Cancer therapy using capacitib and fluvestant

Abstract

The present disclosure relates to therapeutic combinations of kapatinib and fulvestrant for use in treating specific patient populations with advanced breast cancer, and methods of treating specific breast cancer patient populations with a combination of kapatinib and fulvestrant.

Description

Technical Field

[0001] The present disclosure relates to a therapeutic combination of capivasertib and fulvestrant for treating a specific patient population suffering from advanced breast cancer, and methods of treating a specific breast cancer patient population with a combination of capivasertib and fulvestrant. Background Art

[0002] In women, breast cancer is both the most common cancer worldwide and the second leading cause of cancer death (Cardoso et al., Breast (2017) 31:244 - 259). Approximately 60% of premenopausal breast cancer patients and 75% of postmenopausal breast cancer patients have estrogen receptor - positive (ER + ) cancer. ER expression and activation are important factors controlling tumor growth and recurrence (Chen, OMICS (2011) 15:347 - 352). Although there are several treatment methods for postmenopausal women with ER + breast cancer, endocrine therapy has become the standard adjuvant treatment (Cardoso et al., Breast (2017) 31:244 - 259). Drugs that selectively target ER, such as selective ER down - regulators (SERDs), such as fulvestrant, or selective ER modulators (SERMs), such as tamoxifen, or drugs that block 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 an impending or actual visceral crisis, endocrine - based therapy is the preferred treatment modality because it has higher activity and better tolerance than cytotoxic chemotherapy. However, almost all tumors develop tolerance to endocrine - based therapy, and new methods are needed to circumvent tolerance, extend the pre - chemotherapy window, and prolong survival.

[0003] It has been determined that the phosphatidylinositol 3 - kinase (PI3K) / protein kinase B (AKT) and mammalian target of rapamycin (mTOR) signaling pathways play a role in the development of tolerance and are altered in approximately 50% of ER+ advanced breast cancer tumors. Mutations in exon 9 and exon 20 of PIK3CA, which encodes the p110α subunit, are the most common mutations, but loss - of - function mutations in PTEN, a negative regulator of PI3K / AKT signaling, and activating mutations in AKT1 also occur. Activation of the PI3K / AKT pathway via mTORC1 signaling promotes tumor cell growth and survival and causes ligand - independent activation of ER and tolerance to endocrine therapy ( Figure 1) Alternatively, inhibition of the PI3K pathway causes a compensatory increase in ligand-dependent ER transcription and an increase in ER signaling.

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

[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, which are encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ).

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

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

[0008] The phase 2 FAKTION trial (NCT01992952) showed that in postmenopausal women with aromatase inhibitor (AI)-resistant ER-positive, HER2-negative advanced breast cancer who had not previously been exposed to cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors, adding capivasertib to fulvestrant endocrine therapy significantly improved progression-free survival (PFS).

[0009] The FAKTION trial was initially designed in 2012, and the status of PI3K / AKT / PTEN pathway alteration was defined according to whether the tumor carried one of four specific PIK3CA mutations (E542K or E545K in exon 9 or H1047R or H1047L in exon 20 detected by pyrosequencing or digital droplet PCR [ddPCR] testing (or both) of tumor tissue or cell-free DNA [cfDNA], or loss of PTEN expression determined by immunohistochemistry). Using these original methods to identify the tumor PI3K / AKT / PTEN pathway status, subgroup analysis of secondary endpoints showed that adding capivasertib to fulvestrant conferred a beneficial effect on participants with advanced breast cancer with PI3K / AKT / PTEN pathway alteration or advanced breast cancer with unaltered pathway (herein referred to 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 analyzed overall survival and updated PFS analysis in the FAKTION intention-to-treat population after an additional 34 months of follow-up. In a pre-specified exploratory analysis, the investigators considered the beneficial effect of capivasertib on the status of tumor PI3K / AKT / PTEN pathway alteration after expanding the testing of initially collected tumor or plasma samples to include next-generation sequencing (NGS) assays. Retrospective use of the NGS test identified an extended pathway-altered subgroup of FAKTION participants whose tumors carried PIK3CA mutations or AKT1 E17K or deleterious PTEN alterations, and a corresponding extended pathway-unaltered subgroup. The updated FAKTION data showed a significant PFS and overall survival beneficial effect of capivasertib in the extended PI3K / AKT / PTEN pathway-altered subgroup, but no such beneficial effect was observed in the extended PI3K / AKT / PTEN pathway-unaltered subgroup (Howell et al., Lancet Oncol (2022) 23:851–64). The investigators hypothesized that the primary analysis (Jones RH et al., Lancet Oncol (2020) 21:345–57) failed to detect an increased beneficial effect of capivasertib on participants with tumors with PI3K / AKT / PTEN pathway alteration because limitations of the original test misclassified some participants with tumors with bone-specific pathway alterations into the pathway-unaltered subgroup.

[0011] Safety issues were undetermined, and the FAKTION results led to the design and initiation of the Phase 3 CAPItello-291 trial (NCT04305496). The purpose of the Phase 3 CAPItello-291 trial (NCT04035496) was to evaluate the efficacy and safety of the combination of capivasertib and fulvestrant compared to placebo and 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] It is further understood the impact of mutations in the PI3K / AKT / PTEN pathway on the response to combination therapy of 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, which are used as combination therapy for treating patients with hormone receptor-positive (HR+) breast cancer, wherein the tumor cells of the patients do not contain any of the following mutations:

[0014] i. E17K in the AKT1 gene;

[0015] ii. Any of the mutations in the PIK3CA gene listed in Table 2; and

[0016] iii. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0017] A second aspect of the present invention provides a method for treating patients 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 tumor cells of the patient do not contain any of the following mutations:

[0018] i. E17K in the AKT1 gene;

[0019] ii. Any of the mutations in the PIK3CA gene listed in Table 2; and

[0020] iii. Any of the mutations in the PTEN gene listed in Table 3 or Table 4. Brief Description of the Drawings

[0021] Figure 1 is a graphical representation of the PI3K / AKT / PTEN and ER signaling pathways.

[0022] Figure 2It is a figure showing the progression-free survival (PFS) in the total population. There were 258 PFS events (N = 355) in the capivasertib + fulvestrant group, with a median PFS of 7.2 months (95% CI: 5.5 months to 7.4 months). There were 293 PFS events (N = 353) in the placebo + fulvestrant group, with a median PFS of 3.6 months (95% CI: 2.8 months to 3.7 months). The adjusted hazard ratio (HR) was 0.60 (95% CI: 0.51, 0.71; two-sided p-value < 0.001). The "+" in the figure indicates censored observations. The Cox proportional hazards model was used to estimate the HR, and this Cox proportional hazards model was stratified by the presence of liver metastases, previous use of CDK4 / 6 inhibitors, and geographical region.

[0023] Figure 3 It is a figure showing the PFS in the population with altered AKT pathway. There were 121 PFS events (N = 155) in the capivasertib + fulvestrant group, with a median PFS of 7.3 months (95% CI: 5.5 months to 9.0 months). There were 115 PFS events (N = 134) in the placebo + fulvestrant group, with a median PFS of 3.1 months (95% CI: 2.0 months to 3.7 months). The adjusted hazard ratio (HR) was 0.50 (95% CI: 0.38, 0.65; two-sided p-value < 0.001). The "+" in the figure indicates censored observations. The Cox proportional hazards model was used to estimate the HR, and this Cox proportional hazards model was stratified by the presence of liver metastases and previous use of CDK4 / 6 inhibitors.

[0024] Figure 4 It is a figure showing the PFS in the population with unaltered pathways (including patients with unknown, i.e., no valid NGS results). There were 137 PFS events (N = 200) in the capivasertib + fulvestrant group, with a median PFS of 7.2 months (95% CI: 4.5 months to 7.4 months). There were 178 PFS events (N = 219) in the placebo + fulvestrant group, with a median PFS of 3.7 months (95% CI: 3.0 months to 5.0 months). The hazard ratio (HR) was 0.70 (95% CI: 0.56, 0.88). The "+" in the figure indicates censored observations.

[0025] Figure 5This is a graph showing PFS in the group where the display pathway was not changed (excluding unknown subjects). There were 103 PFS events in the capivasertib + fulvestrant group (N = 142), with a median PFS of 5.3 months (95% CI: 3.6 months to 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 months to 5.1 months). The hazard ratio (HR) was 0.79 (95% CI: 0.61, 1.02). The "+" in the graph indicates censored observations. Detailed implementation mode

[0026] The present disclosure relates to the following unexpected finding: A combination therapy comprising capivasertib and fulvestrant is used to treat hormone receptor-positive (HR+) advanced breast cancer in a patient population whose tumor tissue does not contain any of a number of specific genetic mutations affecting the PI3K / AKT / PTEN pathway.

[0027] Specifically, the inventors have demonstrated that a combination therapy comprising capivasertib and fulvestrant can be used to increase the progression-free survival (PFS) in a patient population without specific genetic mutations affecting the PI3K / AKT / PTEN pathway.

[0028] The first aspect of the present invention provides a pharmaceutical composition comprising capivasertib and a pharmaceutical composition comprising fulvestrant, and the pharmaceutical composition comprising capivasertib and the pharmaceutical composition comprising fulvestrant are used as a combination therapy for treating patients with hormone receptor-positive (HR+) breast cancer, wherein the tumor cells of the patients do not contain any of the following mutations:

[0029] i. E17K in the AKT1 gene;

[0030] ii. Any of the mutations in the PIK3CA gene listed in Table 2; and

[0031] iii. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0032] The second aspect of the present invention provides a method for 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 tumor cells of the patient do not contain any of the following mutations:

[0033] i. E17K in the AKT1 gene;

[0034] ii. Any of the mutations in the PIK3CA gene listed in Table 2; and

[0035] iii. Any one of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0036] The human wild-type PIK3CA, AKT1, and PTEN genes were identified in Table 1.

[0037] Table 1

[0038]

[0039] Since PIK3CA and AKT1 are oncogenes, mutations that cause protein activation affect the PIK3CA / AKT1 / PTEN pathway. A list of eligible mutations in the AKT1 and PIK3CA genes is provided in Table 2.

[0040] Table 2

[0041] Gene Mutation Exon Annotation AKT1 E17K 2 Hotspot Mutation PIK3CA R88Q 1 PI3K-ABD (p85) Binding Domain PIK3CA N345K 4 PIK3CA C402R 7 PIK3CA E542K 9 Helical Domain PIK3CA E545A 9 Helical Domain PIK3CA E545D 9 Helical Domain PIK3CA E545Q 9 Helical Domain PIK3CA E545K 9 Helical Domain PIK3CA E545G 9 Helical Domain PIK3CA Q546E 9 Helical Domain PIK3CA Q546K 9 Helical Domain PIK3CA Q546R 9 Helical Domain PIK3CA Q546P 9 Helical Domain PIK3CA M1043V 20 PI3_PI4 Kinase Domain PIK3CA M1043I 20 PI3_PI4 Kinase Domain PIK3CA H1047Y 20 PI3_PI4 Kinase Domain PIK3CA H1047R 20 PI3_PI4 Kinase Domain PIK3CA H1047L 20 PI3_PI4 Kinase Domain PIK3CA G1049R 20 PI3_PI4 Kinase Domain

[0042] PTEN is a tumor suppressor gene, so genetic alterations that result in loss of functional protein affect the PIK3CA / AKT1 / PTEN pathway. The inventors have generated a list of seven different criteria to identify 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 other specific eligible missense mutations are provided in Table 4.

[0043] Table 3

[0044]

[0045] Table 4

[0046]

[0047]

[0048] Samples obtained from patients 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.

[0049] There are various methods routinely used in the art for detecting genetic mutations, and any suitable method can be used.

[0050] Next-generation sequencing (NGS) technology can detect hundreds of alterations across multiple genes in a single test, and those skilled in the art will recognize that NGS can be used to define tumor biomarker status. A single NGS assay can sensitively detect activating PIK3CA mutations and AKT1 mutations across their entire gene structures, as well as PTEN alterations and gene deletions.

[0051] In a preferred embodiment, NGS is used to detect the presence or absence of any of the mutations detailed in Tables 2 to 4 in a sample containing tumor cells obtained from a patient. Preferably, the sample is a breast tumor tissue sample.

[0052] Commercially available NGS technologies include the CDx (F1CDx) NGS clinical trial assay (from Foundation Medicine, Cambridge, MA, USA), which can be used to detect single nucleotide variants, insertions and deletions alterations, and copy number alterations in DNA isolated from formalin-fixed paraffin-embedded tumor tissue samples. GuardantOMNI TM (Guardant Health, Redwood City, CA, USA) uses NGS of cfDNA extracted from plasma samples to detect single nucleotide variants, insertions and deletions alterations, copy number alterations, or fusions in 500 genes, including PIK3CA, AKT1, and PTEN alterations. Burning Rock Biotech Limited (Guangzhou, China) is developing a liquid biopsy method using an NGS-based circulating tumor DNA (ctDNA) assay.

[0053] Jones RH et al. (Lancet Oncol (2020) 21:345–57) described the use of pyrosequencing and / or digital droplet PCR [ddPCR] testing of tumor tissue or cell-free DNA [cfDNA] or immunohistochemistry-determined loss of PTEN expression to identify tumor PI3K / AKT / PTEN pathway status.

[0054] As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal, and preferably a human. A patient can be a premenopausal woman or a postmenopausal woman, or a man.

[0055] The patient has hormone receptor-positive (HR+) breast cancer, which means that the tumor cells express surface receptors that bind to estrogen and / or progesterone hormones.

[0056] In one embodiment, the patient has estrogen receptor-positive (ER+) breast cancer (with or without co-expression of progesterone receptor). ER+ cancer can be defined as at least 10% of primary tumor cells or metastatic tumor cells staining positive for estrogen receptor.

[0057] In a preferred embodiment, the cancer is classified as HER2-negative cancer, which means that the tumor cells do not express human epidermal growth factor receptor 2 (HER2). This is histologically confirmed by biopsy or metastasis sampled at the time of diagnosis. In one embodiment, HER2-negative is defined as an immunohistochemistry (IHC) score of 0, 1+, or 2+ and negative for in situ hybridization (ISH).

[0058] In a preferred embodiment, the cancer is classified as advanced breast cancer (ABC), meaning histologically confirmed as locally advanced (inoperable) or metastatic breast cancer by radiological or objective evidence of recurrence or progression (recurrence or progression at the end of or within 12 months of (neo)adjuvant treatment with a regimen containing an aromatase inhibitor (AI) as a single agent or in combination).

[0059] Aromatase inhibitors (AIs) are one of the main treatment methods for estrogen receptor-positive (ER + ) breast cancer in postmenopausal women. They block estrogen biosynthesis by aromatase inhibition, thereby preventing tumor progression. Examples of AIs include anastrozole (sold under the trade name ARIMIDEX, etc.), exemestane (sold under the trade name AROMASIN, etc.), and letrozole (sold under the trade name FEMARA, etc.).

[0060] The patient has been previously treated or not treated with a CDK4 / 6 inhibitor (such as Palbociclib (sold under the trade name IBRANCE, etc.), ribociclib (sold under the trade names KISQALI and KRYXANA), abemaciclib (sold under the trade name VERZENIO, etc.)). In some markets, CDK4 / 6 inhibitors are an approved treatment option in combination with an aromatase inhibitor or fulvestrant for treating patients with advanced or metastatic HR+HER2- breast cancer who have received prior endocrine therapy and / or as an initial endocrine-based therapy. In one embodiment, the patient has been previously treated with a CDK4 / 6 inhibitor.

[0061] According to the present invention, a therapeutically effective amount of capivasertib and fulvestrant can be used to treat advanced breast cancer in a patient.

[0062] Capivasertib (also known as AZD5363 and chemically named (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 therapeutic agent currently in Phase III trials for the treatment of multiple subtypes of breast cancer, prostate cancer, and Phase II trials for hematologic malignancies. The combination of capivasertib, a potent and selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1 / 2 / 3), with existing therapies for tumors with alterations in the PI3K / AKT / PTEN pathway and tumors that rely on signaling through this pathway is being evaluated for survival.

[0063] In a preferred embodiment, capivasertib is administered according to the following dosing schedule: 400 mg, orally, twice daily; 4 days of dosing followed by 3 days off.

[0064] Fulvestrant (sold under the trade name FASLODEX, etc. and chemically named 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 for the treatment of ER+ metastatic breast cancer (including ER+ / HER2-negative breast cancer). Fulvestrant is preferably administered by intramuscular injection and is provided in a prefilled syringe containing 250 mg of fulvestrant dissolved in 5 ml of solution. The recommended dose in adult women is 500 mg at one-month intervals, with an additional 500 mg dose given two weeks after the initial dose.

[0065] The term "effective amount" or "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 may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated (e.g., the subject's weight, age, and gender), 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 (e.g., a reduction in platelet adhesion and / or cell migration) in target cells. 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.

[0066] As used herein, the term "therapeutic effect" encompasses therapeutic beneficial effects and / or prophylactic beneficial effects. Prophylactic effects include delaying or eliminating the onset 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.

[0067] The term "treatment" refers to at least partially alleviating, inhibiting, preventing, and / or ameliorating a disorder, condition, or disease, such as advanced breast cancer. The effectiveness of treatment of advanced breast cancer 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 prolongation of progression-free survival (PFS).

[0068] The term "combination therapy" can refer to the administration of two or more therapeutic agents simultaneously, separately, or sequentially. In one embodiment, "combination" can refer to simultaneous administration (e.g., administration of two agents in a single dosage form). In another embodiment, "combination" refers to separate administration (e.g., administration of two agents in separate dosage forms but substantially simultaneously). In another preferred embodiment of the present invention, "combination" refers to separate and sequential administration (e.g., wherein a first therapeutic agent is administered,

[0069] then delayed, and then a second therapeutic agent or another therapeutic agent is administered). The two therapeutic agents (capivasertib and fulvestrant) can each be administered multiple times within a predetermined treatment cycle. When administration is sequential or separate, the delay in administration of the latter component should be neither too long nor too short so as not to lose the beneficial effects of the combination.

[0070] As used herein, the terms "co-administer," "in combination with," "simultaneously," and "concurrently" encompass the administration of 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.

[0071] The inventors have demonstrated that combination therapy comprising 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 combination therapy is 4 months or longer, 5 months or longer, or about 5.3 months.

[0072] As used herein in the context of clinical trial studies, the term "progression-free survival (PFS)" is defined as the time from randomization to the first documented progression confirmed by the RECIST 1.1 criteria (see Eisenhauer et al., European Journal of Cancer (2009) 45:228-247) or death from any cause (usually measured in months). In a real-world clinical (non-trial) setting, PFS can be defined as the time from the first administration of the combination therapy to the first documented progression confirmed by the RECIST 1.1 criteria or death from any cause.

[0073] By administering to a patient a combination of capivasertib and fulvestrant according to the invention as defined herein, the PFS 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 alone without capivasertib. In one embodiment, the increase in PFS time is clinically meaningful. In another embodiment, the increase in PFS time is statistically significant.

[0074] In a patient population that does not have a specific genetic mutation affecting the PI3K / AKT / PTEN pathway, another beneficial effect of using the combination therapy comprising capivasertib and fulvestrant is an increase in overall survival (OS), which is 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 the administration of the combination therapy to death from any cause.

[0075] By administering to a patient a combination of capivasertib and fulvestrant according to the invention as defined herein, the 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 alone without capivasertib.

[0076] Modes for Carrying Out the Invention

[0077] The invention will now be further defined with reference to the following non-limiting examples.

[0078] Examples

[0079] Methods

[0080] Pre- or post-menopausal women or men with HR+ / HER2- advanced breast cancer who relapse or progress within 12 months during or after AI therapy with or without a CDK4 / 6 inhibitor were randomly assigned 1:1 to: receive fulvestrant (F) (according to the standard dosing schedule (intramuscular injection of 500 mg dose: cycle 1, days 1 and 15 of 28 days; then every 4 weeks)) versus placebo (PBO); or receive the combination of fulvestrant and capivasertib (400 mg, orally, twice daily; 4 days on, 3 days off) for safety and tolerability.

[0081] Randomization was stratified by the presence of liver metastases, prior use of CDK4 / 6 inhibitors, and geographical location.

[0082] Treatment continued until objective radiographic disease progression as defined by Response Evaluation Criteria in Solid Tumors version 1.1, unacceptable toxicity, withdrawal of consent, or death.

[0083] Given the importance of AKT pathway activation, patients were assigned to post-randomization for AKT pathway alteration based on next-generation sequencing analysis in tumor tissue collected prior to randomization (identifying at least one eligible PIK3CA, AKT1, or PTEN alteration).

[0084] Eligible PIK3CA and AKT1 alterations are detailed in Table 2 above. Eligible 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 mutations listed in any of Tables 2 to 4, then the patient is characterized as having a PI3K / AKT / PTEN pathway altered status. If tumor cells are identified as not having any one of the genetic mutations listed in any of Tables 2 to 4, then the patient is characterized as having a PI3K / AKT / PTEN pathway unaltered status.

[0085] The dual primary endpoints were progression-free survival (PFS) as assessed by the investigator in the total population (i.e., subjects with pathway alteration and subjects with unaltered pathway, including unknown subjects) and in the population with pathway alteration.

[0086] Results

[0087] A total of 708 patients were randomized: 355 were assigned to capivasertib + F and 353 were assigned to PBO + F. Overall, 41% of patients had an AKT pathway alteration, as determined using

[0088] The CDx assay (using the Burning Rock assay for the Chinese test cohort) was centrally determined by next-generation sequencing performed on tumor tissue. 22% of the patients were premenopausal / perimenopausal women, 77% were postmenopausal women, and 1% were men. 87% of the patients had received ≥1 line of prior disease-related therapy for locally advanced or metastatic disease: 69% had received a CDK4 / 6 inhibitor, and 18% had received prior chemotherapy. Demographics and baseline characteristics were well balanced between the overall population and the altered population and across treatment experimental groups.

[0089] In the primary analysis, 551 PFS events occurred in the overall population (see Figure 2 ). The PFS of capivasertib + F was significantly longer compared to PBO + F (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51–0.71; p < 0.001; median 7.2 months vs 3.6 months).

[0090] In the population with AKT pathway alteration, 236 PFS events occurred (see Figure 3 ). The PFS of capivasertib + F was significantly longer compared to PBO + F (HR 0.50; 95% CI 0.38–0.65; p < 0.001; median 7.3 months vs 3.1 months).

[0091] For the population with unaltered pathway (including unknown patients (i.e., patients with no valid NGS results)), 315 PFS events occurred (see Figure 4 ). Additionally, it was found that in the population with unaltered AKT pathway, the PFS of capivasertib + F was significantly longer compared to PBO + F (HR 0.7; 95% CI 0.56 - 0.88; median 7.2 months vs 3.7 months).

[0092] For the population with unaltered pathway (excluding unknown patients), 144 PFS events occurred (see Figure 5 ). Additionally, it was found that the PFS of capivasertib + F was significantly longer compared to PBO + F (HR 0.79; 95% CI 0.61 - 1.02; median 5.3 months vs 3.7 months).

[0093] It was found that the PFS of capivasertib + F was longer compared to PBO + F and was similar for patients in the overall population who had previously received a CDK4 / 6 inhibitor (HR 0.62; 95% CI 0.51 - 0.75) and for patients in the overall population who had not previously received a CDK4 / 6 inhibitor (HR 0.65; 95% CI 0.47 - 0.91).

[0094] Relative to the PBO+F experimental group, in the capivasertib+F experimental group, the objective response rate in patients with measurable disease was 22.9%, while the objective response rate in the overall population was 12.2%, and the objective response rate in the altered population was 28.8% versus 9.7%. In the overall population, the most common all-grade adverse events (AEs; not adjusted for exposure) with capivasertib+F were diarrhea (72.4% vs 20.0% in the PBO+F experimental group), nausea (34.6% vs 15.4%), and rash (22.0% vs 4.3%). The most common ≥3-grade AEs were diarrhea (9.3% vs 0.3%), maculopapular rash (6.2% vs 0%), and rash (5.4% vs 0.3%). AEs leading to capivasertib / placebo discontinuation were reported in 13.0% and 2.3% of patients, respectively.

[0095] Conclusions

[0096] This phase 3 clinical trial met the two primary endpoints for capivasertib+F, significantly improving PFS in both the AKT pathway-altered population and the AKT pathway-unaltered population.

[0097] This is a particularly significant result with therapeutic implications for patients in the pathway-unaltered population, as earlier studies found that in the subgroup with NGS-determined unaltered pathways, PFS was similar in the capivasertib+F and PBO+F treatment groups. Although significant PFS and overall survival benefits of capivasertib were observed in the pathway-altered subgroup, such benefits were not observed in the pathway-unaltered subgroup (see Howell et al., Lancet Oncol 2022;23:851–64).

[0098] The overall safety profile of capivasertib+F was consistent with the safety profiles of known combinations. This is the first study to show a statistically significant and clinically meaningful improvement in PFS with an AKT inhibitor in HR+ABC.

Claims

1. A composition comprising capivasertib and a composition comprising fulvestrant, wherein the composition comprising capivasertib and the composition comprising fulvestrant are used as a combination therapy for treating patients with hormone receptor-positive (HR+) breast cancer, wherein the tumor cells of the patients do not contain 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. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

2. The composition comprising capivasertib and the composition comprising fulvestrant used according to claim 1, wherein the patient has estrogen receptor-positive (ER+) breast cancer.

3. The composition comprising capivasertib and the composition comprising fulvestrant used according to claim 1 or claim 2, wherein the patient has aromatase inhibitor-tolerant breast cancer.

4. The composition comprising capivasertib and the composition comprising fulvestrant used according to any one of the preceding claims, wherein the patient has HER2-negative breast cancer.

5. The composition comprising capivasertib and the composition comprising fulvestrant used according to any one of the preceding claims, wherein the composition comprising capivasertib and the composition comprising fulvestrant are administered separately.

6. A method for 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 tumor cells of the patient do not contain 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. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

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

8. The method according to claim 6 or claim 7, wherein the patient has aromatase inhibitor-tolerant breast cancer.

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

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

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