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WO2022123419A1 - Traitement de sous-types luminaux de cancer du sein précoce hr-positif, her2-négatif par le palbociclib - Google Patents

Traitement de sous-types luminaux de cancer du sein précoce hr-positif, her2-négatif par le palbociclib Download PDF

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Publication number
WO2022123419A1
WO2022123419A1 PCT/IB2021/061347 IB2021061347W WO2022123419A1 WO 2022123419 A1 WO2022123419 A1 WO 2022123419A1 IB 2021061347 W IB2021061347 W IB 2021061347W WO 2022123419 A1 WO2022123419 A1 WO 2022123419A1
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WIPO (PCT)
Prior art keywords
breast cancer
her2
luminal
patient
therapy
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PCT/IB2021/061347
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English (en)
Inventor
Maria Jose LECHUGA FREAN
Yuan Liu
Olga Valota
Zhe Zhang
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Pfizer Inc.
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Publication of WO2022123419A1 publication Critical patent/WO2022123419A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to combination therapy for the treatment of luminal subtypes of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer.
  • the invention also relates to associated methods of treatment and patient selection, pharmaceutical compositions and pharmaceutical uses.
  • Breast cancer is the most common cancer amongst women worldwide and is also the leading cause of cancer-related mortality. Breast cancer represents approximately 12% of all new cancer cases and 25% of all cancers in women, with nearly 2.1 million new cases diagnosed globally and 626,679 deaths in 2018. (Bray F. et al., Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424.) Breast cancer occurs predominantly in women, with breast cancer in men accounting for less than 1 % of breast cancer cases in the US. (Chavez-Mcgregor M. et al., Male breast cancer according to tumor subtype and race: a Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418):61 -70.)
  • Breast cancer is a heterogeneous disease.
  • HR+, HER2- tumors are the most prevalent form of breast cancer and account for approximately 70% of all breast cancers.
  • Endocrine therapy in particular tamoxifen or an aromatase inhibitor administered for 5 to 10 years post definitive local therapy has been the standard of care for adjuvant treatment for HR+, HER2- eBC, as per ASCO Guidelines (Burstein HJ et al., Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol 2019; 37(5):423-38.) Despite 5 years of adjuvant endocrine therapy, ER+ tumors retain a substantial risk of late recurrence (Burstein, 2019) and many patients diagnosed with eBC will eventually relapse to advanced or metastatic disease during or relatively soon after adjuvant therapy. (Geurts, 2017).
  • NACT neoadjuvant chemotherapy
  • E adjuvant endocrine therapy
  • the present invention is based in part on the subgroup analysis of a randomized, double-blind placebo-controlled Phase III clinical study (Phase III Study Evaluating Palbociclib (PD-0332991 ), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy (PENELOPE-B), NCT01864746) assessing palbociclib and endocrine therapy as adjuvant therapy in pre- and postmenopausal women with HR+, HER2- early breast cancer at high risk of recurrence after neoadjuvant chemotherapy and surgery.
  • the invention provides a method for the treatment of a patient diagnosed with: (a) estrogen receptor-positive (ER+), progesterone receptor-negative (PgR-), human epidermal growth factor receptor 2-negative (HER2-), luminal A early breast cancer; (b) hormone receptor-positive (HR+), HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, wherein the combination therapy is administered for a period of time effective to increase invasive disease-free survival (iDFS).
  • the combination therapy is administered to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the invention provides a method to reduce the risk of recurrence of invasive breast cancer or death for an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, wherein the risk of recurrence of invasive breast cancer or death is reduced compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the combination therapy is administered to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the invention provides a method of adjuvant therapy, comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery.
  • the combination therapy is administered fora period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )- (6).
  • the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the method comprises administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • the invention provides a method of adjuvant therapy, comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2- luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery, and for a period of time effective to increase invasive disease-free survival (iDFS).
  • iDFS invasive disease-free survival
  • the invention provides a method of adjuvant therapy comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery and reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of selecting a patient diagnosed with early breast cancer for treatment with a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy, comprising: (A) determining the hormone receptor (HR)-status of the patient’s cancer; (B) determining the human epidermal growth factor receptor 2 (HER2)-status of the patient’s cancer; (C) determining the intrinsic molecular subtype of the patient’s cancer; (D) determining the ERBB2 expression status (high versus low level) of the patient’s cancer; and (E) selecting the patient for treatment with the combination therapy when the patient has: (a) an HR-status of ER+, PgR-, a HER2-status of HER2-, and an intrinsic molecular subtype of luminal A; (b) an HR-status of HR+, a HER2-status of HER2-, an intrinsic molecular subtype of luminal A, and an ERBB2 expression status of high
  • the invention provides a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase invasive disease-free survival (iDFS).
  • the combination therapy is effective to increase iDFS excluding second primary invasive non-breast cancer.
  • the invention provides a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase invasive disease-free survival (iDFS).
  • the combination therapy is effective to increase iDFS excluding second primary invasive non-breast cancer.
  • the invention provides the use of a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, for the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of palbociclib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the palbociclib, or a pharmaceutically acceptable salt thereof, is used in combination with an endocrine therapy for a period of time effective to increase invasive disease-free survival (iDFS).
  • the combination therapy is effective to increase iDFS excluding second primary invasive non-breast cancer.
  • the invention provides the use of palbociclib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the palbociclib, or a pharmaceutically acceptable salt thereof, is used in combination with an endocrine therapy to reduce the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • Palbociclib and pharmaceutically acceptable salts and formulations thereof are disclosed in International Publication No. WO 2003/062236 and U.S. Patent Nos. 6,936,612, RE47,739 and 7,456,168; International Publication No. WO 2005/005426 and U.S. Patent Nos. 7,345,171 and 7,863,278; International Publication No. WO 2008/032157 and U.S. Patent No. 7,781 ,583; International Publication No. WO 2014/128588; and International Publication No. WO 2016/193860.
  • the contents of each of the foregoing references are incorporated herein by reference in their entirety.
  • the endocrine therapy is an aromatase inhibitor, a selective estrogen receptor modulator (SERM), or a selective estrogen receptor degrader (SERD).
  • the endocrine therapy is an aromatase inhibitor, preferably letrozole, anastrozole or exemestane.
  • the endocrine therapy is a SERM, preferably tamoxifen, or a pharmaceutically acceptable salt thereof.
  • iDFS invasive disease-free survival
  • additive when used in reference to a combination therapy means that the result of administering the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent administered individually.
  • adjuvant therapy refers to systemic therapy administered after surgery.
  • adjuvant therapy may be administered after definitive surgery to reduce the risk of recurrence.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth.
  • cancer includes solid tumors named for the type of cells that form them. Cancer includes but is not limited to a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from latter one.
  • CPS-EG clinical pathological staging-estrogen receptor grading
  • Mittendorf et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 29:1956-62, 2011.
  • the system involves the tumor stage prior to treatment start and at surgery, the ER-status, and pathologic grading. A higher CPS-EG score indicates a higher risk of relapse.
  • the term “definitive surgery” means the complete removal of the primary tumor(s) and surrounding tissues, as well as any involved lymph nodes. Examples of such surgery include mastectomy, e.g., total mastectomy with or without axillary dissection, or double mastectomy, or breast-conserving surgery (BCS), such as lumpectomy or partial mastectomy.
  • CTMS breast-conserving surgery
  • ears breast cancer means a primary breast cancer that has not spread beyond the breast and axillary lymph nodes.
  • the effective amounts of palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy are the amounts that together are effective to achieve the desired outcome, for example the amounts effective to increase iDFS, or the amounts effective reduce the risk of recurrence in the treated patient.
  • an effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.
  • “Hormone receptor-positive”, “HR-positive” or “HR+” cancer refers to cancer that tests positive for the estrogen receptor (i.e., ER-positive, ER+) and/or the progesterone receptor (PgR-positive, PgR+).
  • “Hormone receptor-negative”, “HR-negative” or “HR-” cancer refers to cancer that tests negative for both the estrogen receptor (i.e., ERnegative, ER-) and the progesterone receptor (i.e., PgR-negative, PgR-). Analysis of HR- status can be performed by any method known in the art.
  • Estrogen receptor-positive”, “ER-positive” or “ER+” cancer refers to cancer that tests positive for the estrogen receptor (ER).
  • Estrogen receptor-negative”, “ER-negative” or “ER-” cancer refers to cancer that tests negative for the estrogen receptor. Analysis of ER-status can be performed by any method known in the art. Typically, an ER+ tumor will have >1 % positive stained cells.
  • Progesterone receptor-positive”, “PgR-positive” or “PgR+” cancer refers to cancer that tests positive for the progesterone receptor (PgR).
  • Progesterone receptor-negative”, “PgR-negative” or “PgR-” cancer refers to cancer that tests negative for the progesterone receptor. Analysis of PgR-status can be performed by any method known in the art.
  • the progesterone receptor may alternatively be referred to as “PR” rather than “PgR”.
  • a PgR+ tumor will have >1 % positive stained cells.
  • Human epidermal growth factor receptor 2-negative “HER2-negative” or“HER2- “ cancer refers to cancer that tests negative for the HER2 receptor (HER2).
  • “Human epidermal growth factor receptor 2-positive”, “HER2-positive” or “HER2+” cancer refers to cancer that has higher than normal levels of HER2. Analysis of HER2- status can be performed by any method known in the art. Typically, a HER2+ tumor will have an IHC score 3+ or an in-situ hybridization (ISH) positive based on: single-probe average HER2 copy number >6.0 signals/cell; or dual-probe HER2/CEP17 ratio of >2.0, with an average HER2 copy number >4.0 signals/cell; or dual-probe HER2/CEP17 ratio of >2.0, with an average HER2 copy number ⁇ 4.0; or dual-probe HER2/CEP17 ratio of ⁇ 2.0, with an average HER2 copy number >6.0 signals/cell (Wolff AC et al., Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO/CAP Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 2018; 142(1364-1382).
  • high expression of ERBB2 refers to patients with HER2-/non-amplified HER2 (as defined by current HER2 standard IHC and/or gene expression tests), where the HER2/ERBB2 expression level is further classified as high based on optimal cut point analysis.
  • the optimal cut point of ERBB2 expression level is calculated empirically as a standardized Z score using an outcome-oriented approach on iDFS with a selection procedure that maximizes the log-rank test statistic.
  • nanoadjuvant therapy refers to systemic therapy administered prior to surgery.
  • lymph node positive refers to breast cancer that has spread to regional lymph nodes, such as axillary lymph nodes located in the underarm area.
  • patient or “subject” may be used interchangeably herein to refer to any single human subject for whom therapy is desired or who is participating in a clinical trial, epidemiological study or used as a control.
  • the patient is a postmenopausal woman.
  • the patient is a pre- or perimenopausal woman, optionally treated with ovarian suppression, e.g., with a luteinizing hormone releasing hormone (LHRH) agonist, such as goserelin.
  • LHRH luteinizing hormone releasing hormone
  • Patients may be treatment naive (i.e., have not received prior treatment for early disease if diagnosed with early breast cancer) or may have received one or more prior treatments, such as endocrine therapy, chemotherapy or radiotherapy.
  • the patient has undergone definitive surgery, and may also have been treated with adjuvant or neoadjuvant endocrine therapy, chemotherapy or radiotherapy.
  • a "patient population” refers to a group of patients, e.g., a clinical trial cohort which may be used to demonstrate statistically significant efficacy and/or safety of a drug, such as palbociclib and/or an endocrine therapy.
  • recur refers to a return of cancer following treatment, which may include the return of cancer in the breast as well as distant recurrence, where the cancer returns to a site outside of the breast.
  • the risk of recurrence is related to the clinical and pathological characteristics of the tumor.
  • relapse or “relapsed” mean showing signs or symptoms of cancer return, e.g., after a period remission, or after administration of adjuvant or neoadjuvant therapy.
  • a patient at “high risk of recurrence” includes an individual with a greater than average chance of experiencing recurrence, for example patients with residual invasive disease following neoadjuvant chemotherapy, or patients having a high CPS-EG score or who are lymph node positive, e.g., a CPS-EG score >3 or 2 and ypN+.
  • resect means surgical removal of malignant tissue, e.g., a primary tumor and related lymph nodes of breast cancer from a patient. Following resection, the presence of residual breast cancer may be undetectable in the patient.
  • synergy or “synergistic” when used in reference to a combination therapy mean that the result of administering the combination of compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent administered individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect.
  • a “synergistic amount” is an amount of the combination of compounds, components or targeted agents that results in a synergistic effect.
  • the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, and/or dose ratios to patients in need of treatment.
  • the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist, as described herein, to measure a synergistic effect.
  • the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic and/or pharmacodynamics methods.
  • treat or “treating” a cancer as used herein means to administer one or more drugs, such as a combination therapy according to the present invention, to a subject having cancer, or diagnosed with cancer.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • treating may include adjuvant or neoadjuvant treatment of a subject.
  • Clinical endpoints are generally defined according to the STEEP system. Hudis et al., Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. (2007) 25(15):2127-32.
  • Invasive disease-free survival is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive non-breast cancer).
  • the endpoint is invasive disease-free survival (iDFS) excluding second primary invasive non-breast cancer.
  • iDFS per treatment group may be determined by, e.g., PAM50 or any other commercially available test at the time of analysis.
  • D-DFS Distant disease free survival
  • D-RFS Distant recurrence-free survival
  • Locoregional recurrence-free interval is the time between randomization (or breast cancer surgery) and the detection of locoregional recurrence.
  • a locoregional recurrence is a breast cancer recurrence that is local and/or regional.
  • OS Overall survival
  • the treatment regimen for a combination of the invention that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art.
  • treatment regimen may be used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination of the invention.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukaemia’s (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).
  • Tumor burden refers to the total amount of tumorous material distributed throughout the body. Tumor burden refers to the total mass of tumor tissue carried by a patient with a malignancy. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., using callipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans.
  • imaging techniques e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans.
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using callipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CR or MRI scans.
  • imaging techniques e.g., bone scan, ultrasound, CR or MRI scans.
  • pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the parent compound.
  • pharmaceutically acceptable salt(s) includes salts of acidic or basic groups which may be present in the compounds of the formulae disclosed herein.
  • Tumor samples were collected from subjects having HR+, HER2- early breast cancer who were participants in a placebo-controlled double blind clinical trial of palbociclib in combination with endocrine therapy, as described in Example 1. Subjects were treated with palbociclib (125 mg QD, 3/1 schedule) plus endocrine therapy in the treatment arm, or placebo (3/1 schedule QD) plus endocrine therapy in the control arm.
  • hormone receptor status may be determined using enzyme immunoassays and IHC staining.
  • HER2 expression level may be determined by tissue microarrays (TMA) of tumor tissue.
  • Immunohistochemistry (IHC) or florescence in situ hybridization (FISH) may also be used to evaluate HER2 status.
  • Gene expression profiling may be performed using standard techniques, including e.g., PAM50.
  • the invention provides a method for the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR- RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • the early breast cancer patient is diagnosed with ER+, PgR- , HER2-, luminal A early breast cancer. In some embodiments, the early breast cancer patient is diagnosed with HR+, HER2-, luminal A early breast cancer with high expression of ERBB2. In other embodiments, the early breast cancer patient is diagnosed with HR+, HER2-, luminal B early breast cancer.
  • the combination therapy is administered for a period of time effective to increase invasive disease-free survival (iDFS). In some embodiments, the combination therapy is administered for a period of time effective to increase iDFS excluding second primary invasive non-breast cancer.
  • iDFS invasive disease-free survival
  • the period of time for which the combination therapy is administered (which may be alternatively referred to as the “first period of time”) is one to five years. In some embodiments, the period of time for which the combination therapy is administered is one to three years. In some embodiments, the period of time for which the combination therapy is administered is at least one year, at least two years, at least three years, at least four years, or at least five years. In some embodiments, the period of time for which the combination therapy is administered is one year or longer, two years or longer, three years or longer, four years or longer, or five years or longer.
  • the patient is administered an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof, for a second period of time following completion of the combination therapy.
  • the second period of time is one to ten years, one to eight years, one to five years, or one to three years.
  • the second period of time is at least one year, at least two years, at least three years, at least four years, or at least five years.
  • the second period of time is one year or longer, two years or longer, three years or longer, four years or longer, or five years or longer.
  • the increase in iDFS, iDFS excluding second primary invasive non-breast cancer, D-DFS, D-RFS, LR-RFI or OS is determined relative to the average time for such endpoint in a relevant patient population, such as the treatment and placebo cohorts from a relevant clinical trial.
  • the method comprises administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the combination therapy is administered to the patient after definitive surgery.
  • an endocrine therapy is administered to the patient as an adjuvant therapy to: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the chemotherapy is neoadjuvant chemotherapy (NACT).
  • NACT is taxane-containing NACT.
  • the patient has residual invasive disease in the breast or lymph node. In some such embodiments, the patient is at high risk of relapse. In particular embodiments, the patient has a clinical-pathologic stage - estrogen/grade (CPS-EG) score 3-6, or a CPS-EG score 2 and residual positive lymph node status (ypN+).
  • CPS-EG clinical-pathologic stage - estrogen/grade
  • ypN+ residual positive lymph node status
  • the invention provides a method to reduce the risk of recurrence of invasive breast cancer or death for a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, wherein the risk of recurrence of invasive breast cancer or death is reduced compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the early breast cancer patient is diagnosed with ER+, PgR-, HER2-, luminal A early breast cancer. In some embodiments, the early breast cancer patient is diagnosed with ER+, PgR-, HER2-, luminal A early breast cancer with high expression of ERBB2. In some embodiments, the early breast cancer patient is diagnosed with HER2-, luminal A early breast cancer with high expression of ERBB2. In other embodiments, the patient is diagnosed with HR+, HER2-, luminal B early breast cancer.
  • the method comprises administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the combination therapy is administered to the patient after definitive surgery.
  • an endocrine therapy is administered to the patient as an adjuvant therapy to: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the chemotherapy is neoadjuvant chemotherapy (NACT).
  • NACT is taxane-containing NACT.
  • the patient has residual invasive disease in the breast or lymph node. In some such embodiments, the patient is at high risk of relapse. In particular embodiments, the patient has a clinical-pathologic stage - estrogen/grade (CPS-EG) score 3-6, or a CPS-EG score 2 and residual positive lymph node status (ypN+).
  • CPS-EG clinical-pathologic stage - estrogen/grade
  • ypN+ residual positive lymph node status
  • the invention provides a method of adjuvant therapy, comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to an early breast cancer patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery and for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free
  • the early breast cancer patient is diagnosed with ER+, PgR- , HER2-, luminal A early breast cancer.
  • the early breast cancer patient is diagnosed with HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • the early breast cancer patient is diagnosed with HR+, HER2-, luminal B early breast cancer.
  • the combination therapy is administered for a period of time effective to increase invasive disease-free survival (iDFS).
  • iDFS invasive disease-free survival
  • the combination therapy is administered for a period of time effective to increase iDFS excluding second primary invasive non-breast cancer.
  • the period of time for which the combination therapy is administered (which may be alternatively referred to as the “first period of time”) is one to five years. In some embodiments, the period of time for which the combination therapy is administered is one to three years. In some embodiments, the period of time for which the combination therapy is administered is at least one year, at least two years, at least three years, at least four years, or at least five years. In some embodiments, the period of time for which the combination therapy is administered is one year or longer, two years or longer, three years or longer, four years or longer, or five years or longer.
  • the patient is administered an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof, for a second period of time following completion of the combination therapy.
  • the second period of time is one to ten years, one to eight years, one to five years, or one to three years.
  • the second period of time is at least one year, at least two years, at least three years, at least four years, or at least five years.
  • the second period of time is one year or longer, two years or longer, three years or longer, four years or longer, or five years or longer.
  • the increase in iDFS, iDFS excluding second primary invasive non-breast cancer, D-DFS, D-RFS, LR-RFI or OS is determined relative to the average time for such endpoint in a relevant patient population, such as the treatment and placebo cohorts from a relevant clinical trial.
  • the method comprises administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • the chemotherapy is neoadjuvant chemotherapy (NACT).
  • NACT is taxane-containing NACT.
  • the patient has residual invasive disease in the breast or lymph node.
  • the patient is at high risk of relapse.
  • the patient has a clinical-pathologic stage - estrogen/grade (CPS-EG) score 3-6, or a CPS-EG score 2 and residual positive lymph node status (ypN+).
  • the invention provides a method of adjuvant therapy comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery, and reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the patient is diagnosed with ER+, PgR-, HER2-, luminal A early breast cancer.
  • the patient is diagnosed with HR+, HER2- , luminal A early breast cancer with high expression of ERBB2.
  • the patient is diagnosed with HR+, HER2-, luminal B early breast cancer.
  • the method comprises administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • the chemotherapy is neoadjuvant chemotherapy (NACT).
  • NACT is taxane-containing NACT.
  • the patient has residual invasive disease in the breast or lymph node.
  • the patient is at high risk of relapse.
  • the patient has a clinical-pathologic stage - estrogen/grade (CPS-EG) score 3-6, or a CPS-EG score 2 and residual positive lymph node status (ypN+).
  • CPS-EG clinical-pathologic stage - estrogen/grade
  • ypN+ residual positive lymph node status
  • the invention provides a method of selecting a patient diagnosed with early breast cancer for treatment with a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy, comprising: (A) determining the hormone receptor (HR)-status of the patient’s cancer; (B) determining the human epidermal growth factor receptor 2 (HER2)-status of the patient’s cancer; (C) determining the intrinsic molecular subtype of the patient’s cancer; (D) determining the ERBB2 expression status (high versus low level) of the patient’s cancer; and (E) selecting the patient for treatment with the combination therapy when the patient has: (a) an HR-status of ER+, PgR-, a HER2-status of HER2-, and an intrinsic molecular subtype of luminal A; (b) an HR-status of HR+, a HER2-status of HER2-, an intrinsic molecular subtype of luminal A, and an ERBB2 expression status of high;
  • the method further comprises: (F) administering the combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the selected patient.
  • the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease- free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1)-(6).
  • the combination therapy is administered to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • the invention provides a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive nonbreast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • the invention provides a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for the treatment of an early breast cancer patient diagnosed with: (a) ER+, PgR- , HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-
  • the invention provides the use of a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of palbociclib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the palbociclib, or a pharmaceutically acceptable salt thereof, is used in combination with an endocrine therapy for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • the invention provides the use of palbociclib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the palbociclib, or a pharmaceutically acceptable salt thereof, is used in combination with an endocrine therapy to reduce the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • the endocrine therapy is an aromatase inhibitor, a selective estrogen receptor modulator (SERM), or a selective estrogen receptor degrader (SERD).
  • SERM selective estrogen receptor modulator
  • SELD selective estrogen receptor degrader
  • the endocrine therapy is an aromatase inhibitor.
  • the aromatase inhibitor letrozole, anastrozole or exemestane.
  • the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole and exemestane.
  • the aromatase inhibitor is letrozole.
  • the aromatase inhibitor is a nonsteroidal aromatase inhibitor (NSAI).
  • NSAI nonsteroidal aromatase inhibitor
  • the nonsteroidal aromatase inhibitor is letrozole or anastrozole.
  • the aromatase inhibitor is a steroidal aromatase inhibitor (SAI).
  • the steroidal aromatase inhibitor is exemestane.
  • the endocrine therapy is a SERM.
  • the SERM is selected from the group consisting of tamoxifen, lasofoxifene, apeledoxifene, toremifene, raloxifene and afimoxifene, or a pharmaceutically acceptable salt thereof.
  • the SERM is tamoxifen, or a pharmaceutically acceptable salt thereof.
  • the endocrine therapy is a SERD.
  • the SERD is selected from the group consisting of fulvestrant, brilanestrant and elacestrant. In some such embodiments, the SERD is fulvestrant.
  • SERDs that may be suitable for use in the invention include SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN- c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine).
  • palbociclib or a pharmaceutically acceptable salt thereof, and the endocrine therapy are administered sequentially, simultaneously or concurrently.
  • the invention provides a method for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy to the patient, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease- free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease- free survival
  • D-DFS distant disease-free survival
  • the invention provides a method to reduce the risk of recurrence of invasive breast cancer or death for a patient diagnosed with: (a) ER+, PgR- , HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy to the patient, wherein the risk of recurrence of invasive breast cancer or death is reduced compared to administration of an endocrine therapy without the CDK4/6 inhibitor.
  • the invention provides a method of adjuvant therapy comprising administering a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery, and for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive nonbreast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-
  • the invention provides a method of adjuvant therapy comprising administering a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery, and reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without the CDK4/6 inhibitor.
  • the invention provides a method of selecting a patient diagnosed with early breast cancer for treatment with a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy, comprising: (A) determining the hormone receptor (HR)-status of the patient’s cancer; (B) determining the human epidermal growth factor receptor 2 (HER2)-status of the patient’s cancer; (C) determining the intrinsic molecular subtype of the patient’s cancer; (D) determining the ERBB2 expression status (high versus low level) of the patient’s cancer; and (E) selecting the patient for treatment with the combination therapy when the patient has: (a) an HR-status of ER+, PgR-, a HER2-status of HER2-, an intrinsic molecular subtype of luminal A; (b) an HR-status of HR+, a HER2-status of HER2-, an intrinsic molecular subtype of luminal A, and an ERBB2 expression status of high; or (c) an HR-stat
  • a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy for use in the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease- free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (a)-(f).
  • iDFS invasive disease- free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence
  • a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy for use in the treatment of a patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without the CDK4/6 inhibitor.
  • a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease- free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease- free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free
  • a combination therapy comprising a CDK4/6 inhibitor and an endocrine therapy for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without the CDK4/6 inhibitor.
  • a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the CDK4/6 inhibitor is used in combination with an endocrine therapy for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free
  • a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the CDK4/6 inhibitor is used in combination with an endocrine therapy to reduce the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without the CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof. In other embodiments, the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof, or abemaciclib, or a pharmaceutically acceptable salt thereof.
  • Each therapeutic agent of the methods and combination therapies of the present invention may be administered either alone, or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, or diluents, according to pharmaceutical practice.
  • combination therapy refers to the administration or use of each therapeutic agent indicated as part of the combination therapy, alone (as single agents) or in a medicament, either sequentially, concurrently or simultaneously.
  • sequential refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and/or the agents are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
  • the term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order. In a preferred embodiment the therapeutic agents are administered concurrently.
  • the term “simultaneous” refers to the administration of each therapeutic agent of the combination therapy of the invention in the same medicament.
  • the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are administered sequentially, simultaneously or concurrently.
  • the palbociclib, or a pharmaceutically acceptable salt thereof is administered before administration of the endocrine therapy.
  • the palbociclib, or a pharmaceutically acceptable salt thereof is administered after administration of the endocrine therapy.
  • the palbociclib, or a pharmaceutically acceptable salt thereof is administered concurrently with administration of the endocrine therapy.
  • the palbociclib, or a pharmaceutically acceptable salt thereof is administered simultaneously with the endocrine therapy.
  • an additional therapeutic agent is administered, it may be administered on the same or a different schedule from the palbociclib, or a pharmaceutically acceptable salt thereof and/or the endocrine therapy.
  • the combination therapy may be usefully administered to a subject during different stages of their treatment.
  • the combination therapy is administered to a subject who is previously untreated, i.e. , is treatment naive. In some embodiments, the combination therapy is administered to a subject who has failed to achieve a sustained response after a prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment experienced.
  • the combination therapy may be administered prior to or following surgery to remove a tumor and I or may be used prior to, during or after radiation therapy, and I or may be used prior to, during or after chemotherapy.
  • Administration of combinations of the invention may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
  • Dosage regimens may be adjusted to provide the optimum desired response.
  • a therapeutic agent of the combination therapy of the present invention may be administered as a single bolus, as several divided doses administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be particularly advantageous to formulate a therapeutic agent in a dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention may be dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dose and dosing regimen is adjusted in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a detectable therapeutic benefit to a subject may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the subject. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present invention. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses.
  • At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as a monotherapy for treating the same cancer.
  • the subject received a lower total amount of at least one of the therapeutic agents in the combination therapy than when the same agent is used as a monotherapy, for example a lower dose of therapeutic agent, a reduced frequency of dosing and / or a shorter duration of dosing.
  • An “intermittent dosing schedule” as used herein refers to an administration or dosing regimen that includes a period of dose interruption, e.g., days off treatment. Repetition of 21 day treatment cycles with a 7 day treatment interruption between the treatment cycles is an example of an intermittent dosing schedule. Such schedules, with 2 or 3 weeks on treatment and 1 week off treatment, are sometimes referred to as a 2/1 - week or 3/1 -week treatment cycle, respectively. Alternatively, repetition of 14 day treatment cycles with a 14 day treatment interruption between the treatment cycles is another example of an intermittent dosing schedule.
  • Such a schedule, with 2 weeks on treatment and 2 weeks off treatment may be referred to as a 2/2-week treatment cycle.
  • the 2/2 dosing schedule may be appropriate in certain patients, e.g., in the context of dose reduction to a dose of 75 mg/day.
  • a “continuous dosing schedule” as used herein is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 21 or 28 day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule.
  • the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are administered in an intermittent dosing schedule. In other embodiments, the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are administered in a continuous dosing schedule.
  • palbociclib is administered in an intermittent dosing schedule (e.g., a 2/1 -week, 3/1 -week or 2/2-week schedule) and the endocrine therapy is administered in a continuous dosing schedule.
  • an intermittent dosing schedule e.g., a 2/1 -week, 3/1 -week or 2/2-week schedule
  • the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are dosed in amounts which together are effective in treating the cancer.
  • the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are dosed in amounts which together are synergistic.
  • the palbociclib, or a pharmaceutically acceptable salt thereof, and the endocrine therapy are dosed in amounts which together are additive.
  • an endocrine therapy is administered in the dose, dosage form and dosing regimen as described on the approved product label of the particular endocrine therapy agent.
  • a “pharmaceutical composition” refers to a mixture of one or more of the therapeutic agents described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules, and the like.
  • a "pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound or therapeutic agent.
  • the pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of the therapeutic agents of the combination therapies of the present invention will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.
  • a pharmaceutical composition useful for the combination therapy of the present invention comprises a single therapeutic agent, for example either palbociclib, or a pharmaceutically acceptable salt thereof, or an endocrine therapy.
  • a pharmaceutical composition useful for the combination therapy of the present invention comprises both palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy.
  • the therapeutic agents of the combination therapies of the present invention may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the invention provides a kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of palbociclib, or a pharmaceutically acceptable salt thereof; the second container comprises at least one dose of an endocrine therapy; and the package insert comprises instructions for treating cancer in a subject using the medicaments.
  • the kit of the present invention may comprise one or both of the active agents in the form of a pharmaceutical composition, which pharmaceutical composition comprises an active agent, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the kit may contain means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit may be particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • the kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes, and the like.
  • the embodiment is selected from the group consisting of embodiments A1 to A25:
  • A2 The method of embodiment A1 , comprising administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • a method of adjuvant therapy comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery.
  • A4 The method of embodiment A3, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free survival
  • LR-RFI locoregional recurrence-free interval
  • OS overall survival
  • A6 The method of any one of embodiments A3 to A5, comprising administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • A12 The method of any one of embodiments A1 to A11 , wherein the endocrine therapy is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • A15 The method of embodiment A14, wherein the aromatase inhibitor is letrozole, anastrozole or exemestane.
  • A16 The method of any one of embodiments A1 to A15, wherein the endocrine therapy is optionally administered with ovarian suppression.
  • a method of selecting a patient diagnosed with early breast cancer for treatment with a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy comprising: (A) determining the hormone receptor (HR)-status of the patient’s cancer; (B) determining the human epidermal growth factor receptor 2 (HER2)-status of the patient’s cancer; (C) determining the intrinsic molecular subtype of the patient’s cancer; (D) determining the ERBB2 expression status of the patient’s cancer; and (E) selecting the patient for treatment with the combination therapy when the patient has: (a) an HR-status of estrogen receptorpositive (ER+), progesterone receptor-negative (PgR-), a HER2-status of human epidermal growth factor receptor 2-negative (HER2-), and an intrinsic molecular subtype of luminal A; (b) an HR-status of hormone receptor-positive (HR+), a HER2-status of HER2-, an intrinsic molecular subtype of luminal
  • A20 The method of embodiment A19, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free survival
  • LR-RFI locoregional recurrence-free interval
  • OS overall survival
  • A21 The method of embodiment A19, wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • A22 The method of any one of embodiments A19 to A21 , comprising administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer.
  • A24 The combination therapy of embodiment A23, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease- free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease- free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free survival
  • LR-RFI locoregional recurrence-free interval
  • OS overall survival
  • E5. The method of embodiment E4, wherein an endocrine therapy is administered to the patient as an adjuvant therapy to: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • E14 The method of any one of embodiments E1 to E13, wherein the endocrine therapy is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • E15 The method of embodiment E14, wherein the SERM is tamoxifen, raloxifene or toremifene.
  • E16 The method of any one of embodiments E1 to E13, wherein the endocrine therapy is an aromatase inhibitor.
  • E26 A method to reduce the risk of recurrence of invasive breast cancer or death for a patient diagnosed with: (a) estrogen receptor-positive (ER+), progesterone receptor-negative (PgR-), human epidermal growth factor receptor 2-negative (HER2-), luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to the patient, wherein the risk of recurrence of invasive breast cancer or death is reduced compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • ER+ estrogen receptor-positive
  • PgR- progesterone receptor-negative
  • HER2- human epidermal growth factor receptor 2-negative
  • E27 The method of embodiment E26, where the patient is diagnosed with: (a) estrogen receptor-positive (ER+), progesterone receptor-negative (PgR-), human epidermal growth factor receptor 2-negative (HER2-), luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • ER+ estrogen receptor-positive
  • PgR- progesterone receptor-negative
  • HER2- human epidermal growth factor receptor 2-negative
  • luminal A early breast cancer or
  • HR+ HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • E29 The method of any one of embodiments 26 to 28, comprising administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • E38 The method of embodiment E37, wherein the combination therapy is administered for at least three years.
  • E39 The method of any one of embodiments E26 to E38, wherein the endocrine therapy is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • E46 The method of any one of embodiments E26 to E45, wherein the patient is a postmenopausal woman or a premenopausal woman.
  • a method of adjuvant therapy comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery, and for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • E52 The method of embodiment E51 , wherein the patient is diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • E54 The method of any one of embodiments E51 to E53, comprising administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • E55 The method of embodiment E54, wherein an endocrine therapy is administered to the patient as an adjuvant therapy to: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • E62 The method of embodiment E61 , wherein the combination therapy is administered for at least two years.
  • E63 The method of embodiment E62, wherein the combination therapy is administered for at least three years.
  • E64 The method of any one of embodiments E61 to E63, wherein the endocrine therapy is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • E71 The method of any one of embodiments E61 to E70, wherein the patient is a postmenopausal woman or a premenopausal woman.
  • a method of adjuvant therapy comprising administering a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy to a patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered after definitive surgery and reduces the risk of recurrence of invasive breast cancer or death compared to administration of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • E79 The method of any one of embodiments E76 to E78, comprising administering the combination therapy to the patient after completion of: (i) chemotherapy; or (ii) radiotherapy; or (i) and (ii).
  • E89 The method of any one of embodiments E86 to E88, wherein the endocrine therapy is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • E96 The method of any one of embodiments E86 to E95, wherein the patient is a postmenopausal woman or a premenopausal woman.
  • a method of selecting a patient diagnosed with early breast cancer for treatment with a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy comprising: (A) determining the hormone receptor (HR)-status of the patient’s cancer; (B) determining the human epidermal growth factor receptor 2 (HER2)-status of the patient’s cancer; (C) determining the intrinsic molecular subtype of the patient’s cancer; (D) determining the ERBB2 expression status of the patient’s cancer; and (E) selecting the patient for treatment with the combination therapy when the patient has: (a) an HR-status of estrogen receptorpositive (ER+), progesterone receptor-negative (PgR-), a HER2-status of human epidermal growth factor receptor 2-negative (HER2-), and an intrinsic molecular subtype of luminal A; (b) an HR-status of hormone receptor-positive (HR+), a HER2-status of HER2-, an intrinsic molecular subtype of luminal
  • E103 The method of embodiment E102, wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS distant recurrence-free survival
  • LR-RFI locoregional recurrence-free interval
  • OS overall survival
  • E105 The method of any one of embodiments E102 to E104, comprising administering the combination therapy to the patient after completion of: (i) definitive surgery; (ii) chemotherapy; or (iii) radiotherapy; or any combination of two or more of (i), (ii) and (iii).
  • a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR- RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS
  • E107 The combination therapy of embodiment E106, wherein the patient is diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for use in the treatment of a patient diagnosed with: (a) ER+, PgR- HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • E110 The combination therapy of embodiment E109, wherein the patient is diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy is administered for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free survival
  • D-RFS distant
  • E113 The use of embodiment E112, wherein the patient is diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • E115 The use of a combination therapy comprising palbociclib, or a pharmaceutically acceptable salt thereof, and an endocrine therapy for the treatment of a patient diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the combination therapy reduces the risk of recurrence of invasive breast cancer or death compared to use of an endocrine therapy without palbociclib, or a pharmaceutically acceptable salt thereof.
  • E116 The use of embodiment E115, wherein the patient is diagnosed with: (a) ER+, PgR-, HER2-, luminal A early breast cancer; or (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2.
  • palbociclib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of (a) ER+, PgR-, HER2-, luminal A early breast cancer; (b) HR+, HER2-, luminal A early breast cancer with high expression of ERBB2; or (c) HR+, HER2-, luminal B early breast cancer; wherein the palbociclib, or a pharmaceutically acceptable salt thereof, is used in combination with an endocrine therapy for a period of time effective to increase: (1 ) invasive disease-free survival (iDFS); (2) iDFS excluding second primary invasive non-breast cancer; (3) distant disease-free survival (D-DFS); (4) distant recurrence-free survival (D-RFS); (5) locoregional recurrence-free interval (LR-RFI); or (6) overall survival (OS); or any combination of two or more of (1 )-(6).
  • iDFS invasive disease-free survival
  • D-DFS distant disease-free
  • the PENELOPE-B study was a randomized, double-blinded, placebo- controlled, two-arm phase III study in women with HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing NACT and at high-risk of relapse, to assess the efficacy of palbociclib in addition to adjuvant endocrine therapy for one year, versus placebo plus adjuvant endocrine therapy in these patients.
  • the study was carried out in collaboration with the German Breast Group (GBG) as sponsor.
  • the primary endpoint was invasive disease-free survival (iDFS) in months.
  • the final analysis was planned after 290 iDFS events with efficacy boundary p ⁇ 0.0463 due to two interim efficacy analyses.
  • iDFS excluding second primary invasive non-breast cancer
  • D-DFS distant disease free survival
  • OS overall survival
  • LR-RFI loco- regional relapse free interval
  • iDFS per treatment group in patients with luminal- B tumors as determined by e.g. PAM50 or any other commercially available test at the time of analysis
  • Eligibility Ages Eligible for Study: 18 Years and older (Adult, Older Adult); Sexes Eligible for Study: Female; Accepts Healthy Volunteers: No.
  • Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.
  • hormone-receptor-positive >1 % ER and/or PgR positive stained cells
  • HER2-normal IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio) ⁇ 2.0 status
  • ISH in-situ hybridization
  • Ki-67, pRB, and Cyclin D1 status assessed preferably on post-neoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion or core biopsy.
  • tumor tissue of both sides needs to be assessable.
  • atients must have received neoadjuvant chemotherapy of at least 16 weeks. This period must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception: For patients with progressive disease that occurred after at least 6 weeks of taxane containing neoadjuvant treatment, a total treatment period of less than 16 weeks is also eligible).
  • dequate surgical treatment including resection of all clinically evident disease and ipsilateral axillary lymph node dissection. Histologically complete resection (RO) of the invasive and ductal in situ tumor is required in case of breast conserving surgery as the final treatment. No evidence of gross residual disease (R2) is required after total mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients with a negative sentinel-node biopsy before (pNO, pN+(mic)) or after (ypNO, ypN+(mic) neoadjuvant chemotherapy. ess than 16 weeks interval since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) at date of randomization.
  • the patient must be accessible for scheduled visits, treatment and follow-up. Patients registered on this trial must be treated at the participating center which could be the Principal or a Co- investigator's site.
  • organ function immediate prior to randomization including: Hemoglobin ⁇ 10g/dL (100g/L); ANC ⁇ 2000/mm 3 ( ⁇ 2.0 x 109/L); Platelets ⁇ 100,000/mm 3 ( ⁇ 100 x 109/L); AST or ALT >1 .5 x upper limit of normal (ULN); alkaline phosphatase > 2.5 x ULN, total serum bilirubin > 1.25 x ULN; serum creatinine >1.25 x ULN or estimated creatinine clearance ⁇ 60 mL/min as calculated using the method standard for the institution; severe and relevant co-morbidity that would interact with the participation in the study
  • HIV Human Immunodeficiency Virus
  • Uncontrolled electrolyte disorders e.g., hypocalcemia, hypokalemia, hypomagnesemia.
  • Table 2 shows the efficacy results, based on the primary endpoint of iDFS, in biomarker-selected subgroups of patients treated with palbociclib plus endocrine therapy or placebo plus endocrine therapy for one year.
  • the iDFS rate (%) is provided at two years (2-yr) and three years (3-yr).
  • Treatment effect remains statistically significant in the multivariable Cox regression analysis after adjusting for the stratification factors at randomization (i.e., age at first diagnosis, central Ki67, global region of participating site, histological lymph node status at surgery, risk status) (Table 3).

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Abstract

L'invention concerne des combinaisons, des méthodes et des utilisations pour le traitement du cancer du sein précoce luminal A ER+, PgR-, HER2-, du cancer du sein précoce luminal A HR +, HER2- avec une expression élevée de ERBB2, ou du cancer du sein précoce luminal B HR+, HER2-, à l'aide d'une polythérapie comprenant du palbociclib, ou un sel pharmaceutiquement acceptable de celui-ci, et une thérapie endocrinienne.
PCT/IB2021/061347 2020-12-08 2021-12-06 Traitement de sous-types luminaux de cancer du sein précoce hr-positif, her2-négatif par le palbociclib WO2022123419A1 (fr)

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