Combination Therapy for Breast Cancer

Abstract

This application discloses a combination for treating estrogen receptor positive and HER2 positive breast cancer patients. The combination comprises pertuzumab and trastuzumab (e.g., pertuzumab and trastuzumab fixed dose combination, PH FDC) + giledestrant. In one embodiment, the combination further comprises a CDK4 / 6 inhibitor, such as abemaciclib or palbociclib.

Description

[Technical field]

[0001] Claiming priority This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 269,326, filed March 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated by reference in its entirety. The XML copy, created on Feb. 22, 2023, is named P37389-WO.xml and is 12,228 bytes in size.

[0003] The present invention relates to a combination therapy for patients with estrogen receptor positive and HER2 positive breast cancer. The combination comprises pertuzumab and trastuzumab (e.g., pertuzumab and trastuzumab fixed dose combination, PH FDC) + giledestrant, and optionally further comprises a CDK4 / 6 inhibitor (e.g., abemaciclib or palbociclib). [Background technology]

[0004] Pertuzumab (PERJETA®) Pertuzumab is a HER2 / neu receptor antagonist administered by intravenous infusion for: -Used in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. - in combination with trastuzumab and chemotherapy as: -Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or lymph node positive) as part of a complete treatment regimen for early stage breast cancer. -Adjuvant treatment of patients with HER2-positive early-stage breast cancer who are at high risk of recurrence.

[0005] Trastuzumab (HERCEPTIN®) Trastuzumab is a HER2 / neu receptor antagonist administered by intravenous infusion for: - Treatment of HER2-overexpressing breast cancer. Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

[0006] Recombinant Hyaluronidase Human Injection (HYLENEX®) Recombinant hyaluronidase human injection is a tissue permeability regulator administered by subcutaneous fluid administration used in: - In subcutaneous fluid administration to achieve hydration -To increase the dispersion and absorption of other injectable drugs -In subcutaneous urography to improve resorption of radiopaque agents

[0007] Trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA™) Trastuzumab and hyaluronidase-oysk is a combination of the HER2 / neu receptor antagonist trastuzumab and the endoglycosidase recombinant human hyaluronidase, which has been shown in adults to: - Treatment of HER2-overexpressing breast cancer.

[0008] Pertuzumab and trastuzumab fixed-dose combination (PH FDC, PHESGO™) PH FDC (PHESGO™) is a combination of the HER2 / neu receptor antagonists pertuzumab and trastuzumab with the endoglycosidase hyaluronidase, which has been shown to: In combination with chemotherapy as: -Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or lymph node positive) as part of a complete treatment regimen for early stage breast cancer. -Adjuvant treatment of patients with HER2-positive early-stage breast cancer who are at high risk of recurrence.

[0009] For use in combination with docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. PH FDC SC is disclosed in U.S. Patent Application Publication No. 2018 / 0296470, U.S. Patent Application Publication No. 2021 / 0403599, and WO 2022 / 013189.

[0010] Ado-trastuzumab emtansine Ado-trastuzumab emtansine for injection for intravenous use is a HER2-targeted antibody and microtubule inhibitor conjugate indicated as a single agent for: Treatment of patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, either separately or in combination. Patients are either: have had prior treatment for metastatic disease, or - Have had disease recurrence during or within 6 months of completing adjuvant therapy. - Adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant taxane- and trastuzumab-based treatment.

[0011] Gilledestran Giledestrand is a potent, orally bioavailable ER antagonist and inducer of ER degradation that competes with estrogen for binding to the ER with low nanomolar potency. It is being developed as a new endocrine therapy (ET) for the treatment of ER-positive advanced breast cancer (ABC) and early breast cancer (EBC) patients (Liang et al. J Med Chem. 64: 11841-56 (2021)). Giledestrand has higher potency compared to fulvestrant, tamoxifen, and other oral SERDs in development (Liang et al.).

[0012] Giledestran antagonizes the effects of estrogen with nanomolar potency through competitive binding to the ligand-binding domain (LBD) of both wild-type and mutant ER. Upon binding, giledestran induces an inactive conformation to the ER LBD as measured by displacement of the coactivation peptide. In addition to its direct antagonist properties, giledestran's mechanism of action includes the reduction of ER protein levels through proteasome-mediated degradation. Degradation of ER is hypothesized to allow complete suppression of ER signaling, which is not achieved by first-generation ER treatments such as tamoxifen, which exhibit partial agonism. Giledestran potently inhibits the growth of multiple ER-positive BC cell lines in vitro, including cells engineered to express clinically relevant mutations in the ER.

[0013] In a phase I study (study GO39932), giledestrant monotherapy showed signs of promising clinical activity at the recommended phase 2 dose of 30 mg daily and was safe in patients with previously treated ER-positive, HER2-negative ABC (Jhaveri et al. J Clin Oncol 39(15 suppl):1017(2021)).

[0014] The phase II randomized coopERA study (study WO42133) demonstrated that neoadjuvant, gildedestrant was superior to anastrozole for achieving Ki67 suppression and complete cell cycle arrest in patients with ER-positive, HER2-negative EBC (Hurvitz et al. Ann Oncol 2021;32:S1285-6(2021)).

[0015] Studies evaluating endocrine therapy (ET) in combination with anti-HER2 antibody therapy include:Witters et al.Breast Cancer Res Treat.42:1-5(1997);Kunisue et al.Br J Cancer.82:46-51(2000);Kaufman et al.J Clin Oncol.27:5529-37(2009);Leary et al.Clin Cancer Res.16:1486-97(2010);Schwartzberg et al.Oncologist.15(2):122-9(2010)Erratum in:Oncologist.15(3):327(2010);Wang et al.Breast Cancer Res.13(6):R121(2011);Huober et al.Breast.21:27-33(2012);Rimawi et al.J Clin Oncol. 36:2826-35(2018); and Metzger et al. Cancer Res 79(4_Supplement):OT3-02-07(2019). These studies did not evaluate the safety and efficacy of gildedestrant, a novel oral selective estrogen receptor degrader (SERD), in combination with pertuzumab and trastuzumab.

[0016] NCT04802759 (initial submission date: March 17, 2021, last update date: February 7, 2022) is a phase Ib / II, open-label, multicenter, randomized umbrella study in participants with breast cancer. Cohort 1 will focus on participants with inoperable locally advanced or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer with disease progression during or after treatment with cyclin-dependent kinase 4 / 6 inhibitors (CDK4 / 6i; e.g., palbociclib or abemaciclib) in the first- or second-line setting. Cohort 2 will focus on inoperable locally advanced or metastatic ER-positive, HER2-positive breast cancer with prior disease progression on trastuzumab plus taxanes and ado-trastuzumab emtansine-based therapy. Cohort 2 includes arms evaluating giledestrant + PH FDC, giledestrant + PH FDC + abemaciclib, and giledestrant + PH FDC + palbociclib.

[0017] ER-positive, HER2-positive breast cancer therapy ER expression in HER2-positive BC implies a significantly different biology compared to ER-negative HER2-positive BC: patients diagnosed with ER-positive HER2-positive BC have tumors that are less proliferative, have lower HER2 gene amplification, and have lower response rates to chemotherapy with anti-HER2 therapy.Baselga et al.N Engl J Med.366:109-19(2012);Gianni et al.Lancet Oncol.13:25-32(2012);Schneeweiss et al.Ann Oncol.24:2278-84.Epub 2013 May 22;Loi et al.JAMA Oncol.2:1040-7(2016).

[0018] The bidirectional crosstalk between the HER family and ER has been thoroughly characterized at the cellular level, and inhibition of either receptor alone is associated with upregulation of the other, ultimately resulting in resistance to treatment (Cortes et al. Nat Rev Clin Oncol. 8:307-11(2011)). PERTAIN (study MO27775) also demonstrated a beneficial effect of dual HER2 blockade with ET. By adding pertuzumab to trastuzumab (PH) + aromatase inhibitor (AI), improved progression-free survival (PFS) was observed, along with better tolerability, than trastuzumab + AI alone (Rimawi et al. J Clin Oncol. 2018;36:2826-35(2018)).

[0019] ER-positive HER2-positive patients with ABC are more frequently identified as having the luminal BC subtype, which is more dependent on the ER pathway, and frequently undergo a shift / increased dominance of the intrinsic molecular subtype from HER2-enriched to luminal BC when exposed to chemotherapy + anti-HER2 therapy (Perou et al. Nature. 406:747-52 (2000); Carey et al. J Clin Oncol. 2016;34:542-9. Epub 2015 Nov 2; Cejalvo et al. Ann Oncol. 28(suppl_5):v595-v604 (2017); Braso-Maristany et al. Nat Commun. 11:385 (2020).

[0020] Patients with ER-positive HER2-positive BC benefit from augmentation of endocrine therapy partners with trastuzumab and lapatinib, exploratory analysis of phase 3 trial shows. Lambertini et al. Breast Cancer Res Treat. 177:103-14. Epub 2019 May 27.

[0021] Available maintenance therapies for ER-positive HER2-positive ABC, fulvestrant and anastrozole, are reported in Robertson et al. Breast Cancer Res Treat. 136:503-11. Epub 2012 Oct 13; Ellis et al. J Clin Oncol. 33:3781-7 (2015); and Robertson et al. Lancet. 388:2997-3005 (2016).

[0022] Despite advances in early diagnosis and curative multimodality treatments, some patients may still experience metastatic recurrence or present with "de novo" metastatic breast cancer (MBC). In this setting, the primary goal of treatment is to improve quality of life and extend patient survival, as there is still no cure (Cardoso et al. Ann Oncol. 31:1623-49 (2020)). Thus, there remains a need for treatments with a more favorable benefit / risk profile that will prolong PFS and other survival endpoints for patients with ER-positive, HER2-positive ABC. Summary of the Invention

[0023] In one aspect, the invention relates to a method of treating a patient with estrogen receptor positive and HER2 positive breast cancer, comprising administering to the patient a combination of pertuzumab, trastuzumab, and giledestrant in amounts effective to treat the breast cancer.

[0024] In another aspect, the invention provides a method of treating an estrogen receptor positive and HER2 positive breast cancer patient having advanced breast cancer, comprising administering to the patient: a. Induction therapy comprising 4 to 8 cycles of a combination of pertuzumab and trastuzumab fixed-dose combination (PH FDC) and docetaxel or paclitaxel in amounts effective to treat breast cancer, followed by: b. A method comprising administering a maintenance therapy comprising a combination of giledestrant and PH FDC in an amount effective to treat breast cancer.

[0025] In yet another aspect, the invention relates to a method of treating an estrogen receptor positive and HER2 positive breast cancer patient with advanced breast cancer, comprising administering to the patient a combination of pertuzumab and trastuzumab fixed dose combination (PH FDC), giledestrant, and palbociclib in an amount effective to treat the advanced breast cancer.

[0026] In a further aspect, the present invention provides a method of treating an estrogen receptor positive and HER2 positive breast cancer patient with advanced breast cancer comprising administering to the patient a combination of pertuzumab and trastuzumab fixed dose combination (PH FDC), giledestrant, and abemaciclib in an amount effective to treat the advanced breast cancer.

[0027] In certain embodiments of any of the above methods, -Pertuzumab and trastuzumab are administered as a pertuzumab-trastuzumab fixed-dose combination (PH FDC); - The breast cancer is advanced breast cancer, including locally advanced unresectable breast cancer and / or metastatic breast cancer; -Treatment with the combination is more effective than treatment with pertuzumab and trastuzumab without giledestrant, or treatment with PH FDC and palbociclib or abemaciclib without giledestrant; - The combination is administered as maintenance therapy following induction therapy; - The combination further includes a CDK4 / 6 inhibitor, e.g., palbociclib or abemaciclib, e.g., if the patient has progressed on prior HER2 therapy, e.g., if the patient has had prior disease progression on trastuzumab treatment and a HER2 antibody drug conjugate treatment (e.g., including ado-trastuzumab emtansine ADC or trastuzumab deruxtecan ADC). [Brief description of the drawings]

[0028] [Figure 1A-1B] Figure 1A and Figure 1B show the amino acid sequences of the Pertuzumab light chain (Figure 1A; SEQ ID NO: 1) and heavy chain (Figure 1B; SEQ ID NO: 2). The CDRs are indicated by bold lines. A carbohydrate moiety is attached to Asn299 of the heavy chain. The boundaries of the variable light chain domain (SEQ ID NO: 5) and the variable heavy chain domain (SEQ ID NO: 6) are indicated by arrows. [Figure 2A-2B] Figures 2A and 2B show the amino acid sequences of the trastuzumab light chain (Figure 2A; SEQ ID NO: 3) and heavy chain (Figure 2B; SEQ ID NO: 4), respectively. The boundaries of the variable light chain domain (SEQ ID NO: 7) and the variable heavy chain domain (SEQ ID NO: 8) are indicated by arrows. [Diagram 3] 3 shows the in vitro anti-proliferative activity of ER inhibition with giledestrant and / or HER2 inhibition with a combination of trastuzumab and pertuzumab, assessed using the growth rate (GR) method of Example 1. The growth rate (GR) under control conditions is set to 1; a lower growth rate equates to a greater anti-proliferative effect. Individual points reflect GR values ​​at 0.3 μM giledestrant and 30 μM trastuzumab and pertuzumab. [Figure 4] FIG. 4 shows the study scheme of the combination therapy trial of PH FDC+giledestrant±CDK4 / 6 inhibitor in Example 2 (Morpheus Breast). [Diagram 5]Figure 5 shows the study scheme of the PH FDC and giredestrant combination therapy trial in Example 3 (heredERA). ABC = advanced breast cancer; AI = aromatase inhibitor; CR = complete response; ER = estrogen receptor; ET = endocrine therapy; LHRHa = luteinizing hormone-releasing hormone agonist; LVEF = left ventricular ejection fraction; R = randomized; PD = progressive disease; SD = stable disease. Docetaxel or paclitaxel will follow standard of care at the investigator's discretion. Patients must receive a minimum of four complete cycles of induction therapy (including cycles received prior to study enrollment, if applicable). At the investigator's discretion, participants who tolerate six induction therapy cycles well and have not experienced progressive disease (PD) may be given up to two additional cycles (up to a maximum of eight cycles). Any endocrine therapy (ET) chosen by the investigator is permitted based on standard of care (ET may include aromatase inhibitors or tamoxifen ± LHRHa or gonadal ablation). Pre- and peri-menopausal women, as well as all men, will receive LHRHa every 28 days and up to 28 days prior to the first gildedestrant dose. Alternatively, pre- or peri-menopausal women may be treated with bilateral oophorectomy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] I. Definition TIFF2025509510000001.tif255170TIFF2025509510000002.tif13170

[0030] For purposes of this specification, "pertuzumab" refers to an antibody comprising a variable light chain amino acid sequence of SEQ ID NO:5 and a variable heavy chain amino acid sequence of SEQ ID NO:6. In one embodiment, pertuzumab comprises an intact IgG1 antibody. In one embodiment, pertuzumab comprises a light chain amino acid sequence of SEQ ID NO:1 and a heavy chain amino acid sequence of SEQ ID NO:2. In one embodiment, pertuzumab is produced by recombinant Chinese hamster ovary (CHO) cells.

[0031] For purposes of this specification, "trastuzumab" refers to an antibody comprising a variable light chain amino acid sequence of SEQ ID NO: 7 and a variable heavy chain amino acid sequence of SEQ ID NO: 8. In one embodiment, trastuzumab comprises an intact IgG1 antibody. In one embodiment, trastuzumab comprises a light chain amino acid sequence of SEQ ID NO: 3 and a heavy chain amino acid sequence of SEQ ID NO: 4. In one embodiment, trastuzumab is produced by Chinese Hamster Ovary (CHO) cells.

[0032] As used herein, "Pertuzumab and Trastuzumab fixed dose combination" or "PH FDC" refers to a ready-to-use co-formulation containing a fixed dose of Pertuzumab and a fixed dose of Trastuzumab, and optionally recombinant human hyaluronidase (rHuPH20). The PH FDC is administered subcutaneously.

[0033] "Loading dose FDC" refers to an initial dose FDC containing 1200 mg pertuzumab and 600 mg trastuzumab, and optionally 30,000 units of rHuPH20. An exemplary loading dose formulation includes: pertuzumab (dose: 1200 mg; concentration: 80 mg / mL); trastuzumab (dose: 600 mg; concentration: 40 mg / mL); rHuPH20 (concentration: 2000 U / mL); pH: 5.5; 20 mM L-histidine / HCl; trehalose: 70 mM; sucrose: 133 mM; polysorbate 20 (PS20): 0.04% (0.4 mg / mL); 10 mM methionine; nominal fill volume 15 mL; vial: 20 mL / 20 mm.

[0034] "Maintenance dose FDC" refers to a maintenance dose FDC containing 600 mg pertuzumab and 600 mg trastuzumab, and optionally 20,000 units of rHuPH20. Exemplary maintenance dose formulations include: Pertuzumab (Dose: 600 mg; Concentration: 60 mg / mL); Trastuzumab (Dose: 600 mg; Concentration: 60 mg / mL); rHuPH20 (Concentration: 2000 U / mL); pH: 5.5; 20 mM L-histidine / HCl; Trehalose: 105 mM; Sucrose: 100 mM; Polysorbate PS20: 0.04% (0.4 mg / mL); 10 mM methionine; Nominal fill volume: 10 mL; Vial: 15 mL / 20 mm.

[0035] "Endocrine therapy" or "ET" refers to a therapy that delays or stops the growth of hormone-sensitive tumors by blocking the body's ability to produce hormones or by interfering with the effect of hormones on breast cancer cells.Examples of ET drugs include aromatase inhibitors (AIs), such as anastrozole, exemestane and letrozole; selective estrogen receptor modulators (SERMs), such as tamoxifen, raloxifene, toremifene and giledestrant; estrogen receptor antagonists, such as fulvestrant, toremifene and giledestrant; luteinizing hormone releasing hormone agonists (LHRHa), such as goserelin acetate, leuprolide acetate, triptorelin pamoate.The preferred ET herein is giledestrant. For purposes of this specification, "giledestrant" or "GDC-9545" refers to a compound having the following structure: [ka] Giledestrant refers to the compound having the chemical name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, including pharmaceutically acceptable salts thereof. In one embodiment, giledestrant is the tartrate salt. As used herein, "giledestrant" refers to the free base and pharmaceutically acceptable salts of giledestrant, including the tartrate salt thereof. Giledestrant is also known as GDC-9545.

[0036] "Taxanes" are chemotherapy drugs that inhibit mitosis and interfere with microtubules. Examples of taxanes include paclitaxel (TAXOL®; Bristol-Myers Squibb Oncology, Princeton, NJ); a cremophor-free albumin engineered nanoparticle formulation of paclitaxel or nab-paclitaxel (ABRAXANE™; American Pharmaceutical Partners, Schaumberg, Illinois); and docetaxel (TAXOTERE®; Rhone-Poulenc Rorer, Antony, France). In one embodiment, the taxane is paclitaxel. In one embodiment, the taxane is docetaxel.

[0037] A "CDK4 / 6 inhibitor" is a cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 and / or CDK6 cell cycle pathway. Exemplary such inhibitors include abemaciclib (VERZENIO®), palbociclib (IBRANCE®), and ribociclib (KISQALI®).

[0038] "Abemaciclib" specifically inhibits CDK4 and CDK6 and contains the following chemical structure: (2-pyrimidinamine, N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl).

[0039] "Palbociclib" selectively inhibits CDK4 and CDK6 and has the chemical structure: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one.

[0040] The term "cancer" refers to the physiological condition in mammals characterized by unregulated cell growth.

[0041] An "advanced" cancer is one that has spread outside the original site or organ, either by local invasion ("locally advanced") or by metastasis ("metastatic"). Thus, the term "advanced" cancer includes both locally advanced and metastatic disease.

[0042] "Locally advanced breast cancer" or "LABC" refers to cancer that has spread from where it began in the breast to nearby tissues or lymph nodes, but has not spread to other parts of the body. In one embodiment, LABC is unresectable.

[0043] The term "metastatic breast cancer" or "MBC" refers to cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be referred to as stage IV breast cancer.

[0044] "Early stage breast cancer" or "EBC" as used herein refers to breast cancer that has not spread beyond the breast or axillary lymph nodes. Such cancers are generally treated with neoadjuvant or adjuvant therapy.

[0045] "Neoadjuvant therapy" or "neoadjuvant treatment" or "neoadjuvant administration" refers to systemic therapy given prior to surgery.

[0046] "Adjuvant therapy" or "adjuvant treatment" or "adjuvant administration" refers to systemic therapy given after surgery.

[0047] As used herein, a "patient" or "subject" is a human patient. The patient may be a "cancer patient", i.e., a cancer patient suffering from or at risk of suffering from one or more symptoms of cancer, particularly breast cancer.

[0048] "HER2 positive" cancers include cancer cells that have higher than normal levels of HER2. In one embodiment, a HER2 positive cancer has an immunohistochemistry (IHC) score of 2+ or 3+ and / or is in situ hybridization (ISH), fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) positive, e.g., an ISH / FISH / CISH amplified non->2.0.

[0049] An "estrogen receptor positive" or "ER positive" patient has a protein (receptor) that binds to the hormone estrogen on the patient's cancer cells. Estrogen receptor positive cancer cells may require estrogen to grow. These cells may stop growing or die when treated with a substance that blocks the binding and action of estrogen. In one embodiment, a patient with an ER positive tumor has 1% or more tumor cells that are ER positive, for example according to the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines. In one embodiment, an ER positive patient also has a HER2 positive cancer, where ER positivity is based on the same lesions used to determine HER2 positivity.

[0050] A patient who "had prior disease progression on trastuzumab treatment and HER2-ADC treatment" is a patient who has experienced disease progression while receiving standard of care anti-HER2 therapy, such as: first-line therapy including trastuzumab therapy (e.g., in the early setting, systemic therapy based on trastuzumab and a taxane, including where relapse occurred within 6 months of completing adjuvant therapy) and second-line therapy including HER2 antibody drug conjugate (ADC) treatment (e.g., ado-trastuzumab emtansine or trastuzumab deruxtecan treatment), prior to treatment with the combination therapy disclosed herein.

[0051] "Induction therapy" refers to the first systemic treatment given to advanced or metastatic breast cancer from initial diagnosis. In one embodiment, induction therapy comprises treatment with PH FDC + taxane. In one embodiment, induction therapy results in minimal stable disease (SD) in the patient, i.e., the patient does not have progressive disease (PD).

[0052] "Maintenance therapy" refers to treatment administered to maintain and optionally improve upon the benefits obtained with induction therapy. In one embodiment, maintenance treatment comprises treatment with PH FDC plus giledestrant. In one embodiment, maintenance therapy maintains stable disease. In one embodiment, maintenance therapy extends progression-free survival (PFS) over PH FDC alone.

[0053] "Treatment" refers to treatment with a drug or combination of drugs (e.g., PH FDC and giledestrant ± CDK4 / 6 inhibitor) that achieves one or more efficacy endpoints in treating breast cancer in a patient. For combination therapy disclosed herein with PH FDC and giledestrant, in one embodiment, the treatment achieves one or more efficacy endpoints that are better than those achieved with PH FDC alone. In one embodiment, the treatment achieves one or more efficacy endpoints that are better than those achieved with giledestrant alone. In one embodiment, the treatment achieves one or more efficacy endpoints that are better than those achieved with PH FDC alone and giledestrant alone.

[0054] "Efficacy endpoint" refers to an event or outcome that can be objectively measured to determine whether the intervention being studied is beneficial. Exemplary efficacy endpoints herein include: 1. Progression-free survival (PFS), 2. Overall survival (OS); 3. Overall response rate (ORR), 4. Duration of response (DOR), 5.Disease control rate (DCR), 6.Clinical usefulness rate (CBR), 7. Mean change from baseline scores in function (role, physical) and HRQoL per cycle and between treatment arms as assessed by use of the EORTC QLQ-C30 function and GHS / QoL scales. Treatment may result in 1, 2, 3, 4, 5, 6, or 7 of these endpoints being superior to treatment with PH FDC alone or superior to treatment with PH FDC + giledestrant without a CDK4 / 6 inhibitor.

[0055] "Progression-free survival" or "PFS" is defined as the time from randomization (e.g., from the start of treatment or from the start of maintenance therapy) to the first occurrence of disease progression or death from any cause, whichever occurs first. In one embodiment, PFS is assessed according to RECIST v1.1 (Eisenhauer et al. European J. Cancer 45:228-247 (2009)).

[0056] "Overall survival" or "OS" is defined as the time from randomization (or from start of treatment) to death from any cause.

[0057] "Overall response rate" or "ORR" is defined as the proportion of participants with two consecutive complete responses (CR) or partial responses (PR) at least four weeks apart. In one embodiment, CR and PR are assessed according to RECIST v1.1.

[0058] "Duration of response" or "DOR" is defined as the time from the first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first. In one embodiment, DOR is assessed according to RECIST v1.1.

[0059] "Disease control rate" or "DCR" is defined as the proportion of patients with stable disease for ≥12 weeks or a complete or partial response as determined by the investigator according to RECIST v1.1.

[0060] "Clinical benefit rate" or "CBR" is defined as the proportion of participants with stable disease (SD) or CR or PR for 24 weeks or more. In one embodiment, CBR is assessed according to RECIST v1.1.

[0061] A "fixed" or "flat" dose of a therapeutic agent herein refers to a dose administered to a human patient without regard to the patient's body weight (WT) or body surface area (BSA). A fixed or flat dose may thus be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but rather as an absolute amount of therapeutic agent.

[0062] The "initial" or "loading" dose herein generally comprises an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance doses. Generally, a single loading dose is administered, but multiple loading doses are contemplated herein. In one embodiment, the loading dose exceeds the maintenance dose so as to achieve a desired steady-state concentration of the therapeutic agent more quickly than can be achieved with the maintenance dose. An exemplary loading dose of subcutaneous pertuzumab is 1200 mg. An exemplary loading dose of subcutaneous trastuzumab is 600 mg.

[0063] "Maintenance" dose herein refers to one or more doses of therapeutic agent administered to patient over treatment period.Usually, maintenance dose is administered by interval treatment interval, for example, about every week, about every 2 weeks, about every 3 weeks, or about every 4 weeks, preferably every 3 weeks.Exemplary maintenance dose of subcutaneous pertuzumab is 600mg.Exemplary maintenance dose of subcutaneous trastuzumab is 600mg.

[0064] An "administration period" or "cycle" refers to a period that includes administration of one or more agents described herein (e.g., PH FDC, giledestrant, abemaciclib, and / or palbociclib) and any period that does not include administration of one or more agents described herein. For example, a cycle can be a total of 21 days with no rest period, or a total of 28 days (including 21 days of administration of one or more agents and a 7-day rest period). A "rest period" refers to a period during which at least one of the agents described herein (e.g., palbociclib) is not administered.

[0065] A "dosing regimen" refers to a period of administration of an agent described herein that includes one or more cycles, each cycle can include administration of an agent described herein at different times or in different amounts.

[0066] "QD" refers to administration of the compound once daily.

[0067] "BID" (bis in die) refers to administration of the compound twice daily.

[0068] "PO" (per os) refers to oral administration of the agents described herein.

[0069] "SC" refers to subcutaneous administration of the agent(s) described herein.

[0070] A "vial" is a container suitable for holding a liquid or lyophilized preparation. In one embodiment, the vial is a single-use vial, for example a 10 ml or 20 ml single-use vial with a stopper, such as a 10 ml single-use glass vial with a 20 mm stopper.

[0071] A "package insert" is a leaflet that must be included inside the package of all prescription drugs by mandate of the U.S. Food and Drug Administration (FDA) or other regulatory agency. This leaflet typically contains the trademark for the drug, its generic name, and its mechanism of action, describes its indications, contraindications, warnings, precautions, adverse effects, and dosage forms, and includes instructions for the recommended dose, time, and route of administration.

[0072] Administration "in combination" encompasses concomitant administration as well as separate administration, in which case administration of one therapeutic agent may occur prior to, simultaneously with, and / or after administration of the other therapeutic agent. Thus, administration of FDC and giledestrant (and optionally a CDK4 / 6 inhibitor) in combination encompasses concomitant administration as well as separate administration in either order.

[0073] A drug that is administered "concurrently" with one or more other drugs is administered on the same treatment day as the one or more other drugs during the same treatment cycle, and optionally at the same time as the one or more other drugs. For example, in the case of a cancer therapy given every three weeks, each of the drugs that are administered simultaneously is administered on at least day 1 of the three-week cycle.

[0074] "Subcutaneous administration device" refers to a device capable of administering the FDCs disclosed herein by subcutaneous administration to a patient. Exemplary devices contemplated herein include syringes, injection devices, infusion pumps, pen injectors, needleless devices, autoinjectors, and subcutaneous patch delivery systems. In one embodiment, the device is a hand-held syringe, e.g., including a 25G-27G (3 / 8"-5 / 8") hypodermic needle attached or attachable to the syringe.

[0075] "Graded adverse events" refers to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table: TIFF2025509510000004.tif47170

[0076] II. Combinations and Methods of Treatment The present invention relates to a method of treating a patient with estrogen receptor positive and HER2 positive breast cancer comprising administering to the patient a combination of pertuzumab, trastuzumab, and giledestrant in amounts effective to treat the breast cancer.

[0077] The present invention also relates to a method of treating an estrogen receptor positive and HER2 positive breast cancer patient with advanced breast cancer comprising administering to the patient: a. an induction therapy comprising 4 to 8 cycles of a combination of a fixed dose combination of pertuzumab and trastuzumab (PH FDC) and docetaxel or paclitaxel in an amount effective to treat the breast cancer, followed by: b. a maintenance therapy comprising a combination of giledestrant and a PH FDC in an amount effective to treat the breast cancer.

[0078] The present invention also provides a method of treating an estrogen receptor positive and HER2 positive breast cancer patient with advanced breast cancer, comprising administering to the patient a combination of pertuzumab and trastuzumab fixed dose combination (PH FDC), giledestrant, and palbociclib in an amount effective to treat the advanced breast cancer.

[0079] The present invention further provides a method of treating an estrogen receptor positive and HER2 positive breast cancer patient with advanced breast cancer, comprising administering to the patient a combination of pertuzumab and trastuzumab fixed dose combination (PH FDC), giledestrant, and abemaciclib in an amount effective to treat the advanced breast cancer.

[0080] In certain embodiments of the above treatment methods: - The breast cancer is advanced breast cancer. - The breast cancer is locally advanced unresectable breast cancer. - The breast cancer is metastatic breast cancer. - Patients had prior disease progression on trastuzumab treatment and HER2-ADC treatment (e.g., ado-trastuzumab emtansine). - the breast cancer is early stage breast cancer and the combination is given as neoadjuvant or adjuvant therapy to treat the early stage breast cancer; - Patients have a left ventricular ejection fraction (LVEF) of at least 50% measured by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) prior to the procedure (including prior to the induction procedure and / or prior to the maintenance procedure) -Pertuzumab and trastuzumab will be administered as a pertuzumab-trastuzumab fixed-dose combination (PH FDC). -Treatment with the combination of pertuzumab + trastuzumab + giledestrant or PH FDC + giledestrant is more effective than treatment with pertuzumab and trastuzumab without giledestrant.

[0081] In one embodiment, the combination is administered as a maintenance therapy following induction therapy.

[0082] Induction therapy may include treatment of the patient with pertuzumab and trastuzumab and a taxane, for example, treatment of the patient with a fixed dose combination (PH FDC) of pertuzumab and trastuzumab and a taxane selected from paclitaxel or docetaxel for 4 to 8 cycles. The PH FDC and taxane are administered in amounts effective to treat the cancer. For example, achieving a minimum of stable disease (i.e., no progressive disease) prior to maintenance therapy.

[0083] According to such induction therapy, which includes taxane chemotherapy: -Paclitaxel, optionally at 80 mg / m on days 1, 8, and 15 of each 21-day cycle 2 administered intravenously as a dose; or -Docetaxel, optionally at 75 mg / m on day 1 of each 21-day cycle 2 The docetaxel dose is administered intravenously at a dose of 100 mg / m2 if the initial dose is well tolerated. 2 is gradually increased to.

[0084] Maintenance therapy may include administering giledestrant together with pertuzumab and trastuzumab (eg, as PH FDC) for one or more additional cycles to further treat breast cancer.

[0085] In one embodiment, giledestrant is administered daily in an amount of about 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 30 mg. In another embodiment, giledestrant is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, giledestrant is administered in an amount of about 10, 30, 50, or 100 mg. In yet another embodiment, giledestrant is administered in an amount of 30 mg. In one embodiment, giledestrant is administered orally once daily in a dose of 30 mg on days 1 to 21 of a three-week or four-week cycle.

[0086] In one embodiment, patients are treated with the combination until disease progression or unacceptable toxicity.

[0087] The methods of treating breast cancer provided herein can include administration of a combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least two cycles. In another aspect, provided herein is a dosing regimen that includes 1-200 cycles of treatment, such as 20-180 cycles, or 24-180 cycles. In one embodiment, the dosing regimen includes administration of a combination therapy described herein in any number of cycles until a desired response (e.g., PFS, ORR, OS, DOR, DCR, CBR) is achieved with a desired outcome (e.g., increased PFS, ORR, OS, DOR, DCR, CBR compared to a control described herein). In another embodiment, the dosing regimen includes administration of a combination therapy described herein in any number of cycles until toxicity occurs or the patient otherwise experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen comprises administration of a combination therapy described herein in any number of cycles until disease progression.

[0088] In one embodiment, maintenance therapy comprises administering 30 mg of giledestrant orally once daily on days 1-21 of a 21 day cycle in combination with administering PH FDC subcutaneously on day 1 of a 21 day cycle.

[0089] The combination treatments, induction treatments and maintenance treatments herein are therapeutically effective. For example, - treatment with the combination of giledestrant and PH FDC achieves one or more clinical endpoints R selected from PFS, ORR, OS, DOR, DCR, and CB (e.g., 1, 2, 3, 4, 5, 6 of these endpoints) that are greater than or better than PH FDC alone; -Treatment with the combination of giledestrant and PH FDC extends progression-free survival (PFS) compared with PH FDC alone; -Treatment with the combination of giledestrant and PH FDC increases median PFS by ≥4.5 months or ≥6.7 months compared with the median PFS with PH FDC alone; - treatment with the combination of giledestrant + PH FDC + abemaciclib or palbociclib achieves one or more clinical endpoints selected from PFS, ORR, OS, DOR, DCR, and CBR (e.g., 1, 2, 3, 4, 5, 6 of these endpoints) that are greater than or superior to PH FDC + giledestrant without abemaciclib or palbociclib; and / or -Treatment with PH FDC + giledestrant + abemaciclib or palbociclib achieves a greater ORR than that achieved with PH FDC + giledestrant without abemaciclib or palbociclib.

[0090] The PH FDC may be administered subcutaneously as a loading dose FDC comprising 1200 mg pertuzumab and 600 mg trastuzumab, optionally further comprising 30,000 Units of hyaluronidase, followed by a maintenance dose FDC comprising 600 mg pertuzumab and 600 mg trastuzumab, optionally further comprising 20,000 Units of hyaluronidase. Such a PH FDC is optionally administered on day 1 of a 3 week cycle.

[0091] In one embodiment, for patients receiving intravenous pertuzumab and trastuzumab less than 6 weeks after their last dose, the PH FDC is administered as a maintenance dose of 600 mg pertuzumab and 600 mg trastuzumab, and every 3 weeks for subsequent doses.

[0092] In one embodiment, for patients receiving intravenous pertuzumab and trastuzumab 6 weeks or more since their last dose, the PH FDC is administered as an initial dose of 1,200 mg pertuzumab and 600 mg trastuzumab, followed by maintenance doses of 600 mg pertuzumab and 600 mg trastuzumab every 3 weeks thereafter.

[0093] In one embodiment, if dosing is discontinued and the time between doses of PH FDC is more than 6 weeks (and optionally not more than 9 weeks), a loading dose of PH FDC (1200 mg pertuzumab + 600 mg trastuzumab) should be given. Subsequent maintenance doses are given every 3 weeks.

[0094] In one embodiment, the method comprises administering an FDC loading dose of pertuzumab, trastuzumab, and recombinant human hyaluronidase (rHuPH20) by subcutaneous injection into the patient's thigh using a subcutaneous administration device (e.g., a syringe) at a rate of about 2 mL / min over a period of about 8 minutes. Optionally, administration of the loading dose is followed by an observation period of about 30 minutes.

[0095] In one embodiment, the method optionally further comprises administering one or more FDC maintenance doses to the patient's thigh via a subcutaneous administration device at a rate of about 2 mL / min over a period of about 5 minutes. Optionally, if the loading dose is well tolerated, administration of the maintenance dose is followed by an observation period of about 15 minutes.

[0096] For EBC, 2-10 (e.g., about 4) administrations of FDC are given to the patient (e.g., as neoadjuvant therapy prior to surgery), and optionally, a further post-operative administration, e.g., about 10-20 (e.g., about 18) maintenance administrations of FDC are given to the patient after surgery.

[0097] For advanced breast cancer (ABC), including locally advanced breast cancer (LABC) and metastatic breast cancer (MBC), patients can be treated until disease progression or unacceptable toxicity. In one embodiment, 1-200 maintenance doses, or 20-180 maintenance doses, or 24-180 maintenance doses are administered.

[0098] Optionally, the patient is further administered abemaciclib. For example, abemaciclib can be administered orally at 150 mg twice daily (during each 28-day or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression occurs.

[0099] Optionally, palbociclib is further administered to the patient. For example, palbociclib can be administered orally at a dose of 125 mg daily on days 1-21 of each 28-day cycle. For example, palbociclib can be administered orally at 125 mg once daily on days 1-21 of each 28-day cycle until unacceptable toxicity or disease progression.

[0100] Exemplary dose administration modes, doses, and dosing regimens of drugs for use herein include the following: TIFF2025509510000005.tif94170

[0101] In one embodiment, the treatment excludes any additional endocrine therapy given concomitantly.

[0102] In another embodiment, additional drugs or treatments that may be further combined with the treatments herein include, but are not limited to, endocrine therapy (e.g., tamoxifen or one of the designated third generation AIs anastrozole, letrozole, or exemestane), LHRHa (e.g., leuprolide acetate, goserelin acetate, or triptorelin pamoate), bilateral oophorectomy, radiation therapy, and / or chemotherapy.

[0103] III. Manufactured products In another embodiment of the present invention, an article of manufacture is provided containing materials useful for the treatment of cancer. The article of manufacture includes a subcutaneous administration device, such as a syringe, an injection device, an infusion pump, a pen injector, a needleless device, an auto-injector, and a subcutaneous patch delivery system, capable of administering the FDCs disclosed herein by subcutaneous administration to a patient.

[0104] In one embodiment, the device is a hand-held syringe, for example, containing a 25G-27G (3 / 8''-5 / 8'') hypodermic needle.

[0105] The subcutaneous administration device contains and delivers a FDC of pertuzumab and trastuzumab, for example comprising approximately 600 mg or approximately 1200 mg of pertuzumab in combination with approximately 600 mg of trastuzumab, optionally further comprising 20,000 or 30,000 units of rHuPH20.

[0106] The article of manufacture preferably further comprises a package insert, which may provide instructions for administering the FDC to patients with HER2-positive, estrogen receptor-negative breast cancer, including locally advanced unresectable or metastatic breast cancer.

[0107] Another form of article of manufacture is a syringe containing the formulation to be administered, which can be attached to a stainless steel hypodermic needle for subcutaneous administration.

[0108] Optionally, the subcutaneous administration device is equipped with a 25G-27G (3 / 8''-5 / 8'') hypodermic needle.

[0109] Optionally, the volume of the formulation in the subcutaneous administration device is adjusted to 15 mL for the initial or loading dose and 10 mL for subsequent or maintenance doses.

[0110] In one embodiment, the article of manufacture includes two vials, the first containing the loading dose FDC (e.g., comprising 1200 mg pertuzumab, 600 mg trastuzumab, 30,000 units of rHuPH20, e.g., a total volume of about 15 mL) and the second vial containing the maintenance dose FDC (e.g., comprising 600 mg pertuzumab, 600 mg trastuzumab, 30,000 units of rHuPH20, e.g., a total volume of about 10 mL).

[0111] Further details of the present invention are illustrated by the following non-limiting examples, the disclosures of all citations herein are expressly incorporated herein by reference.

[0112] Example 1 Evaluation of the antiproliferative activity of gildedestrant in combination with trastuzumab and pertuzumab in ER+ / HER2+ breast cancer cell lines Context: HER2 amplification has been proposed to be an important resistance mechanism limiting the activity of endocrine therapy in ER+ / HER2+ breast cancer. In this study, we evaluated whether the antiproliferative activity of the ER antagonist and degrader gildedestrant was enhanced in the presence of the HER2-targeted therapies trastuzumab and pertuzumab in ER+ / HER2+ breast cancer cell lines.

[0113] Materials and Methods: ER+ / HER2+ cell lines UACC-812, HCC1419 and ZR-75-30 cells were seeded in 50μL culture medium in 384-well plates. Cells were incubated overnight (37 degrees, 5% CO2) in a humidified incubator. Test materials were dispensed into 384-well plates on day 1; giledestrant was evaluated as a 9-point dose response (3-fold dose dilution from a maximum concentration of 300nM), traztuzumab and pertuzumab were evaluated as 10-fold dose dilution from a maximum concentration of 300nM, respectively. TIFF2025509510000006.tif6170 was evaluated as a fixed dose of 1000 mg / mL. Fluorescence-based cell proliferation (CyQUANT®; ThermoFisher Scientific, Cat. No. C7026) readings were taken on day 1 to establish a baseline and 6 days after drug treatment. Analysis of drug response was performed using the growth rate (GR) inhibition method to avoid bias between slow and fast growing strains (Hafner et al., Nat Methods 2016 Jun;13(6):521-7)). Growth rate inhibition value of cells under control conditions is set to 1 (GR=1), and no net increase in cell number is set to 0 (GR=0).

[0114] Results: Giledestran exhibits significant single-agent antiproliferative activity in UACC-812 and HCC1419 cells (GR<0.5) and more modest activity in ZR-75-30 cells. In contrast, ZR-75-30 cells show the greatest sensitivity to trastuzumab and pertuzumab. For each of the three cell lines, the GR values ​​are lowest when giledestrant, trastuzumab and pertuzumab are combined (see Figure 3).

[0115] Conclusions: Combined inhibition of ER with giledestrant and HER2 suppression with trastuzumab and pertuzumab results in greater antiproliferative effects than either ER or HER2 suppression alone in UACC-812, HCC1419, and ZR-75-30.

[0116] Example 2 Gileadestrant + PH FDC ± CDK4 / 6 inhibitor combination therapy This study evaluates the efficacy, safety, and pharmacokinetics of fixed-dose combinations of giredestrant and pertuzumab with trastuzumab (PH FDC) for subcutaneous administration, and triplet combinations of giredestrant and PH FDC SC with either abemaciclib (Gire+PH FDC SC+Abema) or palbociclib (Gire+PH FDC SC+Palbo) in patients with inoperable locally advanced unresectable or metastatic ER+, HER2-positive breast cancer with previous disease progression on trastuzumab and ado-trastuzumab emtansine-based therapy.

[0117] Gileadestrand + PH FDC SC Patients in the giledestrant + PH FDC SC arm will receive treatment as outlined in Table 1 until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. [Table 1]

[0118] Gileadestrant + PH FDC SC + Abemaciclib Patients in the giledestrant + PH FDC SC + abemaciclib arm will receive treatment as outlined in Table 2 until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. [Table 2]

[0119] Gileadestrant + PH FDC SC + palbociclib Patients in the giledestrant + PH FDC SC + palbociclib arm will receive treatment as outlined in Table 3 until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. [Table 3] [Table 4]

[0120] Patients treated in the study 1. Women 2. ECOG performance status 0 or 1 3. Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced unresectable disease amenable to curative resection. 4.HER2 positive as defined by ASCO / CAP guidelines: a.>10% of contiguous homogenous tumor cells show protein overexpression (3+) with complete and strong circumferential membrane staining by IHC b. ISH positivity based on counting at least 20 cells within an area of ​​>10% contiguous homogenous tumor cells indicates: Single-probe mean HER2 copy number ≥ 6.0 signals / cell Dual-probe HER2 / CEP17 ratio ≥ 2.0, mean HER2 copy number ≥ 4.0 signals / cell Dual-probe HER2 / CEP17 ratio ≥ 2.0, mean HER2 copy number < 4.0 signals / cell (rare cases, e.g., monosomy 17) Dual-probe HER2 / CEP17 ratio <2.0, mean HER2 copy number ≥6.0 signals / cell 5. Documented ER+ tumor according to ASCO / CAP guidelines (defined as ≥1% of tumor cells staining positively based on the most recent tumor biopsy (or archived tumor sample) as assessed locally) 6. Patients must be considered suitable for ET and anti-HER2 therapy. 7. Previous progression to standard-of-care anti-HER2 therapy (one of which was trastuzumab and taxane-based systemic therapy (including initial setting if relapse occurred within 6 months of completing adjuvant therapy) and one was ado-trastuzumab emtansine) 8. Up to 1 line of ET was allowed in the advanced setting, including fulvestrant if fulvestrant was given >28 days before randomization, but excluding other SERDs. 9. Measurable disease (at least one target lesion) by RECIST v 1.1 10. Baseline LVEF ≥ 50% as measured by ECHO or MUGA scan

[0121] Efficacy and safety outcomes Treatment with the combination of giledestrant + PH FDC was effective according to any one or more of the primary and secondary endpoints and had an acceptable safety profile in patients with locally advanced unresectable or metastatic estrogen receptor-positive HER2-positive breast cancer.

[0122] Treatment with the combination of giledestrant + PH FDC + abemaciclib is more effective than treatment with giledestrant + PH FDC without abemaciclib and has an acceptable safety profile according to any one or more of the primary and secondary endpoints in patients with locally advanced unresectable or metastatic estrogen receptor-positive HER2-positive breast cancer.

[0123] Treatment with the combination of giledestrant + PH FDC + palbociclib is more effective and has an acceptably safer profile than treatment with giledestrant and PH FDC without palbociclib according to any one or more of the primary and secondary endpoints in patients with locally advanced unresectable or metastatic estrogen receptor-positive HER2-positive breast cancer.

[0124] Example 3 Gileadestrant Combined with Pertuzumab and Trastuzumab Fixed-Dose Combination (PH FDC) Versus PH FDC Following Induction Therapy with PH FDC Plus Taxane in Patients with HER2-Positive, Estrogen Receptor-Positive Advanced Breast Cancer This study will evaluate the efficacy and safety of gildedestrant, a novel oral selective estrogen receptor degrader (SERD), in combination with PHESGO® (fixed-dose combination pertuzumab, trastuzumab and rHuPH20 injection for SC use) in participants with previously untreated, locally advanced unresectable, or metastatic estrogen receptor (ER)-positive, HER2-positive breast cancer (BC) following 4-8 cycles of induction therapy with PH FDC + taxane (i.e., docetaxel or paclitaxel per standard of care). Despite advances in early diagnosis and curative multimodality treatments, some patients may still experience metastatic recurrence or present with "de novo" metastatic breast cancer (MBC). There remains a need for treatments with a more favorable benefit / risk profile that extend progression-free survival (PFS) and other survival endpoints in patients with ER-positive, HER2-positive advanced breast cancer (ABC).

[0125] The primary comparison of interest is the hazard ratio (HR) for PFS. The primary objective is to demonstrate superiority of the giledestrant + PH FDC arm versus the PH FDC arm.

[0126] In this protocol, "induction therapy" refers to treatment with PH FDC plus taxane, and "maintenance treatment" refers to PH FDC plus giledestrant or PH FDC.

[0127] This phase III, randomized, two-arm, open-label, multicenter study will evaluate the efficacy and safety of PH FDC plus gildedestrant compared with PH FDC following taxane induction in participants with HER2-positive, ER-positive advanced breast cancer (metastatic or locally advanced disease not amenable to curative treatment) who have not received prior systemic non-hormonal anticancer therapy in the advanced setting.

[0128] During the induction phase, participants will receive 4-6 cycles of PH FDC in combination with a taxane (i.e., docetaxel or paclitaxel per standard of care). At the investigator's discretion, participants who tolerate 6 cycles of induction therapy well and have not experienced progressive disease (PD) may be given up to 2 additional cycles (up to a maximum of 8 cycles per standard of care). Participants who received 1 or 2 cycles of PH FDC (or trastuzumab SC and pertuzumab IV or PH IV) with docetaxel or paclitaxel prior to enrollment are eligible, and these additional cycles will count toward eligibility for the maintenance phase.

[0129] After the induction phase, eligible participants will be randomized to a maintenance phase during which they will receive PH FDC + giledestrant or PH FDC in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined end of study, whichever occurs first.

[0130] The study scheme is shown in Figure 5 and the endpoints are shown in Table 5. [Table 5]

[0131] Induction Therapy Phase During the induction therapy phase, all participants will receive a PH FDC in combination with a taxane (i.e., docetaxel or paclitaxel) for four to six cycles, according to standard of care.

[0132] At the investigator's discretion, participants who tolerate 6 cycles of induction therapy well and are in the absence of PD or limiting toxicity may receive up to 2 additional cycles of the same combination taxane + PH FDC, up to a total of 8 cycles.

[0133] Participants who received 1 or 2 cycles of PH FDC with docetaxel or paclitaxel (or pertuzumab SC with trastuzumab IV, or PH IV) prior to enrollment are eligible if they did not experience PD or limiting toxicity. Off-study cycles will count toward eligibility for the permitted 4-8 cycles and the maintenance phase.

[0134] Participants who are unable to tolerate their assigned taxane and discontinue before a minimum of four cycles will discontinue all study treatment and enter the follow-up phase. Participants will be treated according to the standard of care, as clinically indicated, at the discretion of the investigator.

[0135] Inclusion criteria 1. Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease amenable to curative resection. 2. HER2-positive ABC confirmed by a central laboratory prior to study enrollment. HER2-positive status was determined based on primary or metastatic disease and defined as 3+ by immunohistochemistry (IHC) and / or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of HER2 gene copy number to chromosome 17 copy signal number ≥2. 3. ER-positive tumors as assessed locally and defined as ≥1% of tumor cells staining ER positive, preferentially based on the same lesions used to determine HER2 positivity, per the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines. 4. At least one measurable lesion and / or nonmeasurable disease evaluable according to RECIST version 1.1 5. Disease-free interval of 6 months or more from completion of adjuvant or neoadjuvant systemic non-hormonal treatment until recurrence 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. LVEF of at least 50% measured by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA).

[0136] Maintenance therapy phase After the induction phase, participants who meet the following criteria are eligible for the maintenance phase: 1. Complete at least 4 cycles of induction therapy, defined as any of the following: -4 PH FDC injections + 4 docetaxel injections or -4 PH FDC injection + 12 paclitaxel injection NOTE: If a participant has received 1 or 2 cycles of induction therapy prior to enrollment, these cycles should be counted toward the number of cycles required for eligibility for the maintenance phase (e.g., if a participant received 1 cycle of PH FDC [or trastuzumab SC and pertuzumab IV, or PH IV] + docetaxel prior to enrollment, a minimum of 3 cycles of on-study PH FDC + docetaxel are required before entering the maintenance phase). 2. Achieve minimal stable disease (SD) (i.e., did not experience progressive disease [PD]) according to RECIST v1.1 at the time of the last tumor assessment in the induction phase 3. Left ventricular ejection fraction (LVEF) ≥ 50% at the end of the induction phase.

[0137] Eligible participants will be randomized in a 1:1 ratio to one of two treatment arms: no crossover between the two treatment arms will be allowed. Prior to randomizing participants, the investigator must determine and document whether any ET will be prescribed according to standard of care if the participant is randomized to arm A.

[0138] Arm A (PH FDC: control arm): Participants receive PH FDC subcutaneously every 3 weeks (Q3W). Optional concomitant ET at the investigator's choice is permitted based on standard of care (ET can include AI or tamoxifen). Pre- and peri-menopausal women or men receiving AI must also receive a luteinizing hormone releasing hormone agonist (LHRHa). Alternatively, pre- or peri-menopausal women can be treated with bilateral oophorectomy.

[0139] Arm B (PH FDC + giledestrant: experimental arm): Participants receive giledestrant 30 mg once daily (QD) orally (PO) on days 1-21 of each 21-day cycle in combination with PH FDC subcutaneous Q3W. Pre- and peri-menopausal women, as well as all men, receive LHRHa every 28 days and up to 28 days prior to the first giledestrant dose. Alternatively, pre- or peri-menopausal women can be treated with bilateral oophorectomy.

[0140] Table 6 provides a description of the study treatments assigned to this study. [Table 6]

[0141] In applicable facilities, during the maintenance phase, study procedures may be performed by trained nursing professionals in the participant's home or another appropriate location if the participant has given written informed consent to participate in mobile nursing (MN) visits and if national regulations allow this.

[0142] PH FDC The PH FDC will be provided in a single-dose, ready-to-use glass vial and will be administered subcutaneously as a fixed, non-weight-based dose. During the induction phase, the PH FDC will be administered prior to taxane-based chemotherapy (i.e., docetaxel or paclitaxel). If administered prior to enrollment, the same taxane used outside the trial should be administered during the induction phase. Participants who experience injection-related symptoms may be pre-medicated with analgesics and antihistamines prior to subsequent injections.

[0143] In the induction phase, a loading dose (1200 mg pertuzumab, 600 mg trastuzumab, 30,000 U rHuPH20) is administered in the first cycle. In subsequent cycles, maintenance doses (600 mg pertuzumab, 600 mg trastuzumab, 20,000 U rHuPH20) are administered subcutaneously Q3W. If the participant received one or two doses of PH FDC (or trastuzumab SC + pertuzumab IV, or trastuzumab IV + pertuzumab) less than 6 weeks prior to enrollment in the induction phase, a PH FDC maintenance dose will be administered. However, if dosing is paused and the time between doses of PH FDC is 6 weeks or less but not more than 9 weeks, a loading dose should be given. Subsequent maintenance doses are given Q3W. No dose reductions are permitted for PH FDC.

[0144] PH FDC will be administered according to the prescribing information. All doses of PH FDC will be administered as a SC injection into the thigh at a rate of 2 mL / min or less over 5-8 minutes (other anatomical locations are not permitted). The loading dose(s) should be administered over 8 minutes; the maintenance doses should be administered over 5 minutes. The injection rate should be adjusted to a rate that is comfortable for the participant. A new injection should be given at least 2.5 cm from the previous site and never into an area where the skin is red, bruised, tender, or hard. The entire volume (15 mL volume for the loading dose; 10 mL volume for the maintenance dose) must be injected into one site: splitting the volume into two syringes or injecting into two different sites is not permitted.

[0145] After the first loading dose injection, participants are observed for injection-related symptoms for 30 minutes after the end of the injection. If the participant experiences injection-related symptoms during the injection, the injection should be slowed or interrupted (but not reduced). If the first injection is well tolerated, participants are observed for 15 minutes after subsequent injections.

[0146] Gilledestran Giledestrant will be supplied as immediate-release capsules and packaged in high-density polyethylene bottles with induction seals and plastic child-resistant caps with desiccant. On days 1-21 of each 21-day cycle during the maintenance treatment phase, participants randomized to Arm B will orally self-administer one capsule of 30 mg Giledestrant at approximately the same time each day. Giledestrant may be taken with or without meals.

[0147] For cycles in which the PH FDC is administered in the clinic, the day 1 dose of gildedestrant will be administered in the clinic. For any cycles in which the PH FDC is administered outside the clinic (participant's home or other appropriate location), the day 1 gildedestrant dose may also be administered outside the clinic. If a dose is missed, it should be made up unless the next dose is due within 6 hours. If a dose is missed, participants should resume dosing with the next scheduled dose and the missed dose will not be made up.

[0148] If giledestrant needs to be withheld or permanently discontinued due to treatment-related toxicity, participants should continue to receive treatment with the PH FDC alone.

[0149] Taxanes During the induction phase, the investigator's choice of taxane-based chemotherapy (i.e., docetaxel or paclitaxel) will be administered following the PH FDC. If the participant received a taxane prior to enrollment, the same taxane used outside the study should be administered during the induction phase. Please refer to currently approved prescribing information for docetaxel and paclitaxel for formulation, handling and dosing instructions, as appropriate.

[0150] The recommended dosing schedule is shown in Table 7. [Table 7]

[0151] Any endocrine therapy at the investigator's choice Optional ET will be tamoxifen or one of the designated third generation AIs (anastrozole, letrozole or exemestane). ET dosing should be done according to the local prescribing information for the respective product. If ET selection needs to be permanently discontinued due to treatment-related toxicity, ET should be permanently discontinued and participants should continue to receive treatment with PH FDC alone.

[0152] Luteinizing hormone-releasing hormone agonists LHRHa may include, but is not limited to, leuprolide acetate, goserelin acetate, or triptorelin pamoate and is administered to male participants and to pre- and peri-menopausal female participants while administering giledestrant in arm B. LHRHa may be administered to male participants receiving tamoxifen and pre- and peri-menopausal female participants in arm A and should be administered to participants receiving an AI in arm A.

[0153] The investigator will determine and provide an appropriate LHRHa locally approved for use in BC. LHRHa will be administered according to local prescribing information. Monthly injections are preferred to minimize the potential for exposure to drug decreasing to subtherapeutic levels toward the end of the treatment cycle.

[0154] If a participant becomes intolerant to their current LHRHa, they may switch to another approved LHRHa during the study. Bilateral oophorectomy for premenopausal or perimenopausal women is permitted.

[0155] Treatment outcome Treatment with the combination of giledestrant and PH FDC achieves any one or more of the efficacy endpoints superior to PH FDC alone with acceptable toxicity, e.g., treatment with the combination extends progression-free survival (PFS) more than PH FDC alone with acceptable toxicity.

[0156] In one embodiment, treatment with giledestrant and PH FDC extends the median progression-free survival (PFS) from randomization (i.e., from the start of maintenance therapy) by at least 4.5 months, or at least 6.7 months, compared to the median PFS with PH FDC alone.

Claims

1. (i) pertuzumab, (ii) trastuzumab, (iii) Gilledesrant; (iv) pertuzumab and trastuzumab, (v) pertuzumab and giledestrant; (vi) trastuzumab and giledestrant, or (vii) Pertuzumab, trastuzumab, and giledestrant 1. A medicament for treating a patient with estrogen receptor-positive and HER2-positive breast cancer, comprising:

2. 2. The pharmaceutical composition of claim 1, comprising a fixed-dose combination of pertuzumab and trastuzumab (PH FDC).

3. The pharmaceutical composition according to claim 1 or 2, wherein the breast cancer is advanced breast cancer.

4. The pharmaceutical composition of claim 3, wherein the advanced breast cancer is locally advanced unresectable breast cancer or metastatic breast cancer.

5. 2. The method of claim 1, wherein treatment with the combination is more effective than treatment with pertuzumab and trastuzumab without giledestrant.

6. The method of claim 1, wherein the combination is administered as maintenance therapy after induction therapy.

7. 7. The method of claim 6, wherein the induction therapy comprises treatment of the patient with pertuzumab and trastuzumab and a taxane.

8. The pharmaceutical agent of claim 7, wherein the induction therapy comprises 4 to 8 cycles of a combination of a fixed-dose combination of pertuzumab and trastuzumab (PH FDC) and paclitaxel or docetaxel in an amount effective to treat the breast cancer.

9. The paclitaxel is administered at 80 mg / m on days 1, 8, and 15 of each 21-day cycle. ２ Docetaxel was administered intravenously at a dose of 75 mg / m on day 1 of each 21-day cycle. ２ If this initial dose is well tolerated, the docetaxel dose is increased to 100 mg / m ２ The pharmaceutical composition of claim 8, wherein the dose is increased to

10. 7. The method of claim 6, wherein the maintenance therapy comprises administering 30 mg of giledestrant orally once daily on days 1 to 21 of a 21-day cycle in combination with administering PH FDC subcutaneously on day 1 of the 21-day cycle.

11. 3. The method of claim 2, wherein said treatment with the combination of gildedestrant and PH FDC extends progression-free survival (PFS) more than PH FDC alone.

12. 12. The method of claim 11, wherein said treatment with the combination of giledestrant and PH FDC increases median PFS by 4.5 months or more compared to median PFS with PH FDC alone.

13. 3. The medicament of claim 2, wherein the PH FDC is administered subcutaneously as a loading dose FDC comprising 1200 mg of pertuzumab and 600 mg of trastuzumab, followed by a maintenance dose FDC comprising 600 mg of pertuzumab and 600 mg of trastuzumab.

14. The method of claim 13, wherein the PH FDC is administered on day 1 of a three-week cycle.

15. 15. The pharmaceutical composition of claim 13 or claim 14, wherein the loading dose FDC further comprises 30,000 units of hyaluronidase and the maintenance dose FDC further comprises 20,000 units of hyaluronidase.

16. 2. The method of claim 1, wherein the giledestrant is administered orally at a dose of 30 mg once daily in a 3-week or 4-week cycle.

17. The method of claim 1, further comprising administering a CDK4 / 6 inhibitor to the patient.

18. The pharmaceutical composition of claim 17, wherein the CDK4 / 6 inhibitor comprises palbociclib.

19. 19. The method of claim 18, wherein the palbociclib is administered orally at a dose of 125 mg daily on days 1-21 of a 28-day cycle.

20. The pharmaceutical composition of claim 17, wherein the CDK4 / 6 inhibitor comprises abemaciclib.

21. 21. The method of claim 20, wherein the abemaciclib is administered orally at a dose of 150 mg twice daily for a 21-day cycle.

22. The method of claim 1, wherein the patient has had previous disease progression on trastuzumab treatment and HER2-ADC treatment.

23. A pharmaceutical agent for treating estrogen receptor-positive and HER2-positive breast cancer patients with advanced breast cancer, comprising a fixed-dose combination of pertuzumab and trastuzumab (PH FDC), comprising: a. induction therapy comprising 4 to 8 cycles of a combination of PH FDC and docetaxel or paclitaxel in an amount effective to treat said breast cancer, followed by: b. A maintenance therapy comprising a combination of giledestrant and PH FDC in an amount effective to treat said breast cancer. is administered to said patient.

24. A pharmaceutical composition for treating an estrogen receptor-positive and HER2-positive breast cancer patient with advanced breast cancer, comprising a fixed-dose combination of pertuzumab and trastuzumab (PH FDC), wherein a combination of PH FDC, gildestrant, and palbociclib is administered to the patient in an amount effective to treat the advanced breast cancer.

25. A pharmaceutical composition for treating an estrogen receptor-positive and HER2-positive breast cancer patient with advanced breast cancer, comprising a fixed-dose combination of pertuzumab and trastuzumab (PH FDC), wherein a combination of PH FDC, gildestrant, and abemaciclib is administered to the patient in an amount effective to treat the advanced breast cancer.

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