Combination of SERD for treating cancer

Abstract

The present specification relates to a method for treating a patient suffering from hormone receptor positive (HR +), human epidermal growth factor receptor 2 negative (HER2-), breast cancer, comprising administering to the patient in need thereof an oral selective estrogen receptor degrading agent (SERD) in combination with an AKT inhibitor or an mTOR inhibitor and / or a cyclin dependent kinase 4 / 6 inhibitor (CDK4 / 6i).

Description

Technical Field

[0001] This specification relates to the use of an oral SERD in combination with an AKT or mTOR and / or CDK4 / 6 inhibitor for treating cancers such as breast cancer. Background Art

[0002] Next-generation oral selective estrogen receptor degraders (ngSERDs) are intended to become the backbone endocrine therapy (ET) for patients with estrogen receptor (ER)-positive breast cancer by delivering a more potent blockade of ER signaling than existing therapies and addressing key mechanisms of resistance. Camizestrant (AZD9833) is an ngSERD for treating ER+ breast cancer, which has demonstrated selective ERα degradation, pure ER antagonism, and significant anti-tumor activity in both ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors, as well as encouraging clinical activity in early clinical trials.

[0003] ER+ breast cancer responds to therapies targeting ERα and CDK4 / 6 signaling in both the adjuvant and metastatic settings. To explore the potential of SERDs as backbone ET therapies, camizestrant was used in combination with palbociclib or abemaciclib in in vitro and in vivo models of CDK4 / 6 inhibitor-naive and resistant disease, mirroring the SERENA-1 and SERENA-4 clinical trials. A combinatorial benefit was observed in vitro in 3 parental ER+ breast cancer cell lines, and in addition, camizestrant plus abemaciclib showed activity in palbociclib-resistant cell lines, including those carrying CCNE1amp and RB1 deletions. In vivo, the combination of camizestrant and palbociclib or abemaciclib was well tolerated and promoted improved efficacy in ESR1wt and ESR1m PDX (“patient-derived xenograft”) tumor models relative to the camizestrant and CDK4 / 6 inhibitor monotherapy groups in the study.

[0004] ER+ positive breast cancer has a high incidence of alterations in the PI3K / AKT / PTEN pathway, which provides an opportunity for treatment with PI3K / AKT pathway inhibitors. When combined with the mTOR inhibitor everolimus and the AKT inhibitor capivasertib, the ngSERD camizestrant delivers enhanced efficacy in CTC-174, ESR1m, and PI3KCAm tumor models (i.e., models in which both estrogen receptor and PI3KCA carry mutations). Additionally, in both the PI3K wt and mutant pathways in PDX models, the combination with the AKT inhibitor capivasertib is more effective than single therapies at clinically relevant doses and schedules. These data demonstrate an interaction between PI3K pathway inhibition and the mechanism of action of camizestrant. Notably, in both the ESR1m PDX model and the ESR1wt PDX model, the combination of camizestrant and capivasertib was shown to be significantly more effective than the optimal dose of fulvestrant and capivasertib, indicating that the clinical benefit may derive from the use of camizestrant rather than the combination of fulvestrant and an AKT inhibitor.

[0005] Finally, the present specification also discloses the use of a triple combination of camizestrant, capivasertib, and palbociclib in palbociclib-resistant models representative of PI3KCA / AKT wt and mutant tumors. This strategy delivers robust efficacy in these models compared to single therapies and dual combinations. Regardless of genetic background, the camizestrant, capivasertib, and palbociclib triple combination results in durable regression at clinically achievable doses of all compounds. These preclinical data demonstrate the potential of SERDs such as camizestrant to be backbone ETs, with high combinability in vivo with CDK4 / 6, mTOR, and AKT inhibitors. The activity profiles of these combinations reveal opportunities to impact the care of patients with early and metastatic ER+ breast cancer by delivering benefits in a broad patient population, including those with ESR1wt tumors or ESR1m tumors, that are independent of PI3K pathway mutation status and are manifested in both CDK4 / 6i-naive and refractory patients. Summary of the Invention

[0006] The present specification provides a means of enhancing the anti-proliferative effect of SERD therapy in cancer (such as breast cancer) by utilizing a combination of SERD (such as ngSERD) with mTOR, AKT, and / or CDK4 / 6 inhibitors.

[0007] In one aspect, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

[0008] In one aspect, SERDs for treating cancer are provided, wherein the SERDs are administered in combination with the following:

[0009] - an AKT inhibitor or an mTOR inhibitor;

[0010] - a CDK4 / 6 inhibitor; or

[0011] - an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

[0012] The term "treatment" refers to at least partially alleviating, inhibiting, preventing, and / or ameliorating a disorder, condition, or disease (such as breast cancer). The term "cancer treatment" includes both ex vivo and in vivo treatment, including in warm-blooded animals (such as humans). The effectiveness of cancer treatment can be evaluated in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement of symptoms; duration of remission from treatment; delay of disease progression; and extension of survival. Treatment can also be evaluated based on the nature and extent of side effects associated with the treatment. In addition, effectiveness can be evaluated based on biomarkers, such as the expression or phosphorylation level of a protein known to be associated with a particular biological phenomenon. Other evaluations of effectiveness are known to those skilled in the art.

[0013] The phrase "in combination with" and similar terms encompass administering two or more active pharmaceutical ingredients to a subject and include simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. For triple combinations, a mixed administration in which two drugs are administered simultaneously and one drug is administered separately or sequentially from the other drugs is included in the foregoing definition.

[0014] In embodiments, the administration of the SERD and each inhibitor is separate, sequential, or simultaneous.

[0015] In embodiments, the administration of the SERD and each inhibitor is separate.

[0016] In embodiments, the administration of the SERD and each inhibitor is sequential.

[0017] In embodiments, the administration of the SERD and each inhibitor is simultaneous.

[0018] In another aspect, the use of SERDs in the manufacture of a medicament for treating cancer is provided, wherein the SERDs are administered in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

[0019] In another aspect, a method of treating cancer in an animal patient in need of such treatment is provided, the method comprising administering to the animal patient a therapeutically effective amount of a SERD, wherein the SERD is administered in combination with a therapeutically effective amount of an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

[0020] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo), or the subject to be treated and the disease condition (e.g., the weight, age and sex of the subject), the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to the dose that will induce a specific response in a target cell (e.g., an amount of apoptosis). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying the compound.

[0021] In another aspect, a method of treating cancer in an animal patient in need of such treatment is provided, the method comprising administering to the animal patient a therapeutically effective amount of a SERD, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

[0022] In another aspect, a method of treating cancer in an animal patient in need of such treatment is provided, the method comprising administering to the animal patient a first amount of a SERD, a second amount of an AKT inhibitor or an mTOR inhibitor, and a third amount of a CDK4 / 6 inhibitor, wherein the first amount, the second amount and the third amount together constitute a therapeutically effective amount.

[0023] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0024] The term "pharmaceutically acceptable" is used to indicate that an object (such as a salt, a dosage form [such as a tablet or a capsule], or an excipient [such as a diluent or a carrier]) is suitable for a patient. A list of examples of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0025] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which the salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0026] List of Figures

[0027] Figure 1 : Mouse patient-derived xenograft (PDX) assay. A combination of 10 mg / kg of AZD9833 and 5 mg / kg of everolimus was administered once daily via oral administration (PO) at a volume of 0.1 ml per 10 g of mouse for 28 days, delivering enhanced efficacy in D538G ESR1mt / PI3KCA N345K PDX CTC174 compared to monotherapy. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the logarithm (change in tumor volume) to the vehicle control on the last day of treatment. ****p<0.0001.

[0028] Figure 2 : Mouse patient-derived xenograft assay. A combination of AZD9833 and capesertib was administered via oral administration (PO) at 10 mg / kg and 85 mg / kg, respectively, for 28 days, where camizestrant was administered continuously and capesertib was administered on a schedule of 4 days on, 3 days off, delivering enhanced efficacy in D538G ESR1mt / PI3KCA N345K PDX CTC174 compared to AZD9833 or capesertib monotherapy. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the logarithm (change in tumor volume) to the vehicle control on the last day of treatment. ****p<0.0001.

[0029] Figure 3: Patient-derived xenograft assays in mice. AZD9833 at 10 mg / kg, palbociclib at 50 mg / kg, or a combination of both agents at the same doses were administered once daily by oral gavage throughout the study. The combination of AZD9833 with the CDK4 / 6 inhibitor palbociclib delivered enhanced efficacy in D538G ESR1mt / PI3KCA N345K PDX CTC174 compared to monotherapy. Statistical analysis was performed by unpaired, one-tailed t-tests comparing the log (change in tumor volume) to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0030] Figure 4 : Characterization of palbociclib-resistant cell lines. Genetic alterations were evaluated by whole exome sequencing (WES) of the indicated cell lines. Combination matrix plots were measured using Cell Titer Glo (CTG, Promega), which show a seven-day cell viability assay of treatment with combinations of camisertib and palbociclib or abemaciclib in MCF7 parental and palbociclib-resistant cell lines (PC1, PC6, PC8). One day prior to treatment, cells were seeded in 60 μl of medium. The assay plates were dosed with compounds on the next day (day 0) and read on day 7. Untreated plates were read on day 0. These results were obtained by adding 30 μl of CTG and reading the luminescence value after a 30-minute incubation period at ambient temperature. Data were normalized to initial day 0 seeding and maximal day 7 growth (DMSO only).

[0031] Figure 5 : Patient-derived xenograft assays in mice. Combinations of AZD9833 with CDK4 / 6 and / or mTOR / AKT inhibitors promoted robust activity in PDX models. In PDX ST1799, camisertib at 10 mg / kg daily was administered in combination with palbociclib at 50 mg / kg, abemaciclib at 50 mg / kg daily, and capivasertib at 130 mg / kg in vivo for 40 days (gray area). Note: Due to the large number of treatment groups, the figure is subdivided into two subfigures, and the vehicle and palbociclib groups are the same in both subfigures plotted. Statistical analysis was performed by unpaired, one-tailed t-tests comparing the log (change in tumor volume) to vehicle control on the last day of treatment. Statistical analysis was performed by unpaired, one-tailed t-tests comparing the log (change in tumor volume) to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0032] Figure 6: Patient-derived xenografts in the ST3632 model and ESR1wt model. The combination of AZD9833 and a CDK4 / 6 inhibitor promoted robust activity in ER+ PDX models derived from primary tumors that represent early disease and are insensitive to palbociclib monotherapy. AZD9833 was orally administered at 10 mg / kg per day in combination with palbociclib at 50 mg / kg and abemaciclib at 50 mg / kg per day. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the log (change in tumor volume) compared to vehicle control on the last day of treatment. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the log (change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0033] Figure 7 : Efficacy of the combination of AZ9833, palbociclib, and capivasertib compared to the combination of fulvestrant and palbociclib. Patient-derived xenograft preclinical models were treated with palbociclib and fulvestrant and with a triple combination of camizestrant, capivasertib, and palbociclib in PDX tumor models. Triple therapy combining ER, CDK4 / 6, and AKT inhibition was superior to the palbociclib / fulvestrant combination and was broadly effective in both PI3K pathway mutant and WT PDX models. AZD9833 was administered at 10 mg / kg per day, palbociclib at 50 mg / kg per day, and capivasertib at 130 mg / kg for 4 days followed by 3 days off. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the log (change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0034] Figure 8 . Overview of the model characterization and combination efficacy of the triple combination of AZ9833, palbociclib, and capivasertib. An overview of the model characteristics of patient-derived xenograft preclinical models is presented in a heatmap. The triple active combination of AZD9833, capivasertib, and palbociclib was compared to monotherapy and dual combinations. Triple therapy combining ER, CDK4 / 6, and AKT inhibition was superior to the palbociclib / fulvestrant combination and was broadly effective in both PI3K pathway mutant and wild-type PDX models. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the log (change in tumor volume) compared to vehicle control on the last day of treatment. Statistical analysis was performed by a one-tailed, unequal variance t-test comparing the log (change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0035] Figure 9 .Combined efficacy of AZD9833 dual and triple combinations with capivasertib and / or palbociclib in the ST1799 model (ESR1wt, PI3KCAm E542K). The triple combination of AZD9833, capivasertib and palbociclib was compared with various corresponding monotherapies and dual combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib and camizestrant + capivasertib) using patient-derived xenograft preclinical models. Figure 9 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study showing all treatment groups. Administration: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The triple combination was superior to the dual combinations and monotherapies. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib.

[0036] Figure 10 .Combined efficacy of AZD9833 dual and triple combinations with capivasertib and / or palbociclib in the ST3632 model (ESR1wt, AKT1m E17K). The triple combination of AZD9833, capivasertib and palbociclib was compared with various corresponding monotherapies and dual combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib and camizestrant + capivasertib) using patient-derived xenograft preclinical models. Figure 10 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study showing all treatment groups. Administration: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The triple combination was superior to the dual combinations and monotherapies. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib.

[0037] Figure 11 .Combined efficacy of AZD9833 dual and triple combinations with capivasertib and / or palbociclib in the ST941 model (ESR1mY537S). The triple combination of AZD9833, capivasertib and palbociclib was compared with various corresponding monotherapies and dual combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib and camizestrant + capivasertib) using patient-derived xenograft preclinical models. Figure 11Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study, showing all treatment groups. Administration: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The triple combination was superior to the dual combinations and monotherapies. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib.

[0038] Figure 12 .Combination efficacy of AZD9833 dual and triple combinations with capivasertib and / or palbociclib in the CTC174 model (altered PI3KCA / AKT or PTEN ER+; ESR1m D538G, PI3KCAm N345K). The triple combination of AZD9833, capivasertib, and palbociclib was compared to various corresponding monotherapies and dual combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib, and camizestrant + capivasertib) using xenograft preclinical models. Figure 12 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study, showing all treatment groups. Administration: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The triple combination, as well as the combination of camizestrant and capivasertib, was shown to be superior to other dual combinations and monotherapy groups.

[0039] Figure 13 .Combination efficacy of the AZD9833 / capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapies in the ST1799 model (ESR1 wt, PI3KCAm E542K). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 13 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study, showing all treatment groups. Administration: Subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). In this model, similar tumor growth inhibition was delivered using monotherapies of fulvestrant and camizestrant. The combination of camizestrant and capivasertib was superior to the combination of fulvestrant and capivasertib and the monotherapy groups of this study.

[0040] Figure 14. The combination efficacy of the AZD9833 / capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapies in the ST3632 model (ESR1 wt, AKT1m E17K). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 14 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study showing all treatment groups. Administration: subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The combination of camizestrant and capivasertib was superior to the combination of fulvestrant and capivasertib and the monotherapy groups in this study.

[0041] Figure 15 . The combination efficacy of the AZD9833 / capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapies in the ST941 model (ESR1m Y537S). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 15 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study showing all treatment groups. Administration: subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The combination of camizestrant and capivasertib was superior to the combination of fulvestrant and capivasertib.

[0042] Figure 16 . The combination efficacy of the AZD9833 / capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapies in the CTC174 model (altered PI3KCA / AKT or PTEN ER+: ESR1m D538G, PI3KCAm N345K). Xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 16 Tumor volume plots of ER+ breast cancer PDX in a 28-day efficacy study showing all treatment groups. Administration: subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily (administered on a 4-day on, 3-day off schedule). The combination of camizestrant and capivasertib was superior to the combination of fulvestrant and capivasertib and the monotherapy groups in this study. Detailed Description

[0043] Cancer Treatment

[0044] In an embodiment, the treatment of cancer is the treatment of animal cancer (e.g., mammalian cancer such as human cancer).

[0045] In an embodiment, the cancer is a hormone-sensitive cancer (e.g., estrogen-sensitive cancer or androgen-sensitive cancer). "Estrogen-sensitive or androgen-sensitive" means that the growth of the cancer is at least partially driven by the corresponding hormone pathway such that blocking the hormone attenuates growth and affects treatment.

[0046] In an embodiment, the cancer is breast cancer (e.g., early breast cancer, advanced breast cancer, or metastatic breast cancer).

[0047] In an embodiment, the cancer is early breast cancer.

[0048] In an embodiment, the cancer is advanced breast cancer.

[0049] In an embodiment, the cancer is metastatic breast cancer.

[0050] In an embodiment, the cancer is hormone-sensitive breast cancer.

[0051] In an embodiment, the cancer is estrogen-sensitive breast cancer.

[0052] In an embodiment, the cancer is ovarian cancer.

[0053] In an embodiment, the cancer is estrogen-sensitive ovarian cancer.

[0054] In an embodiment, the cancer is endometrial cancer.

[0055] In an embodiment, the cancer is estrogen-sensitive endometrial cancer.

[0056] In an embodiment, the cancer is prostate cancer.

[0057] In an embodiment, the cancer is androgen-sensitive prostate cancer.

[0058] Patient Selection and Diagnostic Methods

[0059] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer.

[0060] "Estrogen receptor-positive" cancers include tumors that have estrogen receptors (e.g., in at least 1%, at least 10%, at least 20%, or at least 50% of the tumor cells) and are capable of metabolizing estrogen for growth. The ER+ status can be determined by methods known in the art, such as by immunohistochemistry (IHC) testing.

[0061] In an embodiment, the cancer is estrogen receptor-positive breast cancer.

[0062] In an embodiment, the cancer is breast cancer that includes only wild-type estrogen receptor. Such cancer does not contain a mutated estrogen receptor and contains only the receptor found in its normal state.

[0063] In an embodiment, the cancer is breast cancer that includes a mutated estrogen receptor. The mutated estrogen receptor is synthesized by cancer that carries a mutation in its genetic structure (e.g., in the ESR1 gene). Mutations in the estrogen receptor can be determined by methods known in the art, such as by next-generation sequencing.

[0064] In an embodiment, the cancer does not include an ESR1 mutation.

[0065] In an embodiment, the cancer does not include an ESR1 fusion.

[0066] In an embodiment, the cancer does not include an ESR1 mutation or fusion.

[0067] In an embodiment, the cancer includes a mutation in ESR1 selected from the group consisting of E380Q mutation, Y537S mutation, and D538G mutation.

[0068] In an embodiment, the cancer includes an ESR1-CCDC170 fusion.

[0069] In an embodiment, the cancer includes a mutation in ESR1 selected from the group consisting of E380Q mutation, Y537S mutation, and D538G mutation, and / or an ESR1-CCDC170 fusion.

[0070] In an embodiment, the cancer includes a mutation in ESR1 selected from the group consisting of E380Q mutation, Y537S mutation, and D538G mutation, and / or an ESR1-CCDC170 fusion.

[0071] In an embodiment, the cancer is PTEN-deficient (e.g., includes cancer cells (e.g., a population of cancer cells, such as the majority of cancer cells) in which the normal amount [e.g., compared to non-cancer cells of the same patient] or function of the PTEN tumor suppressor protein is reduced). The PTEN status can be determined by methods known in the art.

[0072] In an embodiment, the cancer includes an AKT1 mutation (e.g., a gain-of-function mutation, or a deletion, substitution, or insertion mutation, such as the E17K mutation). The AKT1 mutation status can be determined by methods known in the art.

[0073] In an embodiment, the cancer includes a PI3KCA mutation (e.g., a gain-of-function mutation, or a deletion, substitution, or insertion mutation, such as PI3KCA E542K 、PI3KCA E545K 、PI3KCA Q546R 、PI3KCA 1047Lor PI3KCA H1047R mutation). The PI3KCA mutation status can be determined by methods known in the art.

[0074] In an embodiment, the PI3KCA mutations are selected from R88Q, C420R, E542K, E545A, E545D, E545Q, E545K, E545G, Q546E, Q546K, Q546R, Q546P, M1043V, M1043I, N345K, H1047Y, H1047R, H1047L, and G1049R.

[0075] In an embodiment, the PI3KCA mutations are selected from R88Q, E542K, E545K, and N354K.

[0076] In an embodiment, the PI3KCA mutations are selected from E545K and N345K.

[0077] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, includes an AKT1 mutation (e.g., E17K AKT1 mutation) and / or includes a PI3KCA mutation (e.g., a PI3KCA mutation selected from E545K mutation and N345K mutation).

[0078] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, includes an AKT1 mutation and includes a PI3KCA mutation.

[0079] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, includes an AKT1 mutation or includes a PI3KCA mutation.

[0080] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient.

[0081] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer includes an AKT1 mutation and / or includes a PI3KCA mutation.

[0082] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer includes an AKT1 mutation and a PI3KCA mutation.

[0083] In one embodiment, SERDs for treating cancer are provided, wherein the SERDs are administered in combination with an AKT inhibitor, and the cancer comprises an AKT1 mutation or a PI3KCA mutation.

[0084] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which comprises a mutation in ESR1 (e.g., a mutation in ESR1 selected from the group consisting of E380Q mutation, Y537S mutation, and D538G mutation); and / or an ESR1-CCDC170 fusion; and is PTEN-deficient, comprising an AKT1 mutation (e.g., E17K mutation) and / or comprising a PI3KCA mutation (e.g., a PI3KCA mutation selected from the group consisting of E542K and N345K mutations).

[0085] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which does not comprise an ESR1 mutation or fusion and an E542K PI3KCA mutation.

[0086] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which does not comprise an ESR1 mutation or fusion and an E17K AKT1 mutation.

[0087] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which comprises a Y537S ESR1 mutation.

[0088] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which is PTEN-deficient and comprises an R88Q PI3KCA mutation.

[0089] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which comprises an E380Q ESR1 mutation and an N345K PI3KCA mutation.

[0090] In an embodiment, the cancer is estrogen receptor-positive (ER+) breast cancer, which comprises a D538G ESR1 mutation and an E545K PI3KCA mutation.

[0091] In an embodiment, the cancer is characterized by a biomarker profile (e.g., a genetic biomarker profile) mentioned in the experimental section (e.g., a biomarker associated with the cell lines listed in Table 2 and the corresponding parts of the figures and the specification [such as for example Figure 8 either alone or in combination).

[0092] In an embodiment, the cancer comprises a PIK3CA mutation and is characterized by ATM deletion, BCL2 deletion, and / or MCL1 amplification.

[0093] In an embodiment, the cancer overexpresses Cdc6, cyclin D1, and / or cyclin E.

[0094] In an embodiment, the cancer overexpresses Cdc6 and / or is characterized by Rb deletion.

[0095] In an embodiment, the cancer overexpresses CDK6 and / or CCNE1.

[0096] In an embodiment, the treatment of the cancer is carried out in a postmenopausal woman or a premenopausal woman.

[0097] A woman is an adult human female designed to produce large gametes (eggs).

[0098] In an embodiment, the treatment of the cancer is carried out in a postmenopausal woman.

[0099] In an embodiment, the treatment of the cancer is carried out in a premenopausal woman.

[0100] In an embodiment, the cancer has previously been treated with a selective estrogen receptor degrader, a selective estrogen receptor modulator, or an aromatase inhibitor.

[0101] In an embodiment, during or after treatment with a selective estrogen receptor degrader, a selective estrogen receptor modulator, or an aromatase inhibitor, the cancer in a human patient has reached the maximum response stage (minimal residual disease).

[0102] In an embodiment, the cancer is resistant to treatment with a selective estrogen receptor degrader, a selective estrogen receptor modulator, or an aromatase inhibitor.

[0103] In an embodiment, the cancer has progressed during or after previous treatment with a selective estrogen receptor degrader, a selective estrogen receptor modulator, and / or an aromatase inhibitor. When the growth of the cancer has "progressed", its growth is no longer properly controlled by the therapy under discussion.

[0104] In an embodiment, during or after treatment with fulvestrant or a pharmaceutically acceptable salt thereof, the cancer in a human patient has reached the maximum response stage (minimal residual disease).

[0105] In an embodiment, the cancer is resistant to treatment with fulvestrant or a pharmaceutically acceptable salt thereof.

[0106] In an embodiment, the cancer has progressed during or after previous treatment with fulvestrant or a pharmaceutically acceptable salt thereof.

[0107] In an embodiment, the cancer has previously been treated with a CDK4 / 6 inhibitor.

[0108] In an embodiment, during or after treatment with a CDK4 / 6 inhibitor, the cancer has reached the maximum response stage (minimal residual disease).

[0109] In an embodiment, the cancer is resistant to treatment with a CDK4 / 6 inhibitor.

[0110] In an embodiment, during or after treatment with palbociclib or a pharmaceutically acceptable salt thereof, the cancer in a human patient has reached a stage of maximum response (minimal residual disease).

[0111] In an embodiment, the cancer is resistant to treatment with palbociclib or a pharmaceutically acceptable salt thereof.

[0112] In an embodiment, the cancer has progressed during or after prior treatment with palbociclib or a pharmaceutically acceptable salt thereof.

[0113] In an embodiment, the cancer is CCNE1 amplified (i.e., expresses greater than a normal amount of CCNE1 compared to normal, healthy cells of the same type), RB1 deficient (i.e., expresses less than a normal amount of RB1 compared to normal, healthy cells of the same type), overexpresses CDC6 (i.e., expresses greater than a normal amount of CDC6 compared to normal, healthy cells of the same type) and / or overexpresses CDK6 (i.e., expresses greater than a normal amount of CDK6 compared to normal, healthy cells of the same type).

[0114] In an embodiment, the cancer is CCNE1 amplified and / or RB1 deficient.

[0115] In an embodiment, the cancer is resistant to treatment with a CDK4 / 6 inhibitor and is CCNE1 amplified, RB1 deficient, overexpresses CDC6 and / or overexpresses CDK6.

[0116] In an embodiment, the cancer is resistant to treatment with a CDK4 / 6 inhibitor and is CCNE1 amplified or RB1 deficient.

[0117] In an embodiment, the cancer has progressed during or after prior treatment with a CDK4 / 6 inhibitor.

[0118] In an embodiment, the cancer has never been treated with a CDK4 / 6 inhibitor previously.

[0119] In an embodiment, the cancer has the characteristics (e.g., biomarker characteristics) of any of the cell lines used in the experimental section (e.g., the cell lines and biomarker characteristics shown in Table 2).

[0120] Selective Estrogen Degraders

[0121] A "selective estrogen degrader" (SERD) binds to the estrogen receptor, causing its degradation and thus downregulation.

[0122] In an embodiment, the selective estrogen degrader is a next-generation selective estrogen degrader (“ngSERD”, such as giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, imlunestrant or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof).

[0123] In an embodiment, the selective estrogen receptor degrader is selected from fulvestrant or a pharmaceutically acceptable salt thereof, giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, imlunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

[0124] In an embodiment, the selective estrogen receptor degrader is selected from fulvestrant or a pharmaceutically acceptable salt thereof, giredestrant or a pharmaceutically acceptable salt thereof, and elacestrant or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment, the selective estrogen receptor degrader is selected from giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, imlunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

[0126] In an embodiment, the selective estrogen receptor degrader is selected from giredestrant or a pharmaceutically acceptable salt thereof and elacestrant or a pharmaceutically acceptable salt thereof.

[0127] In an embodiment, the selective estrogen receptor degrader is camizestrant or a pharmaceutically acceptable salt thereof.

[0128] In an embodiment, the selective estrogen receptor degrader is fulvestrant or a pharmaceutically acceptable salt thereof.

[0129] In an embodiment, the selective estrogen receptor degrader is giredestrant or a pharmaceutically acceptable salt thereof.

[0130] In an embodiment, the selective estrogen receptor degrader is imlunestrant or a pharmaceutically acceptable salt thereof.

[0131] In an embodiment, the selective estrogen receptor degrader is camizestrant or a pharmaceutically acceptable salt thereof.

[0132] In an embodiment, the selective estrogen receptor degrader is a PROTAC (proteolysis-targeting chimera).

[0133] In an embodiment, the selective estrogen receptor degrader is ARV-471 or a pharmaceutically acceptable salt thereof.

[0134] Camizestrant (AZD9833) has the following chemical structure:

[0135]

[0136] The chemical name of the free base of camizestrant is known to be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine. Camizestrant is disclosed in WO2018077630A1.

[0137] Elacestrant (LY-3484356) has the following chemical structure:

[0138]

[0139] The chemical name of the free base of elacestrant is known to be (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol. Elacestrant is disclosed in WO2020014435.

[0140] Giredestrant (GDC-9545) has the following chemical structure:

[0141]

[0142] The chemical name of the free base of giredestrant is known to be 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol. Giredestrant is disclosed in WO2016097072A1.

[0143] ARV-471 has the following chemical structure:

[0144]

[0145] ARV-471 is disclosed in WO2018102725.

[0146] AKT Inhibitors

[0147] In one embodiment, SERDs for treating cancer are provided, wherein the SERDs are administered in combination with an AKT inhibitor.

[0148] In one embodiment, AKT inhibitors for treating cancer are provided, wherein the AKT inhibitors are administered in combination with an SERD.

[0149] In embodiments, an AKT inhibitor is any molecule or compound that binds to and inhibits the activity of one or more AKT isoforms (e.g., having a pIC 50 ) relative to the isoform being discussed of > 4.5, > 5, > 6, > 7, > 8, or > 9.

[0150] In embodiments, the AKT inhibitor is a proteolysis targeting chimera (PROTAC).

[0151] In embodiments, the AKT inhibitor is selected from miransertib (ARQ-092) or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0152] In embodiments, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof.

[0153] In embodiments, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, and patritumab (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0154] In embodiments, the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

[0155] Capivasertib has the following chemical structure:

[0156]

[0157] The chemical name of the free base of capivasertib is known to be (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide. Capivasertib is disclosed in WO2009 / 047563, which discloses capivasertib (in Example 9) and describes its synthesis.

[0158] Perifosine has the following chemical structure:

[0159]

[0160] The chemical name of perifosine is known to be 1,1-dimethylpiperidin-4-yl octadecyl phosphate. Perifosine is disclosed in US8383607.

[0161] MK-2206 has the following chemical structure:

[0162]

[0163] The chemical name of the free base of MK-2206 is known to be 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one. MK-2206 is disclosed in WO2008070016.

[0164] GSK690693 has the following chemical structure:

[0165]

[0166] The chemical name of the free base of GSK690693 is 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-piperidin-3-ylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methylbut-3-yn-2-ol. GSK690693 is disclosed in WO2007058850.

[0167] Alflutamide (GSK2110183) has the following chemical structure:

[0168]

[0169] The chemical name of the free base of alflutamide is N-[(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide. Alflutamide is disclosed in WO2008098104.

[0170] Upufutamide (GSK2141795) has the following chemical structure:

[0171]

[0172] The chemical name of the free base of upufutamide is N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide. Upufutamide is disclosed in WO2008098104.

[0173] Patrustamide has the following chemical structure:

[0174]

[0175] The chemical name of the free base of patrustamide is 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one. Patrustamide is disclosed in WO2008006040.

[0176] mTOR Inhibitors

[0177] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an mTOR inhibitor.

[0178] In one embodiment, there is provided an mTOR inhibitor for treating cancer, wherein the mTOR inhibitor is administered in combination with a SERD.

[0179] In an embodiment, an mTOR inhibitor is any molecule or compound that binds to and inhibits the activity of mTOR (e.g., having a pIC of >4.5, >5, >6, >7, >8, or >9 relative to mTOR) 50 ).

[0180] In an embodiment, the mTOR inhibitor is an mTORC1 inhibitor.

[0181] In an embodiment, the mTOR inhibitor is an mTORC1-selective inhibitor. The mTORC1-selective inhibitor has greater activity against the activity of mTORC1 (e.g., >10-fold, >100-fold, or >1000-fold activity) than against any other mTOR complex.

[0182] In an embodiment, the mTOR inhibitor is selected from everolimus (e.g., ) or a pharmaceutically acceptable salt thereof and temsirolimus (e.g., ) or a pharmaceutically acceptable salt thereof.

[0183] In an embodiment, the mTOR inhibitor is everolimus or a pharmaceutically acceptable salt thereof.

[0184] In an embodiment, the mTOR inhibitor is temsirolimus or a pharmaceutically acceptable salt thereof.

[0185] CDK4 / 6 Inhibitors

[0186] In one embodiment, a SERD for treating cancer is provided, wherein the SERD is administered in combination with a CDK4 / 6 inhibitor.

[0187] In one embodiment, a CDK4 / 6 inhibitor for treating cancer is provided, wherein the CDK4 / 6 inhibitor is administered in combination with a SERD.

[0188] In one embodiment, an ngSERD for treating cancer (e.g., giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, elumetinib or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof) is provided, wherein the ngSERD is administered in combination with a CDK4 / 6 inhibitor.

[0189] In one embodiment, a CDK4 / 6 inhibitor for treating cancer is provided, wherein the CDK4 / 6 inhibitor is administered in combination with an ngSERD.

[0190] In an embodiment, the CDK4 / 6 inhibitor is any molecule or compound that binds to and inhibits the activities of CDK4 and CDK6 (e.g., having a pIC of >4.5, >5, >6, >7, >8, or >9 relative to CDK4 and CDK6)50 )。

[0191] In an embodiment, the CDK4 / 6 inhibitor is selected from palbociclib (e.g., ) or a pharmaceutically acceptable salt thereof, ribociclib (e.g., ) or a pharmaceutically acceptable salt thereof, and abemaciclib (e.g., ) or a pharmaceutically acceptable salt thereof.

[0192] In an embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0193] In an embodiment, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[0194] In an embodiment, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof.

[0195] Other Endocrine Therapies

[0196] A "selective estrogen modulator" (SERM) is a compound that agonizes or antagonizes estrogen receptors and typically varies depending on the tissue on which it acts. In an embodiment, the selective estrogen modulator has an anti-estrogenic effect on cancer. In an embodiment, the selective estrogen receptor modulator is selected from tamoxifen (e.g., ) or a pharmaceutically acceptable salt thereof, toremifene (e.g., ) or a pharmaceutically acceptable salt thereof, and raloxifene (e.g., ) or a pharmaceutically acceptable salt thereof.

[0197] In an embodiment, the SERM is tamoxifen or a pharmaceutically acceptable salt thereof.

[0198] In an embodiment, the SERM is toremifene or a pharmaceutically acceptable salt thereof.

[0199] In an embodiment, the SERM is raloxifene or a pharmaceutically acceptable salt thereof.

[0200] An "aromatase inhibitor" is a compound that blocks estrogen biosynthesis. In an embodiment, the aromatase inhibitor is selected from anastrozole (e.g., ) or a pharmaceutically acceptable salt thereof, letrozole (e.g., ) or a pharmaceutically acceptable salt thereof, and exemestane (e.g., ) or a pharmaceutically acceptable salt thereof.

[0201] In an embodiment, the aromatase inhibitor is anastrozole or a pharmaceutically acceptable salt thereof.

[0202] In an embodiment, the aromatase inhibitor is letrozole or a pharmaceutically acceptable salt thereof.

[0203] In an embodiment, the aromatase inhibitor is exemestane or a pharmaceutically acceptable salt thereof.

[0204] Triple Combinations

[0205] In one embodiment, a SERD for treating cancer is provided, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

[0206] In one embodiment, an AKT inhibitor or an mTOR inhibitor for treating cancer is provided, wherein the AKT inhibitor or the mTOR inhibitor is administered in combination with a SERD and a CDK4 / 6 inhibitor.

[0207] In one embodiment, an AKT inhibitor for treating cancer is provided, wherein the AKT inhibitor is administered in combination with a SERD and a CDK4 / 6 inhibitor.

[0208] In one embodiment, an mTOR inhibitor for treating cancer is provided, wherein the mTOR inhibitor is administered in combination with a SERD and a CDK4 / 6 inhibitor.

[0209] In one embodiment, a CDK4 / 6 inhibitor for treating cancer is provided, wherein the CDK4 / 6 inhibitor is administered in combination with a SERD and an AKT inhibitor or an mTOR inhibitor.

[0210] In an embodiment, the administration of the SERD with each inhibitor is separate, sequential, or simultaneous.

[0211] In an embodiment, the administration of the SERD with each inhibitor is separate.

[0212] In an embodiment, the administration of the SERD with each inhibitor is sequential.

[0213] In an embodiment, the administration of the SERD with each inhibitor is simultaneous.

[0214] Specific Combinations

[0215] In one embodiment, an AKT inhibitor or an mTOR inhibitor for treating cancer is provided, wherein the AKT inhibitor or the mTOR inhibitor is administered in combination with a SERD and an optional CDK4 / 6 inhibitor.

[0216] In one embodiment, SERDs for treating cancer are provided, wherein the SERDs are administered in combination with an AKT inhibitor selected from the group consisting of milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and palbociclib or a pharmaceutically acceptable salt thereof; or are administered in combination with an mTOR inhibitor selected from the group consisting of everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof; and / or are administered in combination with a CDK4 / 6 inhibitor selected from the group consisting of palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0217] As can be seen from the data presented herein, the combination therapy of camizestrant and capivasertib delivers superior activity in ESR1wt and ESR1m patient-derived xenograft (PDX) models relative to therapies with fulvestrant and capivasertib. It appears that camizestrant and capivasertib act in a synergistic manner. This surprising and advantageous combination generally delivers greater responses in a range of ESR1wt and ESR1m PDX models than those observed with monotherapy with either agent. In addition, the combination of camizestrant and capivasertib delivers a deeper response than that obtained with the combination of fulvestrant and capivasertib at the optimal dose. Thus, for the first time, the clinical potential of the combination therapy using camizestrant and capivasertib is revealed, which is an important finding considering the results of the Phase 3 CAPitello-291 clinical trial, in which the combination of capivasertib and fulvestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) relative to placebo plus Faslodex in patients with hormone receptor (HR)-positive, HER2-low or negative, locally advanced or metastatic breast cancer at the time of or after recurrence or progression on endocrine therapy (with or without a CDK4 / 6 inhibitor).

[0218] Triplet combinations including camizestrant and capivasertib in combination with a CDK4 / 6 inhibitor were observed to deliver superior synergistic activity in a broad range of PDX models, e.g., those PDX models with clinically relevant mutations of ESR1 in the AKT / PI3K pathway, or those PDX models in which CCNE1 is amplified or RB1 is defective or overexpresses CDC6 and / or overexpresses CDK6.

[0219] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor. In such embodiments, camizestrant or a pharmaceutically acceptable salt thereof can be administered at a dose of 75 mg or 150 mg once daily.

[0220] In an embodiment, capivasertib for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor. In such embodiments, capivasertib or a pharmaceutically acceptable salt thereof can be administered at a dose of 400 mg twice daily on an intermittent dosing schedule.

[0221] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof.

[0222] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof.

[0223] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor. In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor.

[0224] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer that does not include an ESR1 mutation or fusion.

[0225] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer that includes a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the E380Q mutation, the Y537S mutation, and the D538G mutation, and / or an ESR1-CCDC170 fusion.

[0226] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer that includes a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the Y537S mutation and the D538G mutation.

[0227] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for treating cancer, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capmatinib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is PTEN-deficient, including an AKT1 mutation (such as the E17K mutation) and / or including a PI3KCA mutation (such as a PI3KCA mutation selected from the E542K and N345K mutations).

[0228] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for treating cancer, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capmatinib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, optionally the mutation in ESR1 is selected from the E380Q mutation, the Y537S mutation, and the D538G mutation, and / or an ESR1-CCDC170 fusion; and wherein the cancer is PTEN-deficient, including an AKT1 mutation (such as the E17K mutation) and / or including a PI3KCA mutation (such as a PI3KCA mutation selected from the E542K and N345K mutations).

[0229] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for treating cancer, wherein camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capmatinib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the Y537S mutation and the D538G mutation, and wherein the cancer comprises an E17K AKT1 mutation and / or a PI3KCA mutation selected from the E542K and N345K mutations.

[0230] In an embodiment, there is provided capmatinib or a pharmaceutically acceptable salt thereof for treating cancer, wherein capmatinib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor-positive (ER+) breast cancer that does not comprise an ESR1 mutation or fusion.

[0231] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the group consisting of the E380Q mutation, the Y537S mutation, and the D538G mutation, and / or an ESR1-CCDC170 fusion.

[0232] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the Y537S mutation and the D538G mutation.

[0233] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, and wherein the cancer is PTEN-deficient, comprising an AKT1 mutation (such as the E17K mutation) and / or comprising a PI3KCA mutation (such as a PI3KCA mutation selected from the E542K and N345K mutations).

[0234] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from the group consisting of the E380Q mutation, the Y537S mutation, and the D538G mutation, and / or an ESR1-CCDC170 fusion; and wherein the cancer is PTEN-deficient, comprising an AKT1 mutation (such as the E17K mutation) and / or comprising a PI3KCA mutation (such as a PI3KCA mutation selected from the E542K and N345K mutations).

[0235] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administering a CDK4 / 6 inhibitor, wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1 (which is selected from the Y537S mutation and the D538G mutation); and wherein the cancer comprises the E17K AKT1 mutation and / or a PI3KCA mutation selected from the E542K and N345K mutations.

[0236] In one embodiment, a SERD for treating cancer is provided, wherein the SERD is administered in combination with an AKT inhibitor selected from: milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, choline erucate phosphate or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and patritumab or a pharmaceutically acceptable salt thereof; and / or is administered in combination with a CDK4 / 6 inhibitor selected from: palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0237] In one embodiment, a SERD for treating cancer is provided, wherein the SERD is administered in combination with an mTOR inhibitor selected from: everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof; and / or is administered in combination with a CDK4 / 6 inhibitor selected from: palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0238] In one embodiment, SERDs for treating cancer are provided, wherein the SERDs are administered in combination with an AKT inhibitor selected from the group consisting of milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and palbociclib or a pharmaceutically acceptable salt thereof; or are administered in combination with an mTOR inhibitor selected from the group consisting of everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof; and are administered in combination with a CDK4 / 6 inhibitor selected from the group consisting of palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0239] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor selected from the group consisting of milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and palbociclib or a pharmaceutically acceptable salt thereof; and is administered in combination with a CDK4 / 6 inhibitor selected from the group consisting of palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0240] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is administered in combination with an mTOR inhibitor selected from the group consisting of everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof; and is administered in combination with a CDK4 / 6 inhibitor selected from the group consisting of palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0241] In one embodiment, there is provided a SERD for treating cancer, wherein the SERD is camizestrant or a pharmaceutically acceptable salt thereof, which is administered in combination with abemaciclib, and the cancer is resistant to treatment with palbociclib.

[0242] Pharmaceutical Compositions and Dosage Forms

[0243] In one embodiment, there is provided a pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0244] "Pharmaceutically acceptable excipients" include diluents, disintegrants or lubricants. In additional embodiments, the pharmaceutical composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0245] In one embodiment, there is provided a pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and a pharmaceutically acceptable excipient.

[0246] In one embodiment, there is provided a pharmaceutical composition comprising a SERD in combination with a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0247] In one embodiment, there is provided a pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0248] In an embodiment, the composition is an oral dosage form.

[0249] In an embodiment, the composition is in the form of a tablet or a capsule.

[0250] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 75 mg or 150 mg.

[0251] In the combinations disclosed in this specification, capmatinib or a pharmaceutically acceptable salt thereof is generally administered to a subject at a daily dose of about 100 mg to about 1600 mg.

[0252] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 150 mg to about 1500 mg. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 mg to about 1400 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg to about 1300 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 400 mg to about 1200 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 500 mg to about 1100 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg to about 1000 mg. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered to the subject once daily (QD).

[0253] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 1000 mg.

[0254] In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 900 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 850 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 800 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 750 mg.

[0255] In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 350 mg to about 700 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 400 mg to about 650 mg.

[0256] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered to a subject twice daily (BID). In one embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 50 mg to about 900 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 875 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 850 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 825 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 250 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 350 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 350 mg to about 450 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 450 mg to about 550 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 550 mg to about 650 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 650 mg to about 750 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 750 mg to about 850 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg.In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 560 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 800 mg.

[0257] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered under a continuous dosing schedule. In one embodiment, for example, capmatinib or a pharmaceutically acceptable salt thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49 or 56 days. In another embodiment, the dosing cycle is 28 days. The administration of capmatinib or a pharmaceutically acceptable salt thereof and the repetition of the dosing cycle can continue as long as it is tolerable and beneficial for the subject.

[0258] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily (QD) on a continuous dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 900 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 875 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 175 mg to about 850 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 825 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 225 mg to about 800 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 750 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 275 mg to about 700 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 650 mg on a continuous dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) on a continuous dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 800 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 750 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 700 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 225 mg to about 650 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 650 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 600 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 300 mg on a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 400 mg on a continuous dosing schedule.In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 580 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg under a continuous dosing schedule.In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg under a continuous dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 800 mg under a continuous dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered to a subject under an intermittent dosing schedule. Administering capmatinib or a pharmaceutically acceptable salt thereof under an intermittent dosing schedule can, for example, have greater efficacy and / or tolerability than under a continuous dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 1-day dosing / 6-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for one day, followed by a six-day holiday). In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 2-day dosing / 5-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for two days, followed by a five-day holiday). In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 3-day dosing / 4-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for three days, followed by a four-day holiday). In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 4-day dosing / 3-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for four days, followed by a three-day holiday). In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 5-day dosing / 2-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for five days, followed by a two-day holiday). In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered intermittently according to a 6-day dosing / 1-day drug holiday schedule (i.e., capmatinib or a pharmaceutically acceptable salt thereof is administered for six days, followed by a one-day holiday). The dosing cycle of such embodiments is then repeated as long as it is tolerable and beneficial for the subject. In an embodiment, the dosing cycle is 7 days. In an embodiment, the dosing cycle is 14 days. In another embodiment, the dosing cycle is 21 days. In another embodiment, the dosing cycle is 28 days. In another embodiment, the dosing cycle is two months. In another embodiment, the dosing cycle is six months. In another embodiment, the dosing cycle is one year.

[0259] In an embodiment, the dosing cycle is 28 days, but capmatinib or a pharmaceutically acceptable salt thereof is not co-administered to the subject during the fourth week of the dosing cycle (i.e., there is a drug holiday of capmatinib or a pharmaceutically acceptable salt thereof during the last week of the dosing cycle).

[0260] In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily (QD) on an intermittent dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 100 mg to about 900 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 150 mg to about 850 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 175 mg to about 800 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 200 mg to about 750 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 225 mg to about 725 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 250 mg to about 700 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 275 mg to about 675 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dose of about 300 mg to about 650 mg. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) on an intermittent dosing schedule. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 100 mg to about 800 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 150 mg to about 750 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 200 mg to about 700 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 225 mg to about 675 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 250 mg to about 650 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 300 mg to about 625 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 200 mg to about 300 mg. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dose of about 300 mg to about 400 mg.In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 580 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg under an intermittent dosing schedule. In another embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg under an intermittent dosing schedule.In another embodiment, capesertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg on an intermittent dosing schedule. In another embodiment, capesertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 800 mg on an intermittent dosing schedule.

[0261] In an embodiment, a kit is provided that includes a pharmaceutical composition containing camizestrant and instructions for its use in the treatment of ER+ breast cancer, wherein the use is in combination with capesertib, optionally wherein the use is further in combination with a CDK4 / 6 inhibitor. In such embodiments, the instructions may direct the use of the pharmaceutical composition based on the presence of a mutation in PI3KCA or AKT1 or a cancer identified as PTEN-deficient.

[0262] In an embodiment, a kit is provided that includes a pharmaceutical composition containing capesertib and instructions for its use in the treatment of ER+ breast cancer, wherein the use is in combination with camizestrant, optionally wherein the use is further in combination with a CDK4 / 6 inhibitor. In such embodiments, the instructions may direct the use of the pharmaceutical composition based on the presence of a mutation in PI3KCA or AKT1 or a cancer identified as PTEN-deficient.

[0263] In any embodiment where a commercially available or approved drug is mentioned, the commercially available or approved drug may be administered according to its label (e.g., as approved by the US FDA or any other similar regulatory agency).

[0264] In any embodiment where a drug being studied in a human trial is mentioned, the drug may be administered according to the dosing regimen described in any of its publicly available clinical trial protocols (e.g., as described on clinicaltrials.gov or the like).

[0265] Examples

[0266] The following specific examples with reference to the drawings are provided for illustrative purposes only and should not be construed as limiting the teachings herein.

[0267] The additional text in the figures explains how to conduct the experiment. The cells used in the experiment are discussed below.

[0268] MCF7 is a cell line derived from intrapleural fluid / effusion obtained from a human patient with ductal breast cancer. The cell line was obtained from ATCC HTB-22 and carries an activating mutation in PIK3CA E545K. MCF7 cells are routinely cultured in RPMI (Gibco#11835-063) + 5% FCS + 1% L-glutamine and at 37 °C, 5% CO 2Incubate below.

[0269] The MCF7 PC1 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions as those used for parental MCF7 described above.

[0270] The MCF7 PC6 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions as those used for parental MCF7 described above.

[0271] The MCF7 PC8 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions as those used for parental MCF7 described above.

[0272] The MCF7 PC10 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions as those used for parental MCF7 described above.

[0273] All cell lines were generated from parental ATCC HTB-133 stock solutions by long-term exposure to fulvestrant and palbociclib. Before starting the treatment, the cell stock solutions were cultured in T175 flasks. The medium was removed from the flasks, the cells were washed with 10 ml of DPBS and 2 ml of trypsin was added to detach them. Once detached, the cells were resuspended in 10 ml of growth medium, and 10 μl of each was mixed with 10 μl of trypan blue and counted using a ThermoFisher Invitrogen Countess. 10 ml was taken at 2.0×10 4 / ml cells were added to 3×T25 flasks, 2 flasks were dosed with 30 nM fulvestrant + 300 nM palbociclib to generate a resistant pool, and 1 flask was dosed with an equal volume % of DMSO as a control. The cells were transferred to an incubator to adhere overnight. The cells were initially dosed with 30 nM fulvestrant and 300 nM palbociclib, with the aim of gradually increasing to 100 nM fulvestrant + 1 μM palbociclib once the cells started to grow. The medium in the flasks was removed and replaced with 10 ml of medium containing fulvestrant + palbociclib (fulvestrant: 2.2 μl of 300 μM fulvestrant stock solution was added to 22 ml of growth medium, diluted 1:10,000 to obtain a final product of 30 nM / palbociclib: 2.2 μl of 3 mM stock solution was added to 22 ml of growth medium, diluted 1:10,000 to obtain a final product of 300 nM). The cells were redosed twice a week and maintained for 6 months as they grew slowly from a small surviving fraction. The cells were expanded into T75 flasks and the dose was gradually increased to 100 nM fulvestrant + 1 μM palbociclib. Subsequently, the cells were expanded for 40 days to generate a stock solution for cryopreservation.

[0274] CTC-174 is a representative patient-derived xenograft of metastatic breast cancer with ESR1 D538G and PI3KCA N345K mutations (Ladd et al., Oncotarget, 7(34):54120–54136, 2016).

[0275] ST1799 / HI / PBR is an ER+ breast cancer patient-derived xenograft tumor model, derived from a primary tumor sample with a PI3KCA_E542K mutation (provided by XenoSTART).

[0276] ST3632 is an ER+ breast cancer patient-derived xenograft tumor model with an AKT1 mutation (provided by XenoSTART).

[0277] ST3932 is an ER+ breast cancer patient-derived xenograft tumor model, derived from a primary patient sample with a PI3KCA_R88Q mutation (provided by XenoSTART).

[0278] CTG2432 is an ER+ breast cancer patient-derived xenograft tumor model, derived from a primary patient sample with ESR1 E380Q and PI3KCA N345K (provided by Champions Oncology).

[0279] ST3164B / PBR is an ER+ breast cancer patient-derived xenograft tumor model, derived from a metastatic patient sample with an ESR1_CCDC170 fusion (provided by XenoSTART).

[0280] The ST941 / HI / PBR is a patient-derived xenograft tumor model for ER+ breast cancer, derived from a metastatic patient sample with an activating mutation in ESR1 Y537S (provided by XenoSTART).

[0281] CTG1211 is a patient-derived xenograft tumor model for ER+ breast cancer, derived from a primary patient sample with an activating mutation in ESR1 D538G (provided by Champions Oncology).

[0282] Example 1: Combination Experiment of Palbociclib-Resistant Cell Lines

[0283] The Highest Single Agent (HSA) model calculates the synergy score matrix for drug combination blocks. The scores in MCF7 and T47D parental cell lines and palbociclib-resistant variants exposed to the combination of camisertib and AZD5363 or everolimus, abemaciclib, and palbociclib for 7 days were determined according to the method described in Figure 4 and the results are shown in Table 1 below. Table 2 summarizes the genetic characteristics of the tested cell lines.

[0284] Table 1 : of the Combination with Camizestrant HSA Score

[0285]

[0286] Table 2: Cytogenetic Characteristics

[0287] Cell Line Genetic Background MCF7 PIK3CA mut, ATM del, BCL2 del, MCL1 amp PC1 Overexpression of Cdc6, Cyclin D1 and Cyclin E PC6 PC8 Rb Deletion, Cdc6 PC10 T47D PIK3CA mut T47D P1 Rb Deletion, Overexpression of CCNE1 T47D P2 Overexpression of CDK6, CCNE1

[0288] Example 2: Xenograft Experiment

[0289] Patient-derived xenograft models are generated from patient biopsies of metastatic or primary tumors. The samples are implanted into immunocompromised mice using standard techniques well known in the art for expansion and drug treatment. The results of various combination treatments of the xenografts are shown in Figures 1 to 3 and Figures 5 to 16 and are further described in the figure list.

[0290] Example 3: Clinical Data of the Combination of Camizestrant and Capivasertib

[0291] Example 3: Clinical Data of the Combination of Camizestrant and Capivasertib

[0292] The combination of camizestrant and capivasertib was evaluated in parts I and J of the SERENA-1 study (NCT03616587, see https: / / classic.clinicaltrials.gov / ct2 / show / NCT03616587), which was the first human open-label phase I study of camizestrant in women with endocrine-resistant ER+, HER2-breast cancer who were not suitable for curative-intent treatment.

[0293] In the part of the SERENA-1 trial in which camizestrant and capivasertib were used in combination, camizestrant at an oral dose of 75 mg once daily (tablet) was combined with capivasertib 400 mg administered twice daily (BID; intermittently; 4 days on, 3 days off) (in tablet form). In other words, during a weekly treatment course, a 400 mg dose of capivasertib was administered twice daily on days 1, 2, 3, and 4, and capivasertib was not administered on days 5, 6, and 7. Meanwhile, camizestrant was administered once daily at a dose of 75 mg per day of the week.

[0294] Demographic data of study participants who received camizestrant and capivasertib are shown in Table 3. Interim results of the ongoing SERENA-1 study obtained on September 14, 2023 are shown in Table 4.

[0295] Table 3: Demographics of Participants in the SERENA-1 Study Receiving the Combination of Camizestrant and Capivasertib

[0296]

[0297]

[0298] The primary objective was to determine the safety and tolerability of the combination of camizestrant 75 mg once daily (QD) and capivasertib 400 mg twice daily (BID; intermittently; 4 days on, 3 days off). Secondary objectives included the study of antitumor response and pharmacokinetics (PK). Participants were women of any menopausal status (pre-menopausal women received this combination while undergoing ovarian function suppression). Advanced patients with a history of ≤2 lines of chemotherapy were allowed. Advanced patients needed to have been previously treated with endocrine therapy (ET), with no limit on the number of lines of prior ET; prior treatment with CDK4 / 6 inhibitors (CDK4 / 6i) and fulvestrant was allowed.

[0299] Results :

[0300] As of September 14, 2023, 29 patients in Parts I and J of the SERENA-1 study had received the combination of camizestrant and capivasertib. As those skilled in the art will understand, as is typically the case in phase 1 clinical trials, this phase 1 study was not powered to provide definitive evidence of clinical efficacy or to conclusively demonstrate that one treatment group is superior to another. Nevertheless, the results obtained from this study do support the view that the promising preclinical activity of the above-mentioned combination of an ngSERD (such as camizestrant) and an AKT inhibitor (such as capivasertib) can be successfully translated into the clinical setting.

[0301] The safety and tolerability profile of the combination of camizestrant and capivasertib was broadly consistent with that observed for each drug alone, with no significant worsening of the known tolerability of each agent. From a safety and tolerability perspective, the data from the first-in-human of this combination is well guiding for future clinical use.

[0302] Among the heavily pre-treated patients (48% had received chemotherapy, 90% had received CDK4 / 6i, 55% had received fulvestrant; all in advanced disease state) who received the combination of camizestrant and capivasertib in the SERENA-1 trial, 72% had visceral metastases. Additionally, 17 patients had detectable ESR1m (one or more mutations in the gene encoding estrogen receptor) and evaluable C2D1 results at baseline. Among them, in 11 cases (91.7%), ESR1m decreased by >50% at C2D1, and in 8 cases (66.7%), clearance of ESR1m was observed at C2D1. As can be seen from Table 4, the objective response rate (ORR) observed in the camizestrant / capivasertib combination arm was 37.0% (10 / 29), the clinical benefit rate at 24 weeks (CBR24) was 51.7% (15 / 29), and the median progression-free survival (PFS) was 8.5 months (15 / 29, 95% CI). Among patients with detectable ESR1m at baseline, the median PFS was 13.8 months.

[0303] PK and safety data from Parts I and J of SERENA-1 indicate no clinically relevant drug-drug interactions affecting camizestrant or capivasertib.

[0304] Thus, the preclinical promise of the combination of camizestrant and capivasertib as a new therapy for ER+HER2- breast cancer is supported by the positive results obtained in a cohort of heavily pre-treated patients, including those whose tumors had progressed after receiving CDK4 / 6 inhibitors and fulvestrant and those whose tumors had detectable ESR1m.

[0305] Table 4: Interim Results of the SERENA-1 Trial as of September 14, 2023

[0306]

[0307]

[0308] The maturity is the ratio of the number of patients with uncensored PFS to the total number evaluated.

[0309] § Camizestrant and capmatinib are administered orally once daily with the dosing schedule as described above.

[0310] *n, the number of patients who achieved CR or PR; m, the number of patients in the relevant patient population.

[0311] **n, the number of patients with a confirmed response or SD lasting >= 23 weeks after treatment; m, the number of patients with a post-treatment scan having at least (DCO) date - first dose date >= 24 weeks or >= 23 weeks.

Claims

1. A SERD for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

2. The SERD for the use according to claim 1, wherein the SERD is selected from fulvestrant or a pharmaceutically acceptable salt thereof, giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, elumestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

3. The SERD for the use according to claim 1, wherein the SERD is selected from giredestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, elumestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

4. The SERD for the use according to claim 3, wherein the SERD is camizestrant or a pharmaceutically acceptable salt thereof.

5. The SERD for the use according to any one of the preceding claims, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor.

6. The SERD for the use according to any one of the preceding claims, wherein the SERD is administered in combination with an AKT inhibitor.

7. The SERD for the use according to any one of the preceding claims, wherein the AKT inhibitor is selected from milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and pactolisib or a pharmaceutically acceptable salt thereof.

8. The SERD for the use according to any one of the preceding claims, wherein the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

9. The SERD for the use according to any one of claims 1 to 5, wherein the SERD is administered in combination with an mTOR inhibitor.

10. The SERD for the use according to any one of the preceding claims, wherein the mTOR inhibitor is an mTORC1 inhibitor.

11. A SERD for use in the use according to any one of the preceding claims, wherein the mTOR inhibitor is an mTORC1 selective inhibitor.

12. A SERD for use in the use according to any one of the preceding claims, wherein the mTOR inhibitor is selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof.

13. A SERD for treating cancer according to any one of claims 1 to 3, wherein the SERD is administered in combination with a CDK4 / 6 inhibitor.

14. A SERD for treating cancer according to claim 13, wherein the CDK4 / 6 inhibitor is selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

15. A SERD for use in the use according to any one of claims 1 to 4, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

16. A SERD for use in the use according to any one of the preceding claims, wherein the administration of the SERD and each inhibitor is separate, sequential or simultaneous.

17. A SERD for use in the use according to any one of the preceding claims, wherein the cancer is breast cancer.

18. A SERD for use in the use according to claim 17, wherein the cancer is advanced breast cancer or metastatic breast cancer.

19. A SERD for use in the use according to claim 17 or claim 18, wherein the breast cancer is estrogen receptor positive breast cancer.

20. A SERD for use in the use according to claim 19, wherein the breast cancer only includes wild-type estrogen receptor.

21. A SERD for use in the use according to claim 19, wherein the breast cancer includes a mutated estrogen receptor.

22. A SERD for use in the use according to any one of claims 18 to 20, wherein the cancer does not include ESR1 mutation or fusion.

23. A SERD for use in the use according to any one of claims 18, 19 or 21, wherein the cancer includes a mutation in ESR1 selected from E380Q mutation, Y537S mutation and D538G mutation, and / or ESR1-CCDC170 fusion.

24. A SERD for use in the use according to any one of claims 17 to 23, wherein the breast cancer is resistant to treatment with SERD, SERM or aromatase inhibitor.

25. A SERD for use in the use according to any one of claims 17 to 23, wherein the breast cancer has progressed during or after prior treatment with SERD, SERM and / or aromatase inhibitor.

26. A SERD for use in the use according to claim 24 or claim 25, wherein the SERM is selected from tamoxifen or a pharmaceutically acceptable salt thereof, toremifene or a pharmaceutically acceptable salt thereof, and raloxifene or a pharmaceutically acceptable salt thereof.

27. A SERD for use in the use according to claim 24 or claim 25, wherein the aromatase inhibitor is selected from anastrozole or a pharmaceutically acceptable salt thereof, letrozole or a pharmaceutically acceptable salt thereof, and exemestane or a pharmaceutically acceptable salt thereof.

28. A SERD for use in the use according to any one of the preceding claims, wherein the patient is a postmenopausal woman or a premenopausal woman.

29. A SERD for use in the use according to any one of the preceding claims, wherein the cancer is PTEN-deficient.

30. A SERD for use in the use according to any one of the preceding claims, wherein the cancer comprises an AKT1 mutation.

31. A SERD for use in the use according to claim 30, wherein the AKT1 mutation is an E17K mutation.

32. A SERD for use in the use according to any one of the preceding claims, wherein the cancer comprises a PI3KCA mutation.

33. A SERD for use in the use according to claim 32, wherein the PI3KCA mutation is selected from R88Q, N345K, C420R, E542K, E545A, E545D, E545Q, E545K, E545G, Q546E, Q546K, Q546R, Q546P, M1043V, M1043I, H1047Y, H1047R, H1047L, and G1049R.

34. A SERD for use in the use according to any one of claims 29 to 33, wherein the SERD is administered in combination with an AKT inhibitor and the cancer is PTEN-deficient, comprises an AKT1 mutation and / or comprises a PI3KCA mutation.

35. A SERD for use in the use according to any one of the preceding claims, wherein the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor.

36. A SERD for use in the use according to claim 35, wherein the breast cancer is CCNE1-amplified, RB1-deficient, overexpresses CDC6, and / or overexpresses CDK6.

37. A SERD for use in the use according to any one of the preceding claims, wherein the cancer has progressed during or after prior treatment with a CDK4 / 6 inhibitor.

38. A SERD for use in the use according to any one of the preceding claims, wherein the cancer has never been treated with a CDK4 / 6 inhibitor previously.

39. A SERD for use in the said use according to claim 1, wherein the SERD is administered in combination with an AKT inhibitor selected from the following: Milciclib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, Bortezomib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, Capivasertib or a pharmaceutically acceptable salt thereof, Miltefosine or a pharmaceutically acceptable salt thereof, Perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, Erucoylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, Afuresertib or a pharmaceutically acceptable salt thereof, Upadesertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and Patritumab or a pharmaceutically acceptable salt thereof; or is administered in combination with an mTOR inhibitor selected from the following: Everolimus or a pharmaceutically acceptable salt thereof and Temsirolimus or a pharmaceutically acceptable salt thereof; and / or is administered in combination with a CDK4 / 6 inhibitor selected from the following: Palbociclib or a pharmaceutically acceptable salt thereof, Ribociclib or a pharmaceutically acceptable salt thereof, and Abemaciclib or a pharmaceutically acceptable salt thereof.

40. A SERD for use in the said use according to claim 1, wherein the SERD is Camizestrant or a pharmaceutically acceptable salt thereof, the SERD is administered in combination with Abemaciclib, and the cancer is resistant to treatment with Palbociclib.

41. Use of a SERD in the manufacture of a medicament for the treatment of cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

42. A method of treating cancer in an animal patient in need of such treatment, the method comprising administering to the animal patient a therapeutically effective amount of a SERD, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor.

43. The method for treating cancer according to claim 42, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

44. A method of treating cancer in an animal patient in need of such treatment, the method comprising administering to the animal patient a first amount of a SERD, a second amount of an AKT inhibitor or an mTOR inhibitor, and a third amount of a CDK4 / 6 inhibitor, wherein the first amount, the second amount, and the third amount together constitute a therapeutically effective amount.

45. A pharmaceutical composition, the pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

46. The pharmaceutical composition according to claim 45, the pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and a pharmaceutically acceptable excipient.

47. The pharmaceutical composition according to claim 46, the pharmaceutical composition comprising a SERD in combination with a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

48. The pharmaceutical composition according to any one of claims 45 to 47, the pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

49. A kit, the kit comprising a pharmaceutical composition containing camizestrant and instructions for its use in the treatment of ER+ breast cancer, wherein the use is in combination with capivasertib, optionally wherein the use is further in combination with a CDK4 / 6 inhibitor.

50. A kit, the kit comprising a pharmaceutical composition containing capivasertib and instructions for its use in the treatment of ER+ breast cancer, wherein the use is in combination with camizestrant, optionally wherein the use is further in combination with a CDK4 / 6 inhibitor.

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