Cancer therapy with capivasertib and fulvestrant

Abstract

The present disclosure relates to a therapeutic combination of capivasertib and fulvestrant that is useful for treating specific populations of patients with advanced breast cancer, and methods of treating specific populations of breast cancer patients with the combination of capivasertib and fulvestrant.

Description

[Technical Field]

[0001] The present disclosure relates to a therapeutic combination of capivasertib and fulvestrant that is useful for treating specific populations of patients with advanced breast cancer, and methods of treating specific populations of breast cancer patients with the combination of capivasertib and fulvestrant. [Background technology]

[0002] In women, breast cancer is the most common cancer and the second leading cause of cancer death worldwide (Cardoso et al., Breast (2017) 31:244-259). Approximately 60% of premenopausal and 75% of postmenopausal breast cancer patients are estrogen receptor-positive (ER). + ) cancer types. ER expression and activation are important factors for controlling tumor growth and recurrence (Chen, OMICS (2011) 15:347-352). Among several therapeutic approaches, endocrine therapy is one of the most effective treatments for ER. + Endocrine-based therapy has become the standard adjuvant treatment for postmenopausal women with breast cancer (Cardoso et al., Breast (2017) 31:244-259). Drugs that selectively target ER, such as selective ER down-regulators (SERDs) like fulvestrant or selective ER modulators (SERMs) like tamoxifen, or drugs that prevent estrogen biosynthesis, such as aromatase inhibitors (AIs), are important therapeutic tools for blocking the ER signaling pathway that leads to cancer progression. Unless there is evidence of imminent or actual visceral disease, endocrine-based therapy is the preferred treatment modality because it has greater activity and better tolerability than cytotoxic chemotherapy. However, almost all tumors become resistant to endocrine-based therapy, and novel approaches are needed to circumvent resistance, extend the pre-chemotherapy period, and extend lifespan.

[0003] The phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) and mammalian target of rapamycin (mTOR) signaling pathways have been identified as playing a role in the development of resistance and are altered in approximately 50% of ER+ advanced breast cancer tumors. Mutations in exons 9 and 20 of PIK3CA, encoding the p110α subunit, are the most commonly observed mutations, but loss-of-function mutations in PTEN, a negative regulator of PI3K / AKT signaling, and activating mutations in AKT1 also occur. Increased activation of the PI3K / AKT pathway via mTORC1 signaling promotes tumor cell growth and survival, leading to ligand-independent activation of ER and resistance to endocrine therapy (Figure 1). Alternatively, inhibition of the PI3K pathway leads to a compensatory increase in ligand-dependent ER transcription and increased ER signaling.

[0004] Therefore, there is a rationale for simultaneously inhibiting the ER and PI3K / AKT pathways in breast cancer patients.

[0005] AKT is a serine / threonine-specific protein kinase that plays a key role in multiple cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ), which are encoded by different genes.

[0006] Capivasertib is a potent, selective pan-AKT kinase inhibitor that, when combined with the selective ER degrader (SERD) fulvestrant, has shown activity in preclinical models of both endocrine-sensitive and endocrine-resistant BC (Ribas R et al. Mol Cancer Ther (2015) 14:2035-48).

[0007] Fulvestrant, marketed under the trade name FASLODEX, among others, is used in combination with palbociclib (a CDK4 / 6 inhibitor) to treat ER+ metastatic breast cancer, which may also be HER2-negative, and hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer, which is a selective estrogen receptor degrader (SERD), acting by both downregulating and degrading the estrogen receptor.

[0008] The phase 2 FAKTION trial (NCT01992952) demonstrated that the addition of capivasertib to fulvestrant endocrine therapy resulted in a significant improvement in progression-free survival (PFS) in postmenopausal women with aromatase inhibitor (AI)-resistant ER-positive, HER2-negative advanced breast cancer who had no prior exposure to cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors.

[0009] The FAKTION trial was first designed in 2012 to define PI3K / AKT / PTEN pathway alterations as to whether tumors harbored one of four specific PIK3CA mutations (E542K or E545K in exon 9 or H1047R or H1047L in exon 20 detected by either pyrosequencing or digital-droplet PCR (ddPCR) testing on tumor tissue or cell-free DNA (cfDNA)) or showed loss of PTEN expression by immunohistochemistry. Using these original methods to identify tumor PI3K / AKT / PTEN pathway status, secondary endpoint subgroup analyses suggested that the addition of capivasertib to fulvestrant conferred benefit to participants with either PI3K / AKT / PTEN pathway-altered or non-pathway-altered advanced breast cancer (referred to herein as the original pathway-altered and original pathway-unaltered subgroups) (Jones RH et al., Lancet Oncol (2020) 21:345-57).

[0010] Further evaluation of the FAKTION data and an updated PFS analysis in the FAKTION intent-to-treat population after an additional 34 months of follow-up analyzed overall survival. In a prespecified exploratory analysis, investigators considered the benefit of capivasertib according to tumor PI3K / AKT / PTEN pathway alteration status after expanding testing of the initially collected tumor or plasma samples to include next-generation sequencing (NGS) assays. Retrospective use of NGS testing identified an expanded pathway altered subgroup of FAKTION participants whose tumors harbored PIK3CA mutations or AKT1 E17K or deleterious PTEN alterations, as well as a corresponding expanded pathway unaltered subgroup. Updated FAKTION data showed that significant PFS and overall survival benefits of capivasertib were observed in the subgroup with expanded PI3K / AKT / PTEN pathway alterations but not in the subgroup with unaltered PI3K / AKT / PTEN pathways (Howell et al., Lancet Oncol (2022) 23:851-64). The investigators hypothesized that limitations of the original study incorrectly placed some participants with truly pathway-altered tumors in the subgroup with unaltered pathways, and therefore the primary analysis (Jones RH et al., Lancet Oncol (2020) 21:345-57) failed to detect an increased benefit of capivasertib for participants with PI3K / AKT / PTEN pathway-altered tumors.

[0011] No safety concerns were identified, and the FAKTION results led to the design and initiation of the phase 3 CAPItello-291 trial (NCT04305496).The objective of the phase 3 CAPItello-291 trial (NCT04035496) is to evaluate the efficacy and safety of capivasertib in combination with fulvestrant versus placebo with fulvestrant in patients with locally advanced or metastatic hormone receptor-positive / HER2-negative breast cancer after recurrence or progression during or after AI therapy.

[0012] There is a need to further understand the impact of mutations in the PI3K / AKT / PTEN pathway on response to combination treatment with capivasertib and fulvestrant in the target patient population. Summary of the Invention

[0013] A first aspect of the present invention provides a composition comprising capivasertib and a composition comprising fulvestrant for use as combination therapy in the treatment of a patient with hormone receptor-positive (HR+) breast cancer, wherein the patient's tumor cells have any of the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Does not contain any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0014] A second aspect of the invention provides a method of treating a patient with hormone receptor positive (HR+) breast cancer, the method comprising administering to the patient a combination therapy comprising a therapeutically effective amount of capivasertib and a therapeutically effective amount of fulvestrant, wherein the patient's tumor cells possess any of the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Does not contain any of the mutations in the PTEN gene listed in Table 3 or Table 4. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of the PI3K / AKT / PTEN and ER signaling pathways. [Figure 2]This graph shows progression-free survival (PFS) in the overall population. There were 258 PFS events in the capivasertib plus fulvestrant group (N=355), with a median PFS of 7.2 months (95% CI: 5.5-7.4 months). There were 293 PFS events in the placebo plus fulvestrant group (N=353), with a median PFS of 3.6 months (95% CI: 2.8-3.7 months). The adjusted hazard ratio (HR) was 0.60 (95% CI: 0.51, 0.71; two-sided p-value <0.001). A "+" in the figure indicates a censored observation. HRs were estimated using a Cox proportional hazards model stratified by the presence of liver metastases, prior use of CDK4 / 6 inhibitors, and geographic region. [Figure 3] This graph shows PFS in the AKT pathway altered population. There were 121 PFS events in the capivasertib plus fulvestrant group (N=155), with a median PFS of 7.3 months (95% CI: 5.5-9.0 months). There were 115 PFS events in the placebo plus fulvestrant group (N=134), with a median PFS of 3.1 months (95% CI: 2.0-3.7 months). The adjusted hazard ratio (HR) was 0.50 (95% CI: 0.38, 0.65; two-sided p-value <0.001). A "+" in the figure indicates a censored observation. HRs were estimated using a Cox proportional hazards model stratified by the presence of liver metastases and prior use of CDK4 / 6 inhibitors. [Figure 4] This graph shows PFS in the pathway-unaltered population (including unknowns, i.e., patients without valid NGS results). There were 137 PFS events in the capivasertib + fulvestrant group (N = 200), with a median PFS of 7.2 months (95% CI: 4.5-7.4 months). There were 178 PFS events in the placebo + fulvestrant group (N = 219), with a median PFS of 3.7 months (95% CI: 3.0-5.0 months). The hazard ratio (HR) was 0.70 (95% CI: 0.56, 0.88). "+" in the figure indicates a censored observation. [Figure 5]This graph shows PFS in the non-altered pathway population (excluding unknown pathways). There were 103 PFS events in the capivasertib + fulvestrant group (N = 142), with a median PFS of 5.3 months (95% CI: 3.6-7.3 months). There were 141 PFS events in the placebo + fulvestrant group (N = 171), with a median PFS of 3.7 months (95% CI: 3.5-5.1 months). The hazard ratio (HR) was 0.79 (95% CI: 0.61, 1.02). A "+" in the figure indicates a censored observation. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to the surprising discovery that combination therapy comprising capivasertib and fulvestrant is useful for treating hormone receptor-positive (HR+) advanced breast cancer in a patient population whose tumor tissue does not harbor any of a number of specific genetic mutations affecting the PI3K / AKT / PTEN pathway.

[0017] Specifically, the inventors have shown that a combination therapy containing capivasertib and fulvestrant can be used to increase progression-free survival (PFS) in a patient population that does not have specific genetic mutations affecting the PI3K / AKT / PTEN pathway.

[0018] A first aspect of the present invention provides a pharmaceutical composition comprising capivasertib and a pharmaceutical composition comprising fulvestrant for use as combination therapy in the treatment of a patient with hormone receptor positive (HR+) breast cancer, wherein the patient's tumor cells possess any of the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Does not contain any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0019] A second aspect of the invention provides a method of treating a patient with hormone receptor positive (HR+) breast cancer, the method comprising administering to the patient a combination therapy comprising a therapeutically effective amount of capivasertib and a therapeutically effective amount of fulvestrant, wherein the patient's tumor cells possess any of the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Does not contain any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0020] The human wild-type PIK3CA, AKT1, and PTEN genes are identified in Table 1.

[0021] [Table 1]

[0022] PIK3CA and AKT1 are oncogenes, so mutations that result in activation of the proteins affect the PIK3CA / AKT1 / PTEN pathway. A list of eligible mutations in the AKT1 and PIK3CA genes is shown in Table 2.

[0023] [Table 2]

[0024] PTEN is a tumor suppressor gene, and therefore genetic alterations that result in loss of functional protein affect the PIK3CA / AKT1 / PTEN pathway. We have created a list of seven different criteria for identifying such alterations by next-generation sequencing (NGS). Details of the criteria for identifying eligible alterations in the PTEN gene are provided in Table 3, and additional specific eligible missense mutations are provided in Table 4.

[0025] [Table 3]

[0026] [Table 4]

[0027] The sample obtained from the patient can be any sample type containing breast tumor genomic material (e.g., tissue, blood, plasma, or cell-free DNA). Preferably, the sample is a breast tumor tissue sample.

[0028] There are a variety of methods routinely used in the art for detecting genetic mutations, and any suitable method may be used.

[0029] Next-generation sequencing (NGS) technology can detect hundreds of alterations across multiple genes in a single test, and as those skilled in the art will recognize, NGS can be used to define tumor biomarker status. A single NGS assay can sensitively detect activating PIK3CA and AKT1 mutations across their entire gene structure, as well as PTEN alterations and gene deletions.

[0030] In a preferred embodiment, NGS is used to detect the presence or absence of any of the mutations detailed in Tables 2-4 in a sample containing tumor cells obtained from a patient. Preferably, the sample is a breast tumor tissue sample.

[0031] Commercially available NGS technologies include the FoundationOne® CDx (F1CDx) NGS clinical trial assay from Foundation Medicine, Cambridge, MA, USA, which can be used to detect single nucleotide mutations, insertion and deletion changes, and copy number changes in DNA isolated from formalin-fixed, paraffin-embedded tumor tissue specimens. GuardantOMNI™ (Guardant Health, Redwood City, CA, USA) uses NGS of cfDNA extracted from plasma samples to detect single nucleotide mutations, insertion and deletion changes, copy number changes, or fusions in 500 genes, including alterations in PIK3CA, AKT1, and PTEN. Burning Rock Biotech Limited (Guangzhou, China) is developing a liquid biopsy approach using an NGS-based circulating tumor DNA (ctDNA) assay.

[0032] Jones RH et al (Lancet Oncol (2020) 21:345-57) describe identifying tumor PI3K / AKT / PTEN pathway status using pyrosequencing and / or digital droplet PCR [ddPCR] testing on tumor tissue or cell-free DNA [cfDNA], or demonstrated loss of PTEN expression by immunohistochemistry.

[0033] As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal, preferably a human. A patient may be a pre- or post-menopausal female, or a male.

[0034] The patient has hormone receptor-positive (HR+) breast cancer, which means that the tumor cells express surface receptors that bind to the hormones estrogen and / or progesterone.

[0035] In one embodiment, the patient has estrogen receptor-positive (ER+) breast cancer (with or without co-expression of the progesterone receptor). ER+ cancer may be defined as at least 10% of primary or metastatic tumor cells staining positive for the estrogen receptor.

[0036] In a preferred embodiment, the cancer is classified as a HER2-negative cancer, meaning that the tumor cells do not express human epidermal growth factor receptor 2 (HER2). This is confirmed histologically from a biopsy or metastasis taken at the time of diagnosis. In one embodiment, HER2-negative is defined as an immunohistochemistry (IHC) score of 0, 1+, or 2+ and negative in situ hybridization.

[0037] In a preferred embodiment, the cancer is classified as advanced breast cancer (ABC), which means histologically confirmed, locally advanced (inoperable) or metastatic breast cancer with radiological or objective evidence of recurrence or progression, with either recurrence or progression during or within 12 months of the completion of (neo)adjuvant treatment with a regimen containing an aromatase inhibitor (AI) as single agent or in combination.

[0038] Aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER) + )) are one of the main therapeutic approaches for breast cancer. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumor progression. Examples of AIs include anastrozole (sold under the trade name ARIMIDEX, among others), exemestane (sold under the trade name AROMASIN, among others), and letrozole (sold under the trade name FEMARA, among others).

[0039] The patient may or may not have been previously treated with a CDK4 / 6 inhibitor (e.g., palbociclib (sold under the tradename IBRANCE, among others), ribociclib (sold under the tradenames KISQALI and KRYXANA), abemaciclib (sold under the tradename VERZENIO, among others). CDK4 / 6 inhibitors are approved treatment options in certain markets for patients with advanced or metastatic HR+ HER2- breast cancer who have received prior endocrine therapy and / or in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy. In one embodiment, the patient has been previously treated with a CDK4 / 6 inhibitor.

[0040] According to the present invention, therapeutically effective amounts of capivasertib and fulvestrant can be used to treat advanced breast cancer in patients.

[0041] (Also known as AZD5363 and by the chemical name (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide) is an investigational oral treatment currently in Phase III trials for the treatment of multiple subtypes of breast cancer, prostate cancer, and Phase II trials for hematologic malignancies. Capivasertib, a potent, selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1 / 2 / 3), is being evaluated in combination with existing therapies in tumors with alterations in the PI3K / AKT / PTEN pathway and tumors that depend on signaling through this pathway for survival.

[0042] In a preferred embodiment, capivasertib is administered according to the following dosing regimen: 400 mg orally twice daily; 4 days on, 3 days off.

[0043] Fulvestrant, marketed under the trade name FASLODEX and known by the chemical name 7α-[9-[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol, is a selective estrogen receptor degrader (SERD) used to treat ER+ metastatic breast cancer (including ER+ / HER2-negative breast cancer). Fulvestrant is preferably administered intramuscularly and comes in a prefilled syringe containing 250 mg of fulvestrant in a 5 mL solution. The recommended dosage for adult women is 500 mg at monthly intervals, with an additional 500 mg dose given two weeks after the initial dose.

[0044] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to effect the intended application, including, but not limited to, disease treatment. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells (e.g., reduced platelet adhesion and / or cell migration). 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 timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0045] A "therapeutic benefit," as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0046] The terms "treat," "treating," and "treatment" refer to at least partially alleviating, inhibiting, preventing, and / or ameliorating a condition, disorder, or disease, such as advanced breast cancer. The effectiveness of treating advanced breast cancer can be assessed in various ways, including, but not limited to: inhibiting cancer cell proliferation (including reversing cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); symptom improvement; duration of response to treatment; delay in disease progression; and prolongation of progression-free survival (PFS).

[0047] The term "combination therapy" can refer to simultaneous, separate, or sequential administration of two or more therapeutic agents. In one embodiment, "combination" can refer to simultaneous administration (e.g., administration of both agents in a single dosage form). In another embodiment, "combination" refers to separate administration (e.g., administration of both agents in separate dosage forms but at substantially the same time). In further and preferred embodiments of the present invention, "combination" refers to separate and sequential administration (e.g., when a first therapeutic agent is administered, followed by a delay, followed by administration of a second or additional therapeutic agent). Each of the two therapeutic agents (capivasertib and fulvestrant) can be administered multiple times within a given treatment cycle. When administration is sequential or separate, the delay in administration of the subsequent component should not be too long or too short so as not to lose the benefit of the combination.

[0048] The terms "co-administration," "in combination with," "simultaneously," and "concomitant use," as used herein, encompass the administration of two or more active pharmaceutical ingredients to a subject, including simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which more than one active pharmaceutical ingredient is present.

[0049] The inventors have shown that a combination therapy including capivasertib and fulvestrant can be used to increase progression-free survival (PFS) in a patient population that does not have specific genetic mutations affecting the PI3K / AKT / PTEN pathway. In one embodiment, the median PFS in the patient population treated with the combination therapy is 4 months or more, 5 months or more, or about 5.3 months.

[0050] As used herein in the context of a clinical trial study, the term "progression-free survival (PFS)" is defined as the time (usually measured in months) from randomization to either first documented progression confirmed by RECIST version 1.1 criteria (see Eisenhauer et al., European Journal of Cancer (2009) 45:228-247) or death from any cause. In a real-world clinical (non-trial) setting, PFS can be defined as the time from the first administration of combination therapy to either first documented progression confirmed by RECIST version 1.1 criteria or death from any cause.

[0051] By administering a combination of capivasertib and fulvestrant in accordance with the invention as defined herein, PFS can be increased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% compared to treatment with fulvestrant without capivasertib. In one embodiment, the increase in PFS time is clinically meaningful. In another embodiment, the increase in PFS time is statistically significant.

[0052] An additional benefit of using a combination therapy containing capivasertib and fulvestrant in patient populations without specific genetic mutations affecting the PI3K / AKT / PTEN pathway is an increase in overall survival (OS), defined as the time from randomization to death from any cause (usually measured in months). In a real-world clinical (non-trial) setting, OS can be defined as the time from administration of the combination therapy to death from any cause.

[0053] By administering a combination of capivasertib and fulvestrant in accordance with the invention as defined herein, OS can be increased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% compared to treatment with fulvestrant without capivasertib.

[0054] Modes for carrying out the invention The invention will now be further defined by reference to the following non-limiting examples. [Example]

[0055] method Eligible pre- or postmenopausal women or men with HR+ / HER2 advanced breast cancer that had recurred or progressed during or within 12 months of AI therapy with or without a CDK4 / 6 inhibitor were randomized 1:1 to receive fulvestrant (F) (standard dosing schedule: 500 mg intramuscular injection on days 1 and 15 of a 28-day cycle 1; then every 4 weeks) with either placebo (PBO) or capivasertib (400 mg orally twice daily; 4 days on, 3 days off).

[0056] Randomization was stratified by the presence of liver metastases, previous use of CDK4 / 6 inhibitors, and geographic location.

[0057] Treatment continued until objective, radiological disease progression as defined by Response Evaluation Criteria in Solid Tumors version 1.1, unacceptable toxicity, withdrawal of consent, or death.

[0058] Given the importance of AKT pathway activation, patients were assigned as having an AKT pathway alteration after randomization based on next-generation sequencing analysis identifying at least one qualifying PIK3CA, AKT1, or PTEN alteration in tumor tissue collected before randomization.

[0059] Qualifying PIK3CA and AKT1 alterations are detailed in Table 2 above. Qualifying PTEN alterations are detailed in Tables 3 and 4 above. If tumor cells in a sample obtained from a patient are identified as having any one or more of the genetic alterations listed in any of Tables 2-4, the patient is characterized as having an altered PI3K / AKT / PTEN pathway state. If tumor cells are not identified as having any of the genetic alterations listed in any of Tables 2-4, the patient is characterized as having an unaltered PI3K / AKT / PTEN pathway state.

[0060] The dual secondary endpoints were investigator-assessed progression-free survival (PFS) in the overall population (i.e., pathway-altered and non-pathway-altered subjects, including unknowns) and in the pathway-altered population.

[0061] result A total of 708 patients were randomized: 355 to capivasertib + F and 353 to PBO + F. Overall, 41% of patients had AKT pathway alterations, as determined centrally using next-generation sequencing in tumor tissue with the FoundationOne® CDx assay (and for the China study cohort, using the Burning Rock assay). 22% of patients were premenopausal / perimenopausal, 77% were postmenopausal women, and 1% were men. 87% of patients had received at least one prior disease-related therapy for locally advanced or metastatic disease; 69% had received a CDK4 / 6 inhibitor, and 18% had received prior chemotherapy. Demographic and baseline characteristics were broadly balanced between the overall and altered populations and by treatment group.

[0062] In the primary analysis, 551 PFS events occurred in the overall population (see Figure 2). PFS was significantly longer with capivasertib plus F compared with PBO plus F (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51-0.71; p<0.001; median 7.2 vs. 3.6 months).

[0063] 236 PFS events occurred in the AKT pathway altered population (see Figure 3). PFS was significantly longer with capivasertib + F compared with PBO + F (HR 0.50; 95% CI 0.38-0.65; p<0.001; median 7.3 vs. 3.1 months).

[0064] For the pathway-unaltered population (including unknowns, i.e., patients without valid NGS results), 315 PFS events occurred (see Figure 4). Again, PFS was found to be significantly longer with capivasertib + F compared with PBO + F in the AKT pathway-unaltered population (HR 0.7; 95% CI 0.56-0.88; median 7.2 vs. 3.7 months).

[0065] For the pathway-unaltered population (excluding unknown), 144 PFS events occurred (see Figure 5). Again, PFS was found to be significantly longer with capivasertib + F compared with PBO + F (HR 0.79; 95% CI 0.61-1.02; median 5.3 vs. 3.7 months).

[0066] The longer PFS with capivasertib + F compared with PBO + F was found to be similar for patients in the overall population with prior use of a CDK4 / 6 inhibitor (HR 0.62; 95% CI 0.51 to 0.75) and for patients in the overall population without prior use of a CDK4 / 6 inhibitor (HR 0.65; 95% CI 0.47 to 0.91).

[0067] The objective response rates among patients with measurable disease in the capivasertib + F group versus the PBO + F group were 22.9% vs. 12.2% in the overall population and 28.8% vs. 9.7% in the changed population. In the overall population, the most frequent all-grade adverse events (AEs; unadjusted for exposure) with capivasertib + F were diarrhea (72.4% vs. 20.0% in the PBO + F group), nausea (34.6% vs. 15.4%), and rash (22.0% vs. 4.3%). The most frequent grade ≥ 3 AEs were diarrhea (9.3% vs. 0.3%), maculopapular rash (6.2% vs. 0%), and rash (5.4% vs. 0.3%). AEs leading to discontinuation of capivasertib / placebo were reported in 13.0% and 2.3% of patients, respectively.

[0068] conclusion This phase 3 clinical trial met both primary endpoints, with capivasertib+F significantly improving PFS in both AKT pathway altered and AKT pathway unaltered populations.

[0069] This is a particularly significant result with therapeutic implications for patients in the pathway-unaltered population, as a previous study found that in the NGS-identified pathway-unaltered subgroup, PFS was similar for both the capivasertib + F and PBO + F treatment groups. A significant PFS and overall survival benefit for capivasertib was seen in the pathway-altered subgroup, but not in the pathway-unaltered subgroup (see Howell et al., Lancet Oncol 2022;23:851-64).

[0070] The overall safety profile of capivasertib + F appears consistent with the known profile of the combination. This is the first study to demonstrate a statistically significant, clinically meaningful PFS improvement with an AKT inhibitor in HR+ABC.

Claims

1. 1. A composition comprising capivasertib and a composition comprising fulvestrant for use as combination therapy in the treatment of a patient with hormone receptor positive (HR+) breast cancer, wherein the patient's tumor cells have any of the following mutations: i. E17K in the AKT1 gene; ii. any of the mutations in the PIK3CA gene listed in Table 2, and iii. A composition comprising capivasertib and a composition comprising fulvestrant for use, wherein the composition does not contain any of the mutations in the PTEN gene listed in Table 3 or Table 4.

2. 2. A composition comprising capivasertib and a composition comprising fulvestrant for use according to claim 1, wherein the patient has estrogen receptor positive (ER+) breast cancer.

3. A composition comprising capivasertib and a composition comprising fulvestrant for use according to claim 1 or 2, wherein the patient has aromatase inhibitor-resistant breast cancer.

4. A composition comprising capivasertib and a composition comprising fulvestrant for use according to any one of claims 1 to 3, wherein the patient has HER2-negative breast cancer.

5. The composition comprising capivasertib and the composition comprising fulvestrant for use according to any one of claims 1 to 4, wherein the composition comprising capivasertib and the composition comprising fulvestrant are administered separately.

6. 1. A method of treating a patient with hormone receptor positive (HR+) breast cancer, comprising administering to the patient a combination therapy comprising a therapeutically effective amount of capivasertib and a therapeutically effective amount of fulvestrant, wherein the patient's tumor cells possess any of the following mutations: i. E17K in the AKT1 gene; ii. any of the mutations in the PIK3CA gene listed in Table 2, and iii. A method not comprising any of the mutations in the PTEN gene listed in Table 3 or Table 4.

7. 7. The method of claim 6, wherein the patient has estrogen receptor positive (ER+) breast cancer.

8. 8. The method of claim 6 or 7, wherein the patient has aromatase inhibitor-resistant breast cancer.

9. The method of any one of claims 6 to 8, wherein the patient has HER2-negative breast cancer.

10. The method of any one of claims 6 to 9, wherein capivasertib and fulvestrant are administered separately.

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