 15 and trough PK samples are collected at C1D2, C1D8, CID 16, C2D1 and C3D1.

[0124] Table 8 provides clinical data obtained from initial pharmacokinetics (PK) and pharmacodynamics (PD) data from an ongoing phase l / 2a trial (NCT05585320), from certain human subjects enrolled during the first 20 weeks since the first patient was dosed in this Phase 1 clinical trial, showing the calculated half-life based on samples taken at cycle 1 day 1 (C1D1) and cycle 1, day 15 (CID 15), after receiving once-daily oral doses of Compound A at doses of 40 mg, 80 mg, or 160 mg. Each patient was diagnosed with the RAS-mutant cancer diagnosis indicated in Table 8 prior to treatment with Compound A. No dose limiting toxicities (DLT) or severe adverse events (SAE) were observed while dosing these patients through CID 15. No Compound A drug- related adverse events beyond grade 1 were reported in dose levels III or IV. The clinical trial is actively enrolling patients at 320 mg QD p.o. with 2 additional patients already consented (KRAS- GOV pancreatic cancer and KRAS-G12D colorectal cancer). No dose limiting toxicities (DLTs) or serious adverse events (SAEs) were observed in the first 20 weeks since dosing the first patient. Early PK data are approximately dose linear with no Compound A drug accumulation. All patients listed in Table 8 subsequently cleared the dose limiting toxicity (DLT) window.Table 8. Patient Status Summary for Compound A Phase 1 Clinical TrialIMMU.028WO PATENT

[0125] In patients 3 and 4, an approximately 90% pharmacodynamic (PD) inhibition of pERK was observed in patients receiving 160 mg of Compound A administered orally (po) once daily (QD). (Dose Level III, cycle 1, day 1). Compound A PK / PD (pERK) showed MAPK pathway suppression (87-92% reduction p / t-ERK, Cmax > 2,000 ng / mL and Cmin of about 0.1 micromolar free fraction > 6-8 hours). Compound A PK / PD (phosphorylated MEK) data showed suppression of pathway bypass (55-59% reduction p / total-MEK, Cmax > 2,000 ng / mL and Cmin of about 0.1 micromolar free fraction > 6-8 hours). Modeled PK / BK, drug free fraction (FF) showed a high Cmax (see Hoare, Sam RJ. "Analyzing kinetic binding data." Assay Guidance Manual) (>90% MEK occupancy, Cmax > 1 micromolar FF, Cmin of about 0.1 micromolar free fraction > 6-8 hours).

[0126] Dose Level III: Cycle 1 Day 1 (C1D1) PK (solid line), BK (dotted line), and PD (dotted line) for patient 3 (solid line with circles) and 4 (solid line with solid squares), both at 160 mg QD p.o.

[0127] PK plasma: pre-dose (0), 0.5, 1, 1.5, 2*, 4, 6, 8, 24 hours; PD plasma: PK- matched without 0.5 or 1.5 hours (*poor sample quality for Pt.4 at 2 hour)

[0128] PD method: A549 (KRASG12S) cells were exposed to patient plasma for 2- hours before quantifying phosphorylated and total ERK and MEK

[0129] Significant PK Cmax levels (plasma concentration of therapy in a specific area of the body) were observed with Compound A of over 2,000 ng / mL (or approximately 1 uM drug free-fraction at 160 mg once daily oral dose)IMMU.028WO PATENT

[0130] Greater than 90 percent PD inhibition of phosphorylated extracellular signal- regulated kinase (pERK) with Compound A compared to pretreatment baseline for patients at the third dose level (160 mg once daily oral)

[0131] A median plasma half-life (ti / 2) of 1.94 hours observed with Compound A across the first three dose levels evaluable (40 mg, 80 mg and 160 mg once daily oral), in patients with pancreatic and colorectal cancer with different RAS mutations, including KRAS-G12D, the most common mutation presents in pancreatic cancer.

[0132] Patient 5 was diagnosed with KRAS-G12D pancreatic cancer and received 320 mg of Compound A once daily, for 15 days in cycle 1. 8 provides the corresponding half-life measured at day 1 and day 15. FIG. 3 A is a graph showing PK / PD (pERK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 1). FIG. 3B is a graph showing PK / PD (pMEK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 1). FIG. 3C is a graph showing PK / PD (pERK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 15). FIG. 3D is a graph showing PK / PD (pMEK) for Compound A from patient 5 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 15).

[0133] Patient 6 was diagnosed with KRAS-G12V pancreatic cancer and received 320 mg of Compound A once daily, for 15 days in cycle 1. Table 8 provides the corresponding halflife measured at day 1 and day 15. The PK / PD (pERK) for Compound A was obtained from patient 6 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1 , day 1). PK / PD (pMEK) for Compound A was obtained from patient 6 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 1). PK / PD (pERK) for Compound A was obtained from patient 6 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 15). PK / PD (pMEK) for Compound A was obtained from patient 6 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 15).

[0134] Patient 7 was diagnosed with KRAS-G12S colorectal cancer and received 320 mg of Compound A once daily, for 15 days in cycle 1. Table 8 provides the corresponding halflife measured at day 1 and day 15. PK / PD (pERK) for Compound A was obtained from patient 7 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 1). PK / PD (pMEK) for Compound A was obtained from patient 7 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 1). PK / PD (pERK) was obtained for Compound A from patient 7 afterIMMU.028WO PATENT receiving 320 mg administered orally (po) once daily (QD) (cycle 1 , day 15). PK / PD (pMEK) was obtained for Compound A from patient 7 after receiving 320 mg administered orally (po) once daily (QD) (cycle 1, day 15).

[0135] An additional patient was enrolled at 160 mg QD p.o. (NRAS-G13R Melanoma); independent of DLT dose escalation.

[0136] The cohort dose escalation levels included oral administration of Compound A at a dose of 240 mg QD, for up to twelve 28-day cycles. Once daily administration allowed for more than 10 half-lives between doses. Timed serial PK samples were collected on C1D1 and C1D15 and trough PK samples are collected at C1D2, C1D8, C1D16, C2D1 and C3D1. FIG. 4A is a graph showing plasma concentration (PK) for Compound A from patient 13 after receiving 240 mg Compound A administered orally (po) once daily (QD) at cycle 1, day 1 and at cycle 1, day 15. FIG. 4B is a graph showing PK / PD (pERK) for Compound A from patient 13 after receiving 240 mg Compound A administered orally (po) once daily (QD) at cycle 1, day 1 and at cycle 1, day 15.

[0137] This is an example of developing a medicine for a broad population of cancer patients using a universal-RAS therapy in the dose-escalation portion of the Phase l / 2a study for Compound A in patients with advanced solid tumors. The study’s Safety Review Committee completed its evaluation and determined that doses up to and including 320 mg (including, for example, 240 mg) once daily were tolerable with no dose limiting toxicities. Enrollment in the Phase lb expansion portion of the study will commence and is designed to evaluate two dosing cohorts of 12 patients each at an oral dose of 240 mg or 320 mg once daily, with three patients already in the study have so far been dosed at the 320 mg dose level.

[0138] This unique therapy aims for Universal-RAS activity: treating patients with any mutation in KRAS, NRAS, or HRAS. As such, there are plans to enroll 21 additional patients in next part of the study to materially add to a dataset for Compound A in patients with RAS-mutant solid tumors.

[0139] Compound A achieved significant levels of PK Cmax, demonstrated a half-life of approximately two hours, and was well tolerated with no dose limiting toxicities or serious adverse events observed in patients with pancreatic and colorectal cancer. Upon review of the cumulative data from the eight patients dosed in the Phase la study, the SRC endorsed 240 mgIMMU.028WO PATENT daily and 320 mg daily as the dose levels for the expansion cohort and agreed with initiating the Phase lb expansion.

[0140] Compound A is contemplated to achieve universal-RAS activity that selectively impacts cancer cells to a greater extent than healthy cells, through deep cyclic inhibition of the MAPK pathway with once-daily oral dosing. Compound A is currently being evaluated in a Phase l / 2a study in patients with advanced solid tumors harboring RAS mutations for whom there are limited treatment options (NCT05585320).

[0141] Compound A was well tolerated with no DLTs or SAEs observed and no drug- related adverse events beyond Grade 1 observed. An additional patient was enrolled at 160 mg QD p.o. (NRAS-G13R Melanoma); independent of DLT dose escalation.

[0142] About two-thirds of the patients treated with Compound A as a third or later line of therapy, up to 7th line. RAS mutations were reported in 41 patients diagnosed with various forms of RAS mutated cancer each treated with Compound A (N=41). The 41 patients treated with Compound A included 26 pancreatic ductal adenocarcinoma (PDAC), 5 colorectal cancer (CRC), 4 lung adenocarcinoma (LU AD), 2 melanoma (MEL), 1 lung squamous cell carcinoma (LUSC), 1 ampulla of vater carcinoma (AMPCA), 1 mesonephric adenocarcinoma (MNAC), 1 cholangiocarcinoma (CHOL).

[0143] A total of 82% of the 41 patients treated with Compound A never had a prior partial response (PR) or complete response (CR) to any prior therapy before treatment with Compound A, and the patients had a range of 1-6 prior lines of therapy before receiving Compound A (median 2 prior lines of therapy). The 41 patients treated with Compound A included 34 patients with prior treatment history, of which only 6 are known to have had a PR in response (no CR’s) to any prior treatment for metastatic disease (excludes adjuvant). Among these 34 patients with prior treatment history, only 6 are known to have had a partial response (PR) and none are known to have had a complete response (CR), in response to any prior treatment for metastatic disease (excludes adjuvant), Compound A treatment was the median third line of therapy (range 2nd-7th line).

[0144] About two-thirds of the patients treated with Compound A as a third or later line of therapy, up to 7thline. Specifically, among 34 patients treated with Compound A, a total of 32.4% received Compound A as a second line therapy, 38.2% of patients received Compound A as a third line therapy, 14.7% received Compound A as a fourth line of therapy, 8.82% receivedIMMU.028WO PATENTCompound A as a fifth line of therapy, 2,94% received Compound A as a sixth line of therapy and 2.94% received compound A as a seventh line of therapy. RAS mutations were reported in 41 patients diagnosed with various forms of RAS mutated cancer each treated with Compound A (N=41). The 41 patients treated with Compound A included 26 pancreatic ductal adenocarcinoma (PDAC), 5 colorectal cancer (CRC), 4 lung adenocarcinoma (LU AD), 2 melanoma (MEL), 1 lung squamous cell carcinoma (LUSC), 1 ampulla of vater carcinoma (AMPCA), 1 mesonephric adenocarcinoma (MNAC), 1 cholangiocarcinoma (CHOL).

[0145] A total of 82% of the 41 patients treated with Compound A never had a prior partial response (PR) or complete response (CR) to any prior therapy before treatment with Compound A, and the patients had a range of 1-6 prior lines of therapy before receiving Compound A (median 2 prior lines of therapy). The 41 patients treated with Compound A included 34 patients with prior treatment history, of which only 6 are known to have had a PR in response (no CR’s) to any prior treatment for metastatic disease (excludes adjuvant). Among these 34 patients with prior treatment history, only 6 are known to have had a partial response (PR) and none are known to have had a complete response (CR), in response to any prior treatment for metastatic disease (excludes adjuvant), Compound A treatment was the median third line of therapy (range 2nd-7th line).

[0146] The exploratory PK / PD results of 19 patients treated with Compound A were analyzed (N=19). The Compound A plasma drug concentrations (ng.L) were measured over time after doses of Compound A at 40, 80, 160, 240 and 320 PO QD.

[0147] Modeled PK profiles were calculated based on measurements of plasma concentrations (ng / mL) of Compound A versus time (h) from 19 patients on a semilogarithmic scale for different dose groups. Approximately dose linear from 40 to 320 mg PO QD with no drug accumulation. A tight relationship was observed between plasma concentrations and phosphorylated ERK (p-ERK) to total ERK (t-ERK) ratios; Longer time above pMEK IC90 at 320 mg (4.0 hr) vs. 240 mg (3.3 hr). Overall, a tight relationship was observed between the plasma concentrations and p-ERK to total ERK ratios, as well as a low variance in PD (p-ERK) profiles at the 320 mg compared to the 240 mg PO QD dose levels. Overall, Compound A was well- tolerated by patients in the clinical trial, with 100% suppression of acquired RAS alterations observed and individual target lesion regression in about half of the patients. Among the patients treated with Compound A:IMMU.028WO PATENT• Best individual lesion regressions: -35.7% at 320mg in 2L (vs. -11.4% at 240mg) ;• Best RECIST SLD: -18.9% at 320mg in 2L (vs. -7.1% at 240mg);• Longest duration on therapy: 162 days (5+ months) at 240mg; no TRAEs; and• 53% of patients had > 1 target lesions regress at 320mg or 240mg.

[0148] A total of 11 patients receiving Compound A had post-baseline scans at 320mg, 6 patients with post-baseline scans at 240mg, 3 patients with scans at lower doses, 7 patients have started treatment but not yet scanned, 5 patients are pending data entry and 8 patients progressed before they could receive a post-baseline scan, and 1 was not evaluable. 6 of 20 (30%) patients with completed RECIST scans, showed best sum of longest diameters (SLD) of 0% to -18.9%, and 4 of 20 (20%) showed best SLD less than zero. (Note: 2 patients at 320 mg with -35.7% as best individual lesion regression, both in 2L).EXAMPLE 4Compound A in combination with gemcitabine and nab-paclitaxel (mGnP) or in combination with modified FOLFIRINOX (mFFX) for patients with PDAC

[0149] In this example, a method of treating pancreatic cancer with Compound A is provided. Specifically, in this example, methods of treating pancreatic ductal adenocarcinoma (PDAC) and other exocrine tumors with compound A are provided.

[0150] Table 9 provides a summary of prior clinical trials for the treatment of pancreatic cancer.Table 9. Pancreatic Cancer Clinical Trials

[0151] Compound A is evaluated in a Phase l / 2a, multicenter, open-label, nonrandomized study to characterize the safety and anti -tumor activity of Compound AIMMU.028WO PATENT administered to participants with RAS-mutated or RAS / MAPK pathway activated advanced or metastatic solid tumors as monotherapy and in combination with approved agents. This is a Phase l / 2a, multicenter, open-label, nonrandomized study to characterize the safety and anti-tumor activity of Compound A administered to participants with RAS-mutated or RAS / MAPK pathway activated advanced or metastatic solid tumors as monotherapy and in combination with approved agents. This study is comprised of 2 phases, beginning with Phase 1 Dose Exploration (including monotherapy dose escalation and dose expansion stages, as well as cohorts designed to evaluate the safety and tolerability of Compound A in combination with approved agents) followed by Phase 2a featuring multiple proof-of-concept (POC) generating monotherapy and combination cohorts in malignancies of interest.

[0152] Participants are categorized into the following treatment groups (arms):• Treatment Group A: Compound A Monotherapy• Treatment Group B: Compound A in combination with modified gemcitabine and nab- paclitaxel (mGnP) in participants with previously untreated, unresectable advanced or metastatic PDAC• Treatment Group C: Compound A in combination with modified FOLFIRINOX (mFFX) in participants with previously untreated unresectable advanced or metastatic PDAC

[0153] Once adequate Compound A monotherapy safety and tolerability data are collected and evaluated, dose escalation cohorts evaluating the safety, tolerability, and PK of Compound A in combination with approved agents is initiated for enrollment in Treatment Groups B and C. In some aspects, the dose of Compound A to be used in combination with the anti-cancer treatments represented in Treatment Groups B and C is 320 mg QD. In addition, Compound A can also be administered in combination with these agents, at 240 mg QD, one dose level lower.

[0154] In addition, methods of treatment can include the administration of Compound A in combination with mGnP or mFFX. Approximately 30 participants per indication cohort can be enrolled, based on a cohort-specific Simon’s 2-stage design.

[0155] Monotherapy Compound A is administered in a once-daily regimen for up to twelve 28-day cycles (48 weeks). If multiple daily dose regimens are pursued (e.g., BID), the total daily dose administered will not exceed the highest tolerable QD dose evaluated to date.

[0156] In some methods of treatment, Compound A is administered in combination with approved anti-cancer agents, and Compound A is administered once-daily at the dose thatIMMU.028WO PATENT optimally displays DCI, while the combination agents will be administered in commonly used modified regimens that maintain effectiveness while reducing chemotherapy-related toxicides. Combination treatment continues until PD (radiographic or clinical) or other treatment discontinuation criteria are met. Individual components of the chemotherapy regimens can be discontinued if necessary to manage toxicides known to be associated with the agent(s). Likewise, if the entire chemotherapy regimen must be discontinued due to intolerability, participants may continue to receive Compound A as monotherapy until PD or other treatment discontinuation criteria are met. Similarly, participants who achieve a disease response of sufficient depth and duration that may warrant cessation of the approved agents may continue to receive maintenance Compound A until PD or other treatment discontinuation criteria are met. Other recognized maintenance regimens in combination with Compound A may be allowed with approval from the Sponsor MM.

[0157] Treatment will be administered in an inpatient or outpatient setting, as deemed appropriate by the Investigator and / or per discussion with the Sponsor. Participant safety will be monitored throughout the study by an SRC established by the Sponsor.

[0158] In this example, methods of treatment comprise the administration of Compound A in combination with gemcitabine for the treatment of pancreatic adenocarcinoma in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, a gemcitabine-based regimen in Table 3.

[0159] In this example, methods of treatment comprise the administration of Compound A in combination with oxaliplatin and / or fluorouracil for the treatment of pancreatic adenocarcinoma in a patient in need thereof. In one aspect, a method of treating pancreatic adenocarcinoma comprises administering to the patient in need thereof Compound A in combination with, before or after, a fluoropyrimidine-based regimen in Table 4A, a FOLFIRINOX regimen in Table 4B or Table 4C.IMMU.028WO PATENTEXAMPLE 5Preliminary phase 1 safety and activity of Compound A, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumorsBackground:

[0160] About 33% of tumors exhibit activating RAS mutations, making it a significant target for cancer therapy. MEK inhibitors disrupt RAS downstream signaling, but earlier inhibitors have been associated with significant toxicities. Compound A, a MEK inhibitor, inhibits both MEK and ERK phosphorylation, thereby preventing CRAF bypass and hyperactivation of MEK. With a short half-life of 2 hours and once daily dosing (QD), Compound A facilitates deep, pulsatile inhibition of the MAPK pathway at MEK, a process termed Deep Cyclic Inhibition (DCI). This mechanism improves safety and tolerability by allowing daily pathway recovery in healthy tissues while limiting adaptive resistance in tumor cells.Methods:

[0161] A first-in-human Phase 1 study of Compound A was conducted across five U.S. sites. The primary objective was to assess the safety, tolerability and to establish the recommended Phase 2 dose of Compound A in patients with advanced, RAS-mutated solid tumors. A rapid dose escalation scheme was employed with broad inclusion criteria. The study evaluated pharmacokinetics (PK), pharmacodynamics (PD), (circulating tumor DNA) ctDNA, ex vivo pERK, and initial clinical efficacy.Initial Results:

[0162] The Phase 1 study enrolled 45 subjects, including 30 with pancreatic ductal adenocarninoma (PDAC), 5 with colorectal cancer, 5 with lung cancer, 2 with melanoma, 1 with cholangiocarcinoma plus 2 other cancers. Two candidate optimal doses, 240 mg and 320 mg QD, were evaluated and supported DCI of the MAPK pathway. Treatment-related adverse events (TRAEs) occurring in >10% of patients were transient and limited mainly to grade 1 or 2. No doselimiting toxicities or serious TRAEs were reported. Early signs of clinical activity in a heavily pretreated, advanced metastatic patient population were promising. Paired CT scans (32) andIMMU.028WO PATENT ctDNA analyses (27) revealed the following: (1 .) 21 patients (66%) had a RECIST sum of longest diameters (SLD) < 20%, and 8 patients (25%) had an SLD < 0%; (2.) 13 patients (41%) exhibited regression in at least one target lesion (ranging from -4.8% to -50.0%); (3.) reductions in mean ctDNA levels were observed in 9 patients (33%), with decreases ranging from-24% to -81%; and (4.) no new RAS variants emerged in ctDNA.Updated Results:

[0163] The phase 1 study enrolled 54 subjects, including 34 PDAC, 8 colorectal, 5 lung, 2 melanoma, 2 appendiceal, 1 cholangiocarcinoma plus 2 others. The evaluation of two candidate optimal doses, 240 and 320 mg QD, supported DCI of the MAPK pathway. Treatment- related adverse events (TRAEs) occurring in >10% of patients were transient and limited mainly to grade 1 or 2, when observed. No DLTs or serious TRAEs were noted. Although RECIST responses were not observed nor an endpoint of Phase 1, promising signs of clinical activity in heterogeneous, heavily pretreated, advanced metastatic patients were evident. Paired CT scans (40) and ctDNA (36) revealed: (1.) 27 (68%) had SLDs < 20%, 9 (23%) had SLDs 0% to -25%, (2.) 15 (38%) had > 1 target lesion regression (-2.0% to -66.7%), (3.) mean ctDNA reductions were observed in 13 (36%) patients (-3% to -81%), (4.) no new mutation variants in RAS ctDNA and (5.) dose-dependent inhibition ex vivo pERKl. A summary of the total treated patients is described in Table 10.

[0164] Compound A safety data suggests that deep cyclic inhibition (DCI) of MEK is well tolerated at doses up to 240 and 320 mg QD po, where Cmax drug free fractions typically exceeded 1,000 nM followed by daily, near-zero drug troughs. DCI was designed to maximally inhibit the MAPK pathway at MED in a pulsatile fashion.Table 10IMMU.028WO PATENT* = 54 treated patients also included 1 patient treated at 40 mg QD pO, 1 patient treated at 80 mg po and 3 patients treated at 160 mg QD po.** = All treatment-related adverse events (TRAE’s), regardless of occurrence frequency or grade, were reversible and deemed non-serious*** = preferred terms including in the rash term include dermatitis acneiform, photosensitivity reaction, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular

[0165] FIG. 5A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 5B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 5C is a graph showing ctDNA measurements for KRAS G12V from a patient in a Phase 1 clinical trial treated with Compound A.

[0166] FIG. 6A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 6B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 6C is a graph showing ctDNA measurements for KRAS G12D and NRAS G13D from a patient in a Phase 1 clinical trial treated with Compound A.

[0167] FIG. 7A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 7B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 7C is a graph showing ctDNA measurements for KRAS G12D from a patient in a Phase 1 clinical trial treated with Compound A.

[0168] FIG. 8A is a bar graph showing RECIST SLD (mm) for target lesions from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 8B is a graph showing CA-19-9 measurements from a patient in a Phase 1 clinical trial treated with Compound A. FIG. 8C is a graph showing ctDNA measurements for KRAS G12D from a patient in a Phase 1 clinical trial treated with Compound A.IMMU.028WO PATENTPhase 1 Case Study: Patient 1 (KRAS G12V PDAC)

[0169] Patient 1 is a 66-year-old Hispanic male diagnosed with metastatic pancreatic cancer (adeno), who received 6 prior lines of treatment (stable disease). The sixth line of treatment was IFL. The patient was then treated with 240 mg QD po of Compound A for 97 days, resulting in stable disease (> 20% SLD).Phase 1 Case Study: Patient 2 (KRAS G12D PDAC)

[0170] Patient 2 is a 74-year-old Asian male diagnosed with metastatic pancreatic cancer (adeno), who received FOLFIRINOX as a prior line of treatment (partial response). The patient was then treated with 320 mg QD po of Compound A for 55 days. The NRAS mutation was identified and eliminated in Patient 2.Phase 1 Case Study: Patient 3 (KRAS G12D PDAC)

[0171] Patient 3 is a 64-year-old Caucasian male diagnosed with metastatic pancreatic cancer (adeno), who received FOLFIRINOX as a prior line of treatment (stable disease). The patient was then treated with 320 mg QD po of Compound A for 84 days, resulting in lesions regressing and 6-8 hours of pain relief.Phase 1 Case Study: Patient 4 (KRAS G12D PDAC)

[0172] Patient 4 is a 70-year-old Caucasian male diagnosed with metastatic pancreatic cancer (adeno), who received FOLFIRINOX as a first line of treatment (progressive disease) and a combination of gemcitabine / cisplatin / nab-paclitaxel as a second line therapy (progressive disease). The patient was then treated with 240 mg QD po of Compound A for over 150 days, resulting in improved quality of life (QoL) and 7% weight gain, and reduction of CA-19-9 levels and reduction in ctDNA for KRAS G12D. Quality of Life (QoL) was assessed by overall improvement on Functional Assessment of Anorexia / Cachexia Treatment (FAACT) questionnaire (v4) (DOI: 1016670403148)Conclusions:IMMU.028WO PATENT

[0173] Compound A, targeting MAPK-pathway addicted tumors at MEK with through a novel DCI approach, was well tolerated and demonstrated both lesion and molecular level responses as a monotherapy in a heavily pretreated Phase 1 patient population. Phase 2a studies are currently underway.

[0174] Compound A is a short-lived dual MED inhibitor (MEKi) that is resistant to CRAF-bypass and has a unique pulsatile pharmacokinetic and pharmacodynamic mechanism (i.e., DCI MEKi). The primary objective of the Phase 1 clinical trial was to evaluate safety, tolerability and to identify a candidate recommended phase 2 dose (RP2D). A candidate RP2D was identified with a highly differentiated safety and tolerability profile. Pharmacodynamic inhibition of pERK upon testing human plasma samples ex vivo exceeded 90% at Cmax for most patients dosed at 240 or 320 mg QD po, providing optimal Compound A DCI MEKi profiles. Antitumor activity was observed at both 240 and 320 mg QD po, as evidenced by deepening RECIST target lesion regressions as well as reductions in CA 19-9 and relevant ctDNA biomarkers. Emerging clinical data suggest that Compound A (i.e., DCI MEKi) provides class-differentiated activity and tolerability that warrants further evaluation in both monotherapy and select combination therapies. Drug efficacy will be further evaluated in a Phase 2a clinical trial (NCT05585320), actively enrolling at 320 mg Compound A QD po monotherapy in melanoma, lung and pancreatic cancer, and at 240 or 320 mg Compound A QD po of Compound A plus gemcitabine- or fluorouracilcontaining chemotherapy in first-line pancreatic cancer patients.EXAMPLE 6Preliminary phase 2a clinical trial of Compound A in Pancreatic Cancer

[0175] The method of treatment using Compound A was designed to achieve universal- RAS inhibition, selectively targeting cancer cells more than healthy cells through Deep Cyclic Inhibition (DCI) of the MAPK pathway with once-daily dosing. Compound A is currently under investigation in a Phase l / 2a study targeting patients with advanced solid tumors that exhibit RAS mutations, detailed in clinical trial NCT05585320.

[0176] In certain formulations, Compound A was administered alongside gemcitabine / nab-paclitaxel for treating pancreatic cancer. Benchmarks established by the Phase 3 MP ACT study for first-line treatment with gemcitabine / nab-paclitaxel in pancreatic cancer patients included one complete response (CR) out of 431 patients, a 23% overall response rate,IMMU.028WO PATENT and a 48% disease control rate (Von Hoff et al., N Engl J Med 2013;369: 1691-1703). A modified regimen of gemcitabine / nab-paclitaxel has demonstrated an 18.6% overall response rate (Ahn DH, et al. Therapeutic Advances in Medical Oncology. 2017;9(2):75-82).

[0177] This example, and as described generally, herein, details findings from the Phase 2a segment of a clinical trial evaluating Compound A in combination with modified gemcitabine / nab-paclitaxel. Initial results showed complete or partial responses in the first two out of five treated patients, reflecting an initial response rate of 40% and an initial disease control rate of 80%. Treatment continues for all five patients. These early outcomes were from dosages of either 240 mg QD or 320 mg QD of Compound A. The combination of Compound A with modified gemcitabine / nab-paclitaxel were well-tolerated, aligning with the existing safety profiles of the individual treatments.

[0178] Compound A is an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors.

[0179] In this example, Compound A was administered to patients diagnosed with pancreatic cancer, such as patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). In general, more than 90% of PDAC patients display mutation in RAS and / or activation of the MAPK pathway. There is a high unmet clinical need in metastatic setting with very limited options for patients. The preclinical and translational data obtained with Compound A support monotherapy and combination opportunities. The Phase 1 Compound A clinical trial sites included many patients with Gl-tumor diagnoses (including patients diagnosed with PDAC). A total of 20 patients diagnosed with KRAS mutated PDAC were treated with 320 mg QD of Compound A in a Phase 2 clinical trial. The treated patients had the following KRAS mutations: Q61R (2 patients), G12D (3 patients), G12R (4), and G12V (11). Initial treatments showed stable disease after 1 scan (1 patient), progressive disease after 2 scans ( 1 patient) or progressive disease after 1 scan (2 patients).

[0180] The first two patients in the Phase 2a arm evaluating Compound A with modified gemcitabine / nab-paclitaxel in first line pancreatic cancer have recorded complete or partial responses for an initial response rate of 40% (2 / 5) and disease control rate of 80% (4 / 5), with the other three patients earlier in the course of treatment and all five continuing on treatment.

[0181] One patient diagnosed with KRAS G12D PDAC having a total SLD of 186mm (baseline) was treated with 240 mg QD Compound A, resulting in a total SLD reduction of -11.8%IMMU.028WO PATENT in Scan 1, -17.2% SLD reduction in Scan 2, -22.0% SLD reduction in scan 3 and -25% SLD reduction in Scan 4. Prior to treatment with Compound A, this patient received FOLFIRINOX as a first line treatment, and a combination of gemcitabine cisplatin and nab-paclitaxel as a second line therapy, followed by 240 mg QD of Compound A po.

[0182] In this example, patients diagnosed with PDAC receive treatment with Compound A. Compound A or a pharmaceutically acceptable salt thereof is orally administered once daily (QD), at a dose of 160 mg, 240 mg, or 320 mg of Compound A. Table 11 shows initial results from a Phase 2a arm evaluating Compound A in combination with modified gemcitabine / nab-paclitaxel in first line pancreatic cancer patients.Table 11- prior adjuvant treatment** - the scans were conducted about 6 weeks apart from each other

[0183] The patients diagnosed with PDAC receive treatment with a combination of Compound A and a combination of gemcitabine and nab-paclitaxel. Compound A or aIMMU.028WO PATENT pharmaceutically acceptable salt thereof is orally administered once daily (QD) in combination with gemcitabine and nab-paclitaxel, at a dose of 240 mg of Compound A, or at a dose of 160 mg of Compound A per day. The phase 2a protocol employs a modified gemcitabine + nab-paclitaxel (mGnP) regimen where the combination therapy of gemcitabine / nab-paclitaxel chemotherapy is administered on Day 1 and Day 15 of each 28-day cycle as follows:1. Nab-paclitaxel 125 mg / m2via IV infusion over 30 min, followed immediately by,2. Gemcitabine 1000 mg / m2via IV infusion over 30 min.3. Then, starting on day 2, Compound A is dosed daily at 240 mg via oral administration.

[0184] In this example, patients diagnosed with PDAC receive treatment with a combination of Compound A and a combination of gemcitabine and nab-paclitaxel. Compound A or a pharmaceutically acceptable salt thereof is orally administered once daily (QD) in combination with gemcitabine and nab-paclitaxel, at a dose of 240 mg of Compound A, or at a dose of 160 mg of Compound A per day.

[0185] In this example, patients diagnosed with PDAC receive first line treatment with a combination of Compound A and a FOLFIRINOX combination chemotherapy. Compound A or a pharmaceutically acceptable salt thereof is orally administered once daily (QD), at a dose of 240 mg of Compound A, or at a dose of 320 mg of Compound A per day. In this example, patients diagnosed with PDAC receive second line treatment with Compound A as a monotherapy. Compound A was orally administered once daily (QD), at a dose of 240 mg or 160 mg of Compound A per day. Table 12 is a list of patients who received a combination of Compound A with a combination therapy of modified FOLFIRINOX therapy (Patient 010 had a DPD deficiency resulting in inadequate 5FU metabolism, received a reduce dose of 16 mg of Compound A QD and then came off treatment). FOLIFIRINOX is a multi-agent chemotherapy regiment composed of the alkylating agent oxaliplatin, the topoisomerase I inhibitor irinotecan, the antimetabolite fluorouracil, and leucovorin, a folic acid analogue given to potentiate the activity of fluorouracil. This protocol will employ a modified FOLFIRINOX (mFFX) regimen where the chemotherapy will be administered on Day 1 and Day 15 of each 28-day cycle for up to 6 cycles, as follows:1. Oxaliplatin 85 mg / m2via IV infusion over 2 h2. Folinic acid (leucovorin) 400 mg / m2via IV infusion over 2h3. Irinotecan 150 mg / m2via IV infusion over 90 minIMMU.028WO PATENT4. Fluorouracil 2400 mg / m2continuous IV infusion given via home-infusion pump over 46 hours beginning Day 1 and ending on Day 3Table 12- prior adjuvant treatmentEXAMPLE 7Preliminary phase 2a clinical trial of Compound A in Melanoma

[0186] In the Phase 2a, Compound A was evaluated as both monotherapy and in combinations with select approved chemotherapeutic agents. The Phase 2a portion of the clinical trial included an arm focused on RAS mutant melanoma. In this example, Compound A was administered to patients diagnosed with melanoma, such as patients diagnosed with RAS-mutated melanoma. Patients diagnosed with NRAS mutated PDAC were treated with 320 mg QD of Compound A in a Phase 2 clinical trial. The initially treated patients had the following NRAS mutations: Q61H (1 patient), Q61R (3 patients), Q61K (1 patient), and G12V (1 patient). Initial treatments showed stable disease after 1 scan (1 patient), or progressive disease after 1 scan (1IMMU.028WO PATENT patient), with remaining scans pending. Table 13 shows initial results from a Phase 2a arm evaluating Compound A in as monotherapy in treating melanoma cancer patients.Table 13* - dose reduced from 320mg QD to 240 mg QD after 4 weeks (first scan at 4 weeks with SLD - 5%); dose further reduced to 160 mg.EXAMPLE 8Preliminary phase 2a clinical trial of Compound A in Lung Cancer

[0187] In the Phase 2a, Compound A was evaluated as both monotherapy and in combinations with select approved chemotherapeutic agents. The Phase 2a portion of the clinical trial included an arm focused on RAS mutant non-small cell lung cancer (NSCLC). In this example, Compound A was administered to patients diagnosed with lung cancer, such as patients diagnosed with RAS-mutated NSCLC. Patients diagnosed with KRAS mutated NSCLC were treated with 320 mg QD of Compound A in a Phase 2 clinical trial, including patients having the following KRAS mutations: G12D (1 patient), F156L (1 patient), G13A (1 patient) and G12F (1 patient). Initial treatments showed stable disease after 1 scan (3 patients). Table 14 shows initial results from a Phase 2a arm evaluating Compound A as monotherapy in treating NSCLC cancer patients.Table 14IMMU.028WO PATENTEXAMPLE 9Case Study of Compound A administered Patient 001 in Phase 2a clinical trial study Patient Summary:

[0188] Patient 001 is a 45-year-old female who was diagnosed with primary adenocarcinoma of the head of the pancreas with metastatic disease to the biliary tract (mPDAC).

[0189] Past Medical / Oncology History: Past medical history was notable for placement of biliary and hepatic stents due to bile obstruction by the primary tumor, infection due to the stents in right upper quadrant pain, back pain, constipation and vomiting.

[0190] Participation in Compound A clinical trial: The patient consented to enroll in study Compound A Phase 2a - group B safety lead-in with modified Gemcitabine plus nab- Paclitaxel (mGnP) plus Compound A starting on Day 1. The treatment and schedule for modified Gemcitabine plus nab-Paclitaxel (mGnP) in combination with Compound A is detailed below. The first cycle of chemotherapy was administered on 06 / Mar / 2024 and the first dose of Compound A was administered on Day 23. On Day 29, all medications had to be held until Day 32 due to Grade 2 elevation of ALT and AST which was caused by the obstruction of the stent. On Day 32, the ALT and AST were grade 1, thus the Compound A was restarted at dose of 160 mg daily until Day 36, when the patient went back to full dose of 240 mg daily of Compound A. The patient continued therapy and has not had any other dose interruptions or reductions. The only adverse event the patient experienced related to Compound A was grade 1 abdominal cramping from Day 29 to Day 47.IMMU.028WO PATENT

[0191] Scan Data: At baseline, the patient was noted to have one target lesion (20 mm lesion in the head of the pancreas) and no non-target lesions were identified. The first on-treatment scan was completed on Day 70 and this showed a complete regression of the target lesion and was an overall complete response per RECIST vl.l. The second on-treatment scan was completed on Day 113 and this confirmed that the lesion was no longer visible and was also determined to be a complete response. mGnP:

[0192] The phase 2a Compound A protocol employs a modified gemcitabine + nab- paclitaxel (mGnP) regimen where chemotherapy is administered on Day 1 and Day 15 of each 28- day cycle as follows:1. Nab-paclitaxel 125 mg / m2via IV infusion over 30 min, followed immediately by,2. Gemcitabine 1000 mg / m2via IV infusion over 30 min.3. Then, starting on day 2, Compound A is dosed daily at 240 mg via oral administration.

[0193] In the event that one of the chemotherapy components must be discontinued due to toxicities, treatment with the remaining agent may be continued in combination with Compound A.EXAMPLE 10Phase 1 Interim Population PK / PD Modeling and Recommended Phase 2 Dose Exploration for Compound A, A Novel Concept Oral Deep Cyclic Inhibitor of MEKIntroduction

[0194] Activating RAS mutations are present in a third of all cancers. Approved MEK inhibitors are designed to chronically inhibit the downstream signaling of RAS-RAF-MEK-ERK, causing significant toxicity. The first-in-human Study Compound A recently completed Phase 1 dose expansion, and the current PK / PD analysis was aimed at identifying Phase 2 dosing regimens that achieve the desired DCI pattern in targeted patient populations (advanced solid tumors with high prevalence of RAS mutations, e.g., pancreatic, lung, melanoma).Objective

[0195] To provide dose justification and inform on Compound A efficacy in patients, by developing a population PK model of Compound A that describes the relationship betweenIMMU.028WO PATENTCompound A exposure and phosphorylated mitogen-activated protein kinase (p-MEK) and extracellular signal -regulated kinase (p-ERK).Data / Methods

[0196] Pharmacokinetic (PK) sampling was conducted under fasted conditions on Cycle 1, Day 1 (C1D1) and Cycle 1, Day 15 (C1D15). Samples were collected at various time points: pre-dose and then 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours post-dose. Pharmacodynamic (PD) sampling was also performed on CID 1 and CID 15, with samples taken at pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose. The ex vivo surrogate PD endpoint was the inhibition of MEK and downstream ERK phosphorylation in the A549 (KRAS-G12S) cell line, quantified by the ratio of phosphorylated kinase to total kinase.

[0197] For the population modeling analyses of PK and PD data for Compound A — specifically for phosphorylated (p)-ERK / total (t)-ERK and p-MEK / t-MEK — NONMEM® version 7.5.3 was used. In establishing the base model for Compound A PK, various absorption models were evaluated, incorporating weight (WT) as a mechanistic covariate. Further, exploratory covariates such as demographic characteristics, disease manifestation and severity, and comedication were investigated to enhance model robustness.

[0198] Population models were developed to describe the effects of Compound A exposure on p-ERK / t-ERK and p-MEK / t-MEK. These final models enabled simulation of p- ERK / t-ERK and p-MEK / t-MEK responses, including the median and 90% prediction intervals (PI) across different dose groups. This modeling helped assess the time from nadir to return to 20% of the maximum phospho-protein reduction, supporting dose optimization and efficacy predictions.Compound A Phase 1 Data Visualization. PK & PD

[0199] FIG. 9A and FIG. 9B (Compound A PK) depict graphs showing plasma concentration values were available for 45 subjects (1 subject at 40 mg, 1 subject at 80 mg, 3 subjects at 160 mg, 19 subjects at 240 mg and 21 subjects at 320 mg), the majority of whom have metastatic pancreatic cancer. Profiles of individual observations versus time suggest a rapid, complex and highly variable absorption profile. The exposure appears not to increase proportionally with dose, as shown with dose- normalized concentrations. FIG. 9A depicts a graphIMMU.028WO PATENT of individual observed Compound A plasma concentrations versus time after dose (semi- logarithmic scale). FIG. 9B depicts a graph of dose-normalized individual observed Compound A plasma concentrations versus time after dose after 240 or 320 mg (semi-logarithmic scale). Thick lines represent the GAM smooth of the data in each dose level. Caveat: Compound A dissolution is sensitive to stomach pH. While use of acid-reducing agents was restricted, there were some unusually low PK exposures that may have influenced modelling assessments.

[0200] FIG. 10A and FIG. 10B depict the (p-ERK / t-ERK) observations that were available for 45 subjects across various dose groups: One subject at 40 mg, one subject at 80 mg, three subjects at 160 mg, 19 subjects at 240 mg, and 21 subjects at 320 mg. Profiles of individual observations versus time suggest a rapid and direct exposure-effect relationship. FIG. 10A depicts a semi-logarithmic graph of individual observed absolute value versus time post-dose. FIG. 10B depicts a logarithmic scale graph of individual observed values plotted versus individual observed plasma concentrations of Compound A.

[0201] FIG. 11 A and FIG. 1 IB depict the p-MEK / t-MEK observations collected from 12 subjects across different dose groups: 1 subject at 40 mg, 1 subject at 80 mg, 3 subjects at 160 mg, 3 subjects at 240 mg and 4 subjects at 320 mg). Profiles of individual observations versus time suggest a rapid and direct exposure-effect relationship. FIG. 11 A depicts a semi-logarithmic graph of individual observed absolute value versus time post dose. FIG. 1 IB depicts a logarithmic scale graph of individual observed values plotted versus individual observed plasma concentration of Compound A.Population PK Modeling

[0202] PK modeling data for Compound A was obtained using a two-compartment model with absorption transit compartments, as shown in the schematic of FIG. 12A. Weightbased allometric scaling was applied to the clearance and distribution volume parameters to improve model accuracy, and a dose effect on bioavailability was incorporated to account for a potential less-than-dose-proportional increase in exposure.

[0203] FIG. 12B depicts a graph of prediction-corrected visual predictive check of Compound A PK plasma concentrations versus time post-dose, C1D1, using a semi-logarithmic scale. FIG. 12C is a graph of prediction-corrected visual predictive check of Compound A PK plasma concentrations versus time post-dose, CID 15, using a semi -logarithmic scale.IMMU.028WO PATENTPK / PD Modeling

[0204] Maximal target engagement, as indicated by inhibition, was generally achieved at approximately 1 hour post-dose (the first PD time point) and returned to baseline levels of p- ERK or p-MEK between 8 and 24 hours. A direct model with a proportional inhibitory effect on baseline levels was used, informed by observed plasma concentrations.

[0205] FIG. 13 A depicts a graph of a prediction-corrected visual predictive check of p-ERK / t-ERK versus time post-dose, at CID 1, shown on a semi -logarithmic scale. FIG. 13B is a graph of prediction-corrected visual predictive check of p-MEK / t-MEK (right) versus time after Dose, at CID 1 (semi-logarithmic scale).

[0206] FIG. 14 depicts a graph of populations simulations of Compound A plasma concentrations (ng / mL) versus time (h). Solid lines show the median concentration and shaded areas the 90% prediction interval. The dotted, dashed and solid black lines represent the ICso, ICso and IC90 values at 82.2 ng / mL, 329 ng / mL and 740 ng / mL, respectively.Table 14

[0207] FIG. 15 depicts a graph of populations simulations of phospho:total ERK (% baseline) versus time (h) on a linear scale for the different dose groups. Solid lines are colored by treatment group. The dashed black line represents 20% of maximum reduction.IMMU.028WO PATENTTable 15Conclusions

[0208] For the candidate doses of 240 mg and 320 mg explored in accordance with FDA Optimus guidance, plasma concentrations are predicted to remain above the pERK IC90 for an average of 2.7 and 2.8 hours, respectively (see FIG. 14). The majority of subjects — 90% at 240 mg QD and 88% at 320 mg QD — are predicted to experience less than 20% of maximum inhibition at the daily drug trough (FIG. 15). PK / PD modeling, together with Phase 1 safety and activity data, supports that both 240 mg and 320 mg doses are viable options to promote durable clinical inhibition (DCI) of the MAPK pathway.

[0209] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

IMMU.028WO PATENTWHAT IS CLAIMED IS:

1. Use of atebimetinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pancreatic cancer, wherein said medicament is for oral administration once per day (QD) in a total dose providing 320 mg of atebimetinib, wherein the treatment optionally comprises administration of a chemotherapy, or wherein the treatment optionally comprises administration of an immune checkpoint inhibitor for the treatment of melanoma in, or wherein the treatment optionally comprises administration of a G12C inhibitor therapy to treat non-small cell lung cancer (NSCLC), wherein the chemotherapy consists of a modified gemcitabine and nab-paclitaxel chemotherapy (mGnP) or a modified FOLFIRINOX chemotherapy (mFFX), wherein:(a) the mGnP chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 125 mg / m2nab-paclitaxel via IV infusion over 30 min to the patient in need thereof, followed immediately by, administering 1000 mg / m2gemcitabine to the patient in need thereof via IV infusion over 30 min, the mGnP; and(b) the mFFX chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2 oxaliplatin to the patient in need thereof via IV infusion over 2 hours; in combination with administering 150 mg / m2 irinotecan via IV infusion over 90 min; and further administering 2,400 mg / m2 fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle; and wherein the immune checkpoint inhibitor is an anti-PD-1, anti-PD-Ll or anti- CTLA-4 immunotherapeutic.

2. A method of treating pancreatic cancer, melanoma or non-small cell lung cancer (NSCLC) in a patient in need thereof, the method comprising: orally administering atebimetinib, or a pharmaceutically acceptable salt thereof, to the patient in need thereof once per day (QD) in a total dose providing 320 mg ofIMMU.028WO PATENT atebimetinib, optionally in combination with a chemotherapy to treat the pancreatic cancer in the patient in need thereof, or optionally in combination with an immune checkpoint inhibitor to treat the melanoma in the patient in need thereof, or optionally in combination with a G12C inhibitor therapy to treat the NSCLC in the patient in need thereof, wherein the chemotherapy consists of a modified gemcitabine and nab-paclitaxel chemotherapy (mGnP) or a modified FOLFIR1NOX chemotherapy (mFFX), wherein:(a) the mGnP chemotherapy consists of administering nab-paclitaxel and gemcitabine to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle, and(b) the mFFX chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2 oxaliplatin to the patient in need thereof via IV infusion over 2 hours; in combination with administering 150 mg / m2 irinotecan via IV infusion over 90 min; and further administering 2,400 mg / m2 fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle, and wherein the immune checkpoint inhibitor is an anti-PD-1, anti-PD-Ll or anti- CTLA-4 immunotherapeutic.

3. The use of claim 1 or the method of claim 2, wherein the patient is treated with atebimetinib in combination with the chemotherapy to treat an adenocarcinoma pancreatic cancer (PDAC) in the patient in need thereof.

4. The use or the method of claim 3, wherein the patient is treated with the mGnP chemotherapy consisting of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 125 mg / m2nab-paclitaxel to the patient in need thereof, in combination with the gemcitabine to the patient in need thereof.

5. The use or the method of claim 4, wherein the mGnP chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 125 mg / m2nab-paclitaxel via IV infusion over 30 min to the patient in need thereof,IMMU.028WO PATENT followed immediately by, administering 1000 mg / m2gemcitabine to the patient in need thereof via IV infusion over 30 min.

6. The use or method of claim 3, wherein the pancreatic cancer has a RAF or RAS mutation.

7. The use or method of claim 6, wherein the RAS mutation is a KRAS, HRAS or NRAS mutation.

8. The use or method of claim 7, wherein the pancreatic cancer has a KRAS mutation selected from the group consisting of: a G12C, G12D, G12A, G12R, G12S, G12V, Q61 or G13 mutation.

9. The use or method of claim 8, wherein the KRAS mutation is a G12D mutation.

10. The use or method of claim 8, wherein the KRAS mutation is a G12V mutation.

11. The use or the method of claim 3, wherein the patient is treated with the mFFX chemotherapy consisting of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2oxaliplatin to the patient in need thereof; in combination with administering 150 mg / m2irinotecan; and further administering 2,400 mg / m2fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle.

12. The use or the method of claim 11, wherein the patient is treated with the mFFX chemotherapy consisting of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2oxaliplatin to the patient in need thereof via IV infusion over 2 hours; in combination with administering 150 mg / m2irinotecan via IV infusion over 90 min; and further administering 2,400 mg / m2fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle.

13. The use or method of claim 12, wherein the pancreatic cancer has a RAF or RAS mutation.IMMU.028WO PATENT14. The use or method of claim 13, wherein the pancreatic cancer has a KRAS, HRAS or NRAS mutation.

15. The use or method of claim 14, wherein the pancreatic cancer has a KRAS mutation selected from the group consisting of: a G12C, G12D, G12A, G12R, G12S, G12V, Q61 or G13 mutation.

16. The use or method of claim 15, wherein the KRAS mutation is a G12D mutation.

17. The use or method of claim 8, wherein the KRAS mutation is a G12V mutation.

18. The use of claim 1 or the method of claim 2, wherein the patient is treated with atebimetinib to treat the melanoma in the patient in need thereof.

19. The use or method of claim 18, wherein the melanoma has a RAS or RAF mutation.

20. The use or method of claim 19, wherein the melanoma has a NRAS, HRAS or KRAS mutation.

21. The use or method of claim 20, wherein the melanoma has a NRAS Q61R, Q61K, Q61H, G13R, G12D, or G13D mutation, or a HRAS Q61K mutation or a KRAS G12C, G12D, G12A, G12R, G12S, G12V, or Q61 mutation.

22. The use or method of claim 19, wherein the method further comprises administering the atetbimetinib in combination a BRAF inhibitor to treat the melanoma.

23. The use or method of claim 22, wherein the melanoma has BRAF V600E or V600K mutation.

24. The use or method of claim 23, wherein the BRAF inhibitor is encorafenib.

25. The use of claim 1 or the method of claim 2, wherein the patient is treated with atebimetinib in combination with the immune checkpoint inhibitor (ICI) to treat the melanoma in the patient in need thereof.IMMU.028WO PATENT26. The use or method of claim 25, wherein the ICI is nivolumab, atezolizumab, ipilimumab, pembrolizumab, durvalumab, relatlimab or cemiplimab.

27. The use or method of claim 25, wherein the melanoma has a RAF or RAS mutation.

28. The method of claim 27, wherein the melanoma has a NRAS Q61R, Q61K, Q61H, G13R, G12D, or G13D mutation, or a HRAS Q61K mutation or a KRAS G12C, G12D, G12A, G12R, G12S, G12V, or Q61 mutation, or a BRAF V600E or V600K mutation.

29. The use of claim 1 or the method of claim 2, wherein the patient is treated with atebimetinib to treat the NSCLC in the patient in need thereof.

30. The use or method of claim 29, wherein the NSCLC has a RAS mutation.

31. The use or method of claim 30, wherein the NSCLC is a KRAS G12C, G12D, G12A, G12R, G12V, Q61, or G13 mutated NSCLC.

32. The method of claim 31, wherein the cancer is a KRAS G12C mutated NSCLC.

33. The use or method of claim 29, wherein the atebimetinib is administered in combination with a G12C inhibitor therapy to treat the NSCLC in the patient in need thereof.

34. The use or method of claim 33, wherein the atebimetinib is administered in combination with sotorasib or adagrasib to treat the NSCLC in the patient in need thereof.

35. The use or method of claim 31, wherein the atebimetinib is administered in combination with a G12C inhibitor therapy to treat the NSCLC in the patient in need thereof.

36. A method reducing CA-19-9 measurements in a patient diagnosed with pancreatic cancer, the method comprising administering atebimetinib (Compound A),IMMU.028WO PATENTatebimetinib (Compound A) or a pharmaceutically acceptable salt thereof, to the patient in need thereof once per day (QD) at a dose providing 320 mg of atebimetinib to the patient in need thereof.

37. The method of claim 36, wherein the pancreatic cancer has a KRAS mutation.

38. The method of claim 37, wherein the pancreatic cancer has a G12 KRAS mutation.

39. The method of claim 37, wherein the pancreatic cancer has a G12D or G12V KRAS mutation.

40. The method of claim 36, wherein the atebimetinib is administered in combination with a chemotherapy to treat the pancreatic cancer, wherein the chemotherapy consists of a modified gemcitabine and nab-paclitaxel chemotherapy (mGnP) or a modified FOLFIRINOX chemotherapy (mFFX), wherein(a) the mGnP chemotherapy consists of administering nab-paclitaxel and gemcitabine to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle; and(b) the mFFX chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2 oxaliplatin to the patient in need thereof via IV infusion over 2 hours; in combination with administering 150 mg / m2 irinotecan via IV infusion over 90 min; and further administering 2,400 mg / m2 fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle; andIMMU.028WO PATENT41 . The method of claim 40, wherein the atebimetinib is administered in combination with the mGnP chemotherapy to treat the pancreatic cancer.

42. The method of claim 41, wherein the pancreatic cancer has a KRAS mutation.

43. The method of claim 42, wherein the mGnP chemotherapy consists of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 125 mg / m2nab- paclitaxel via IV infusion over 30 min to the patient in need thereof, followed immediately by, administering 1000 mg / m2gemcitabine to the patient in need thereof via IV infusion over 30 min.

44. The method of claim 40, wherein the atebimetinib is administered in combination with the mFFX chemotherapy to treat the pancreatic cancer.

45. The method of claim 44, wherein the pancreatic cancer has a KRAS mutation.

46. The method of claim 45, wherein the patient is treated with the mFFX chemotherapy consisting of administering to the patient in need thereof only on days 1 and 15 of a 28-day treatment cycle: 85 mg / m2oxaliplatin to the patient in need thereof via IV infusion over 2 hours; in combination with administering 150 mg / m2irinotecan via IV infusion over 90 min; and further administering 2,400 mg / m2fluorouracil to the patient in need thereof over 46 hours beginning on Day 1 and ending on Day 3 of the 28-day treatment cycle.

47. The method of claim 36, wherein the pancreatic cancer has a GNAS mutation.

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