EP4719405A1 - Methods and modified dosing regimens comprising a cdk4 inhibitor for the treatment of cancer - Google Patents

Abstract

The disclosure provides a method of treating cancer comprising administering to a subject in need thereof with a therapeutically effective amount of PF-07220060. The disclosure also provides a method of treating cancer comprising administering to a subject in need thereof with a therapeutically effective amount of PF-07220060 and an endocrine therapy agent.

Description

METHODS AND MODIFIED DOSING REGIMENS COMPRISING A CDK4 INHIBITOR FOR THE TREATMENT OF CANCER

FIELD OF THE INVENTION

The present disclosure relates to the therapeutic treatment of cancer with a cyclin-dependent kinase (CDK) inhibitor, 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-threo-pentitol (hereinafter PF-07220060), either alone as a monotherapy or in combination with endocrine therapeutics. The invention also relates to associated combination therapies, pharmaceutical compositions, and pharmaceutical uses.

INTRODUCTION

CDKs are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be useful for the treatment of proliferative disorders, including cancer.

Cancer develops through unregulated cell proliferation, which is reflected by unchecked progression of the cell cycle, a loss of checkpoint controls subsequently permitting uncontrolled cellular proliferation. Rb1 (retinoblastoma protein) is a crucial negative regulator through G1 and quiescent GO phases of the cell cycle until and unless phosphorylated by CDK4 or CDK6. (Weinberg, R.A. The retinoblastoma protein and cell cycle control. Cell, vol.81 , 323-330, 1995). The notion of dysregulation of the CDK4/6- retinoblastoma protein axis in cancer is supported by gene alterations commonly identified in breast cancers, such as cyclin D1 (CCND1) and cyclin E1 (CCNE1) gene amplification and alterations in endogenous CDK4-cyclin D1 inhibitor p16 (INK4a, encoded by the CDKN2A gene), TP53 and PIK3CA genes. (Cancer Genome Atlas Network. Comprehensive genomic characterization of human breast tumours. Nature, 490, 61-70, 2012).

CDK4/6 inhibition has emerged as a promising strategy for cancer therapy, especially for the treatment of endocrine resistant BC. (Rani, A., et. al., Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy. Front Endocrinol (Lausanne) 10:245, 2019). CDK4/6 inhibitors (e.g., palbociclib, abemaciclib, ribociclib) when dosed in combination with endocrine therapy, have significantly improved progression-free survival and/or overall survival for patients with HR-positive/HER2-negative metastatic breast cancer. (Spring, L.M., et. al., Cyclin- dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet, 395, 817-827, 2020).

Although CDK4/6 inhibitors increase response rates and prolong disease control in patients with HR+, HER2- breast cancer, they are associated with dose-limiting hematologic toxicities, primarily neutropenia.

PF-07220060 is a potent inhibitor of cyclin dependent kinase 4 (CDK4). Preparation of PF-07220060 is described in International Patent Publication No. WO 2019/207463, U.S. Patent Nos. 10,766,884 and 11 ,220,494, and US Patent Publication US 2022/0089580; International Publication No. WO 2022/058871 , and International Publication No. WO 2023/100070. The contents of which are incorporated herein by reference in their entirety. Unless indicated otherwise, all references herein to PF- 07220060 include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

PF-07220060 differs from currently approved dual CDK4/6 inhibitors in that it displays greater CDK4-over-CDK6 selectivity. In in vivo models, PF-07220060 reduces dose-limiting neutropenia and is projected to potentially attain higher tolerated plasma concentrations than dual CDK4/6 inhibitors, thus potentially enabling increased inhibition of the CDK4 oncogene in tumors.

There is a need for appropriate and efficacious dosing regimens of PF-07220060 as a single agent and in combination therapies for treating cancers while minimizing adverse events and risks to patients. There is a need for appropriate dose adjustments for patients with organ impairments or experiencing adverse effects during the course of cancer treatment.

SUMMARY

The disclosure relates to both single agent and combination therapies, for treating cancer, which comprise the CDK4 inhibitor, PF-07220060.

In certain embodiments, the disclosure provides a method of treating cancer comprising orally administering to a subject in need thereof a therapeutically effective amount of PF-07220060. Particularly, the method includes administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of PF- 07220060 in a total daily dose of from about 10 mg to about 190 mg per day. In certain embodiments, the disclosure provides a method of treating cancer comprising administering to a subject in need thereof with a therapeutically effective amount of PF-07220060, and an endocrine therapy agent. In embodiments, the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In embodiments, the endocrine therapy agent includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.

Accordingly, embodiments herein provide dosing regimens for PF-07220060 as a single agent and in combination therapies for treating cancer, by which adverse effects are minimized in a subject during the treatment period.

DETAILED DESCRIPTION

The present disclosure may be understood more readily by reference to the following detailed description of the aspects and embodiments of the disclosure and the Examples included herein. It is to be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

Definitions:

As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

The term "about" means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art. In some embodiments, the term "about" means within ± 10% of the indicated value. For example, a dose of about 100 mg should be understood to mean that the dose may vary between 90 mg and 110 mg.

The disclosure described herein may be suitably practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms.

As used herein, “dose limiting toxicity” (DLT) refers to the dosage of PF-07220060 that is contraindicative of a further increase in dosage. As used herein, “measurable lesion” refers to Lesions that can be accurately measured in at least one dimension, lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or MRI (slice thickness 5-8 mm), lesions with longest diameter at least 20 mm when assessed by Chest X-ray, superficial lesions with longest diameter 10 mm or greater when assessed by caliper, or malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.

As used herein “maximum tolerated dose” (MTD) refers to the highest dosage of PF-07220060 that does not cause unacceptable side effects or intolerable toxicities. MTD is estimated using the mTPI based on observed DLT rate, with a target DLT rate of 27.5% and equivalence interval of 22.5-32.5%.

As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects to a subject.

As used herein, a “rest period” is the number of days from administration of one complete dose of the active agent to the next administration of one complete dose of the active agent.

As used herein, the term “week” means 7 consecutive days. Thus, a 4-week period is 28 consecutive days starting on any day of the calendar week.

As used herein, the term “subject” may be a mammal, which refers to any animal species of the Mammalia class. Examples of mammals include: humans; non-human primates such as monkeys; laboratory animals such as rats, mice, guinea pigs; domestic animals such as cats, dogs, rabbits, cattle, sheep, goats, horses, and pigs; and captive wild animals such as lions, tigers, and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a female. In some embodiments, the subject is a male.

As used herein, the phrase "therapeutically effective amount" for use and/or for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, treatments, protocols, or therapeutic regimens, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (/.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “therapeutically effective amount” also means an amount of an active agent effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.

Determination of a therapeutically effective amount is well within the capability of those skilled in the art. In various embodiments, the dosage can vary within the range depending upon the dosage form employed and the route of administration utilized. In some embodiments, a therapeutically effective amount of a compound described herein administered to a subject can be dependent upon factors known to a skilled artisan, including bioactivity and bioavailability of the compound (e.g., half-life and stability of the compound in the body), chemical properties of the compound (e.g., molecular weight, hydrophobility and solubility); route and frequency of administration, and the like. Further, it will be understood that the specific dose of the pharmaceutical composition comprising a compound as disclosed herein can depend on a variety of factors including physical condition of the subject (e.g., age, gender, weight), and medical history of the subject (e.g., medications being taken, health condition other diseases or disorders). The precise dose of a pharmaceutical composition administered to a subject can be determined by methods known to a skilled artisan such as a pharmacologist, or an anesthesiologist.

As used herein, the term “ameliorate” refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject’s condition.

As used herein, “treat” or “treating” a cancer and/or a cancer-associated disease means to administer a mono- or combination therapy according to the present disclosure to a subject, patient or individual having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)).

“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).

As used herein, the term “metastatic,” as it relates to cancer, refers to the spread of cancer from a primary tumor site to distant organs. For example, metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain. (www.cancer.org/cancer/breast-cancer.)

As used herein, the terms “combination” or “combination therapy” refer to the administration of two or more therapeutic agents of the combination therapy, either alone or in the form of a pharmaceutical composition or medicament. The combination therapy may be administered sequentially, concurrently, or simultaneously.

When administering a combination therapy of two or more agents, the agents may be administered on the same treatment cycle or using different cycles. In a preferred embodiment, PF-07220060 is administered continuously on a 28-day cycle. Similarly, letrozole is typically administered continuously on a 28-day treatment cycle. Palbociclib is typically administered using an intermittent 28-day treatment cycle, comprising administration of the drug for 21 days, with a rest period of 7 days between the cycles. Fulvestrant is typically administered intramuscularly on days 1 , 15, 29 of the first treatment cycle and once monthly thereafter. Each therapeutic agent of the methods and combination therapies described herein 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.

The term “sequential” or “sequentially” refers to the administration of each therapeutic agent of the combination therapy, 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 a combination therapy, 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 in the same medicament, for example as a fixed dose combination comprising two or more drugs in a single dosage form.

A "dosing regimen" refers to the period of administration of one or more drugs, compounds or compositions, comprising one or more treatment cycles, wherein each treatment cycle may include administration of one or more agents at different times, frequencies or amounts, using the same or different routes of administration. Repetition of the administration or dosing regimens, or adjustment of the administration or dosing regimen may be conducted as necessary to achieve the desired treatment effect.

Dosage amounts, provided herein, are calculated as the free base equivalent of an administered PF-07220060 free base form, hydrate form or salt form. For example, a dosage or amount of PF-07220060, such as about 10 mg, about 50 mg, about 75 mg, or about 100 mg, refers to the free base equivalent.

The ECOG Scale of Performance Status was developed by the Eastern Cooperative Oncology Group as standard criteria for measuring how the disease impacts a patient’s daily living abilities. It describes a participant’s level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).

Patients are categorized on a scale of 1-5:

Grade ECOG Performance Status

0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work

2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

2 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours

4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair

5 Dead

PF-07220060 (Pfizer Inc.) is a selective CDK4 inhibitor that is currently in phase III clinical trial for the treatment of cancers, and has the following structure of formula (I):

Accordingly, certain embodiments of this disclosure provide a therapeutic dose and dosing regimen comprising administering to a subject a therapeutically effective amount of PF-07220060.

PF-07220060 may be present in a pharmaceutical composition which includes a pharmaceutically acceptable carrier. The therapeutically effective amount of PF- 07220060 in the pharmaceutical compositions can be from about 10 mg to about 190 mg, or any of the therapeutically effective amounts disclosed herein.

In certain embodiments, the therapeutically effective amount of PF-07220060 is from about 10 mg to about 190 mg per day (i.e., total daily dose), for example, from about 20 mg to about 180 mg, from about 30 mg to about 170 mg, from about 40 mg to about 160 mg per day.

In certain embodiments, PF-07220060 may be administered once a day (QD) or twice a day (BID).

In certain embodiments, PF-07220060 is administered in doses of from about 10 mg to about 100 mg once a day (QD), for example, from about 20 mg to about 100 mg QD, from about 30 mg to about 100 mg QD, from about 40 mg to about 100 mg QD, from about 50 mg to about 100 mg QD, from about 60 mg to about 100 mg QD, from about 70 mg to about 100 mg QD, from about 80 mg to about 100 mg QD. In some embodiments, the daily dose is about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35 mg QD, about 40 mg QD, about 45 mg QD, about 50 mg QD, about 55 mg QD, about 60 mg QD, about 65 mg QD, about 70 mg QD, about 75 mg QD, about 80 mg QD, about 85 mg QD, about 90 mg QD, or about 100 mg QD.

In certain embodiments, PF-07220060 is administered in doses of from about 10 mg to about 90 mg twice a day (BID), for example, from about 20 mg to about 90 mg BID, from about 30 mg to about 90 mg BID, from about 40 mg to about 90 mg BID, from about 50 mg to about 90 mg BID, from about 60 mg to about 90 mg BID, from about 70 mg to about 90 mg BID, from about 80 mg to about 90 mg BID. In some embodiments, PF- 07220060 is administered at a dose of about 20 mg BID, about 25 mg BID, about 30 mg BID, about 35 mg BID, about 40 mg BID, about 45 mg BID, about 50 mg BID, about 55 mg BID, about 60 mg BID, about 65 mg BID, about 70 mg BID, about 75 mg BID, about 80 mg BID, about 85 mg BID, or about 90 mg BID.

In some embodiments, the subject is administered PF-07220060 at a dose of any of the therapeutically effective amounts disclosed herein.

The amount of PF-07220060 administered may be increased or decreased based on the weight, age, health, sex, or medical condition of the subject. One of skill in the art would be able to determine the proper dose for a subject based on this disclosure.

PF-07220060 may be administered in treatment cycles, with or without rest periods in between the treatment cycles. A treatment cycle may be a duration of about 7 days, about 14 days, about 21 days, about 28 days, about 35 days and so on, or any days in between. A rest period can be one day, a few days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and so on), one week, several weeks (e.g., 2 weeks, 3 weeks and so on), or any days in between (e.g., 1 week and 3 days). In some embodiments, PF-07220060 is administered continuously without any rest period in between (/.e., continuous treatment until termination). In some embodiments, PF-07220060 is administered for a treatment cycle (e.g., about 28 days) with or without a rest period. In some embodiments, PF-07220060 is administered for about 28 days with a rest period of about one week. PF-07220060 may be administered for at least about 7 days, about 14 days, about 21 days, about 28 days, about 2 months, about 3 months, about 12 months, about 24 months, and more.

The pharmaceutical compositions may be administered with or without food. The pharmaceutical compositions may be administered by one or more routes as considered appropriate by a skilled person in the art and depending on the dosage form. Formulation of drugs is discussed in Remington's Pharmaceutical Sciences, 18th Ed., (1995) Mack Publishing Co., Easton, Pa. Other examples of drug formulations can be found in Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd Ed., New York, N.Y. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier, glidant, or excipient.

The pharmaceutical compositions may be in one or more dosage forms (e.g., capsule, liquid, tablet, powder).

In some embodiments, the pharmaceutical compositions may be administered in an immediate release formulation or a modified release formulation. By “immediate release” or “IR” is meant broadly an oral dosage form formulated to release an API immediately after oral administration. In IR formulations, no deliberate effort is made to modify the drug release rate.

Therapeutic Methods and Uses

In certain embodiments, the disclosure provides a method for treating cancer of a subject in need thereof, which includes administering to the subject a therapeutically effective amount of PF-07220060 as described herein.

In certain embodiments, the disclosure also provides a method for treating cancer of a subject which includes administering to the subject a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapy agent.

In certain embodiments, the disclosure provides a use of PF-07220060 in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof wherein the medicament is administered in a therapeutically effective unit dosage of PF-07220060 as described herein.

In certain embodiments, the disclosure provides a use of PF-07220060 together with endocrine therapy in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof wherein the medicament is administered in a therapeutically effective unit dosage of PF-07220060 as described herein.

In certain embodiments, the disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein for use in treating cancer in a subject in need thereof. In embodiments, the disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapy agent for use in treating cancer in a subject in need thereof.

In certain embodiments of each of the methods, medicaments, combinations and uses described herein, PF-07220060 is administered continuously (/.e., daily).

In certain embodiments, the method disclosed herein includes administering PF- 07220060 to a subject who is suffering from cancer that is mediated by CDK4. In some embodiments, the cancer is characterized by amplification or overexpression of CDK4 and/or CCND1. In one embodiment, the cancer is characterized by amplification or overexpression of CDK4. In one embodiment, the cancer is characterized by amplification of the CCND1 gene or overexpression of cyclin D1.

In certain embodiments, the method disclosed herein includes administering PF- 07220060 to a subject who is suffering from cancer that is selected from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer (including non-small-cell lung carcinoma (NSCLC)), small-cell lung carcinoma (SCLC), squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), kidney cancer (including renal cell carcinoma (RCC)), liver cancer (including hepatocellular carcinoma (HCC)), pancreatic cancer, stomach (/.e., gastric) cancer, endometrial cancer, liposarcoma, and thyroid cancer. In further embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, stomach cancer, or combinations thereof.

In some embodiments, the cancer is advanced or metastatic solid tumors.

In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is adenocarcinoma of NSCLC. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liposarcoma.

In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+), /.e., the breast cancer is estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+). In some embodiments, the breast cancer is hormone receptor negative (HR-), i.e., the breast cancer is estrogen receptor negative (ER-) and progesterone receptor negative (PR-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER2+). In some embodiments, the breast cancer is HR+/HER2- breast cancer. In some embodiments, the breast cancer is HR-/HER2+ breast cancer. In some embodiments, the breast cancer is ER+/HR+. In some embodiments, the breast cancer is ER+/HER2-. In some embodiments, the breast cancer is triple negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR- and HER2-.

In some embodiments, the breast cancer is endocrine resistant breast cancer, trastuzumab or pertuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is resistant to treatment with a standard of care agent; for example, the breast cancer may demonstrate primary or acquired resistance to endocrine therapy, HER2-targeted agents (e.g., tamoxifen, trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib or tucatinib), or CDK4/6 inhibitors. In some embodiments, the subject is refractory to endocrine therapy.

In some embodiments, the breast cancer is refractory or resistant to treatment with, or has progressed on, treatment with antineoplastic chemotherapeutic agents such as platinum agents, taxanes, anthracyclines or anti-metabolites.

In some embodiments, the breast cancer has progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor. In some embodiments, the breast cancer has progressed during treatment or within 12 months of completion of adjuvant therapy with tamxifen.

In some embodiments, PF-07220060 is administered as first line therapy. In other embodiments, PF-07220060 is administered as second (or later) line therapy. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, such as, an aromatase inhibitor; a selective estrogen receptor modulator (SERM), e.g., tamoxifen; or a selective estrogen degrader/downregulator (SERD). In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with HER2 targeted agents.

In certain embodiments, the method disclosed herein further includes administering to a subject a therapeutically effective amount of PF-07220060 and an endocrine therapy agent. An "endocrine therapy agent" is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.

In some embodiments, the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In some embodiments, the endocrine therapy agent is an androgen receptor inhibitor. In some embodiments, the endocrine therapy agent is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole and exemestane. In one embodiment, the aromatase inhibitor is letrozole. In some embodiments, the endocrine therapy agent is a SERD. In some such embodiments, the SERD is selected from the group consisting of fulvestrant, elacestrant (RAD-1901 , Radius Health/Menarini), amcenestrant (SAR439859, Sanofi), giredestrant (GDC9545, Roche), RG6171 (Roche), camizestrant (AZD9833, AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Eli Lilly), and SHR9549 (Jiansu Hengrui Medicine). In some embodiments, the SERD is fulvestrant. In some embodiments, the endocrine therapy agent is a SERM. In some such embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene and afimoxifene. In some such embodiments, the SERM is tamoxifen or raloxifene. In preferred embodiments, the endocrine therapy agent is letrozole or fulvestrant.

The endocrine therapy agent may be administered according to the standard of care per package insert or provided by the health care professionals. The term "package insert" refers to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

In certain embodiments, the endocrine therapy agent is administered to the subject during the course of the treatment with PF-07220060. In certain embodiments, the first dose of the endocrine therapy agent is administered prior to administering the first dose of PF-07220060. In certain embodiments, the first dose of the endocrine therapy agent is administered on the same day as administering the first dose of PF- 07220060. In certain embodiments, the first dose of the endocrine therapy agent is administered after the start of the treatment with PF-07220060.

In certain embodiments, prior to the administration of PF-07220060 to the subject, the subject has been previously treated with one or more lines of endocrine therapy.

In certain embodiments, prior to the administration of PF-07220060 to the subject, the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection.

In certain embodiments, prior to the administration of PF-07220060 to the subject, the subject has been previously treated with a CDK4/6 inhibitor.

In some embodiments, the present treatment results in complete response (CR), partial response (PR), or stable disease (SD) in the subject.

The present disclosure provides a number of exemplary embodiments. Nonlimiting exemplary embodiments of the present disclosure are shown below.

Embodiment 1. A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 10 mg to about 190 mg of a cyclin-dependent kinase (CDK) inhibitor PF-07220060.

Embodiment 2. The method of embodiment 1 , wherein the total daily dose is administered once per day (QD) or in divided doses twice per day (BID).

Embodiment 3. The method of any one of embodiments 1 to 2, wherein PF-

07220060 is administered in an amount of from about 10 mg to about 100 mg QD.

Embodiment 4. The method of any one of embodiments 1 to 2, wherein PF-

07220060 is administered in an amount of from about 50 mg QD.

Embodiment 5. The method of any one of embodiments 1 to 2, wherein PF-

07220060 is administered in an amount of from about 75 mg QD.

Embodiment 6. The method of any one of embodiments 1 to 2, wherein PF-

07220060 is administered in an amount of from about 100 mg QD. Embodiment ?. The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 10 mg to about 75 mg BID.

Embodiment s. The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 50 mg BID.

Embodiment 9. The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 75 mg BID.

Embodiment 10. The method of any one of embodiments 1 to 9, wherein PF- 07220060 is administered continuously.

Embodiment 11. The method of any one of embodiments 1 to 10, wherein PF- 07220060 is administered in a tablet or capsule form.

Embodiment 12. A method for treating cancer comprising administering to a subject in need thereof a daily dose of from about 10 mg to about 190 mg of PF-07220060, in combination with an endocrine therapy agent.

Embodiment 13. The method of embodiment 12, wherein the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

Embodiment 14. The method of embodiment 13, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.

Embodiment 15. The method of any one of embodiments 12 to 14, wherein the endocrine therapy agent is selected from the group consisting of letrozole, anastrozole, exemestane, fulvestrant, elacestrant, amcenestrant, giredestrant, RG6171, camizestrant, AZD9496, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene and afimoxifene. Embodiment 16. The method of any one of embodiments 12 to 15, wherein the endocrine therapy agent is letrozole or fulvestrant.

Embodiment 17. The method of any one of embodiments 12 to 16, wherein the subject is administered the endocrine therapy agent and subsequently administered PF- 07220060.

Embodiment 18. The method of any one of the previous embodiments, wherein the subject has been previously treated with systemic therapy (such as, chemotherapy), radiotherapy, and/or surgical resection.

Embodiment 19. The method of any one of the previous embodiments, wherein the subject has been previously treated with a CDK4/6 inhibitor.

Embodiment 20. The method of any one of the previous embodiments, wherein the subject has been previously treated with an endocrine therapy agent.

Embodiment 21. The method of any one of the previous embodiments, wherein the subject has been previously treated with a CDK4/6 inhibitor in combination with an endocrine therapy agent.

Embodiment 22. The method of any one of the previous embodiments, wherein the endocrine therapy agent is a non-steroidal aromatase inhibitor.

Embodiment 23. The method of any one of the previous embodiments, wherein the subject has been previously received with a treatment targeting estrogen receptor 1 (ESR1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT1 , phosphatase and tensin homolog (PTEN), or breast cancer gene (BRCA).

Embodiment 24. The method of any one of the previous embodiments, wherein the subject has been previously treated with a prior line of systemic therapy for breast cancer. Embodiment 25. The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy for breast cancer.

Embodiment 26. The method of any one of the previous embodiments, wherein the subject has been previously treated with one prior line of systemic therapy comprises a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.

Embodiment 27. The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy, wherein one of the two prior lines of systemic therapy comprises a CDK4/6 inhibitor.

Embodiment 28. The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy, wherein one of the two prior lines of systemic therapy comprises a CDK4/6 inhibitor and a nonsteroidal aromatase inhibitor, and the other one of the two prior lines of systemic therapy comprises a treatment targeting ESR1 , PIK3CA, AKT1 , PTEN, or BRCA.

Embodiment 29. The method of any one of the previous embodiments, wherein the subject has not received any prior systemic therapies but has been previously treated with an adjuvant therapy comprising a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.

Embodiment 30. The method of any one of embodiments 1 to 29, wherein the subject is a mammal.

Embodiment 31. The method of any one of embodiments 1 to 30, wherein the subject is suffering from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer.

Embodiment 32. The method of any one of embodiments 1 to 31 , wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+), hormone receptor negative (HR-), human epidermal growth factor receptor 2 negative (HER2-), human epidermal growth factor receptor 2 positive (HER2+), HR+/HER2-, ER- /HR+, ER+/HER2-and triple negative breast cancer (TNBC).

Embodiment 33. The method of any one of embodiments 1 to 31 , wherein the cancer is NSCLC, prostate, colorectal cancer, liposarcoma, or tumors characterized by amplification or overexpression of CDK4 and/or CCND1.

Embodiment 34. A method of treating cancer comprising administering to a subject in need thereof the following steps:

(a) withholding dose until toxicity is Grade < 2 or has returned to baseline, and

(b) resuming treatment with PF-07722060 at starting dose level or reduced by one dose level.

Examples

The following examples are merely illustrative of the disclosure and should not be considered limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present disclosure and the accompanying claims.

Example 1 : Clinical Trial Protocol

A Phase 3 double-blind, randomized, parallel-group, multicenter clinical trial evaluating whether PF-07220060 in combination with fulvestrant can improve clinical outcomes relative to investigator’s choice of therapy (ICT) (i.e. , either fulvestrant alone or everolimus in combination with exemestane) in participants with HR-positive, HER2- negative advanced or mBC who have progressed after prior CDK4/6 inhibitor based therapy.

Approximately 500 participants will be enrolled in the study. The participants will be randomly assigned on a 1 :1 basis to Arm A and Arm B.

In Arm A (Investigational Arm; N ~ 250), participants will receive PF-07220060 at 300 mg orally, twice daily, continuously, in a 28-day cycle, plus fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from Cycle 2 Day 1 (C2D1) (28-day cycle). In Arm B (Comparator Arm; N ~ 250), participants will receive ICT of either: fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle), or everolimus 10 mg orally, once daily, continuously, in a 28-day cycle, plus exemestane 25 mg orally, once daily continuously, in a 28-day cycle.

Participants will be stratified by:

• Site of disease (visceral vs. non-visceral); visceral = at least one lesion in liver, lung, pleura, peritoneum, brain, other visceral organs; non-visceral = lesions only in bone, skin, lymph node, breast, subcutaneous)

• Treatment duration of prior CDK4/6i (less than 12 months vs. greater than or equal to 12 months)

Inclusion Criteria

Participants must meet the following key inclusion criteria to be eligible for enrollment into the study:

1. At least 18 years of age at screening.

■ Per- and peri-menopausal female and male participants must receive therapy with a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 4 weeks prior to Cycle 1 Day 1 and continue during the study.

2. Histological or cytological confirmation of breast cancer with evidence of locally advanced or metastatic disease having the following specifics:

■ Documented estrogen receptor (ER) and/or progesterone receptor (PR)- positive tumor (as assessed locally), defined as >1% ER and/or PR-positive stained cells utilizing an assay consistent with local standards, on the most recent tumor biopsy, i.e. , at the time of recurrence or metastatic disease.

■ Documented HER2-negative tumor by either IHC or in-situ hybridization per ASCO/CAP guidelines (Wolff et al, 2018).

3. Able to provide a sufficient amount of representative formalin fixed, paraffin embedded (FFPE) tumor tissue specimen.

4. Must have received CDK4/6i plus endocrine therapy as the most recent systemic treatment for breast cancer (BC), either as the 1st line treatment for advanced/mBC or as the adjuvant treatment for early BC. There must be documented progression of disease during or after CDK4/6i treatment.

5. Must have received prior CDK4/6i plus non-steroidal aromatase inhibitor (NSAI) in one of the following scenarios. There must be documented progression of disease /recurrence during or within 12 months after the last dose of CDK4/6L

■ One prior line of systemic therapy for advanced/mBC, which must be CDK4/6i plus NSAI;

■ Two prior lines of systemic therapy for advanced/mBC, one must be CDK4/6i plus NSAI and the other an approved treatment targeting estrogen receptor 1 (ESR1), phosphatidylinositol-4,5-bisphosphate 3- kinase catalytic subunit alpha (PIK3CA), AKT1 , phosphatase and tensin homolog (PTEN), or breast cancer gene (BRCA);

■ No prior systemic therapies for advanced/mBC but received CDK4/6i plus NSAI as the most recent adjuvant therapy.

6. Must have either measurable disease or non-measurable bone only disease. Measurable and non-measurable disease are defined by RECIST version 1.1. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented. Non-measurable bone-only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft tissue component, or mixed lytic-blastic bone lesions without a measurable soft tissue component.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) <2.

Exclusion Criteria

Participants with any of the following key characteristics/conditions will be excluded:

1. Any medical or psychiatric condition that may increase the risk of study participation or make the participant inappropriate for the study.

2. Participants in visceral crisis at risk of immediately life-threatening complications in the short term, including participants with massive uncontrolled effusions (pleural, pericardial, and peritoneal), pulmonary lymphangitis, or liver involvement >50%.

3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.

4. Known or suspected hypersensitivity to active ingredient/excipients of PF- 07220060, fulvestrant, everolimus, or exemestane.

5. Prior treatment with any of the following:

■ Prior therapy with everolimus, or other investigational anti-cancer agents in any setting;

■ Prior chemotherapy in the advanced setting;

■ Radiation within 2 weeks of randomization;

■ Any unresolved toxicities from prior surgeries or therapies > Grade 2 (CTCAE Version 5.0) at the time of starting study intervention, with the exception of alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion in consultation with the sponsor’s medical monitor.

6. Current use or anticipated need for any prohibited food, supplements or concomitant medication(s) (i.e., strong and moderate cytochrome P450 3A4/5 (CYP3A4/5) or uridine 5’ diphosphate-glucuronosyltransferase 2B7 (LIGT2B7) inhibitors and inducers, vitamin K antagonists or factor Xa inhibitors for anticoagulation, proton pump inhibitors).

7. Inadequate renal function, hepatic dysfunction, or hematologic abnormalities.

8. Major surgery within 2 weeks of randomization or has not recovered from major side effects.

Diagnostic Assessments:

Inadequate renal function as defined by an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m² calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equations outlined in Table 1.

Table 1. CKD-EPI Equations

Inker et al., New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med., 2021 , 385(19): 1737-1749

Hepatic dysfunction defined as:

■ Total bilirubin >1.5 x ULN (except for Gilbert’s syndrome, total bilirubin > 3 x II LN is exclusionary)

■ AST >3 x ULN (> 5 x ULN if liver metastases present)

■ ALT >3 x ULN (> 5 x ULN if liver metastases present)

■ Alkaline phosphatase >2.5 x ULN (>5 x ULN in case of bone metastasis) Hematologic abnormalities defined as:

■ ANC < 1500/mm³

■ Platelets < 100, 000/mm³

■ Hemoglobin <9 g/dL

Method of Administration:

PF-07220060

PF-07220060 was provided as tablets for oral administration, as the 100 mg immediate release tablets.

PF-07220060 Dose Modification Levels:

Following dosing interruption due to toxicity, the PF-07220060 dose may remain at the same dose level or be reduced by one dose level when treatment is resumed. Once a dose has been reduced for a given participant, all subsequent cycles will be administered at that dose level.

Table 1. PF-07220060 Dose Modification Levels for Adverse Reactions No dose modification is required for participants demonstrating Grade 1 or 2 adverse effects. Dose modification for participants demonstrating Grade 3 and 4 adverse effects is outlined in Table 2.

Table 2. Dose Modifications of PF-07220060 for Study Intervention Related Toxicity a. Recurrent Grade 3 toxicity is defined as the same event reoccurring within the next 8 weeks as measured from the stop date of the preceding event. b. Persistent Grade 2 toxicity is defined as toxicity that does not resolve despite supportive measures within 7 days to Grade <1 or to baseline. c. Grade 3 ILD/pneumonitis requires permanent discontinuation of PF-07220060. d. Grade 4 ILD/pneumonitis and hepatotoxicity require permanent discontinuation of PF-07220060.

Fulvestrant

Fulvestrant monotherapy is considered a standard treatment option in patients with progressive disease after previous endocrine therapy including an aromatase inhibitor (Rugo et al., 2016; Cardoso et al, 2020). Further, fulvestrant monotherapy is a standard treatment option in patients with progressive disease after previous CDK4/6i plus ET recommended by NCCN Guidelines Version 3.2023 and ESMO Clinical Practice Guidelines).

Fulvestrant (Faslodex®) is available as two 5-mL clear neutral glass (Type 1) barrels, each containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident closure. The syringes are presented in a tray with polystyrene plunger rod and safety needles (SafetyGlideTM) for connection to the barrel. For Arm A participants, Fulvestrant injections are completed before PF-07220060 administration. Fulvestrant was administered intramuscularly in the gluteal area slowly (1-2 minutes per injection) as two 5 mL injections (total dose of 500 mg), per administration instructions provided in the Faslodex® label, during Cycle 1 , on Days 1 and 15 and on Day 1 of each subsequent 28-day cycle.

Everolimus and Exemestane

Everolimus in combination with exemestane is an established therapy option for HR-positive, HER2-negative mBC (Ashai et al., Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets; Cancers (Basel); 2023;15(6)); and this combination is a standard treatment option in patients with progressive disease after previous CDK4/6i plus endocrine therapy recommended by NCCN Guidelines 2023 and ESMO Clinical Practice Guidelines (Gennari et al, 2021).

Everolimus will be administered orally 10 mg QD.

Exemestane will be administered orally 25 mg QD.

Claims

What is claimed:

1. A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 10 mg to about 190 mg of a cyclin-dependent kinase (CDK) inhibitor PF-07220060.

2. The method of claim 1, wherein the total daily dose is administered once per day (QD) or in divided doses twice per day (BID).

3. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 10 mg to about 100 mg QD.

4. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 50 mg QD.

5. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 75 mg QD.

6. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 100 mg QD.

7. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 10 mg to about 75 mg BID.

8. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 50 mg BID.

9. The method of any one of claims 1 to 2, wherein PF-07220060 is administered in an amount of from about 75 mg BID.

10. The method of any one of claims 1 to 9, wherein PF-07220060 is administered continuously.

11. The method of any one of claims 1 to 10, wherein PF-07220060 is administered in a tablet or capsule form.

12. A method for treating cancer comprising administering to a subject in need thereof a daily dose of from about 10 mg to about 190 mg of PF-07220060, in combination with an endocrine therapy agent.

13. The method of claim 12, wherein the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

14. The method of any one of claims 12 to 13, wherein the endocrine therapy agent is selected from the group consisting of letrozole, anastrozole, exemestane, fulvestrant, elacestrant, amcenestrant, giredestrant, RG6171 , camizestrant, AZD9496, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene and afimoxifene.

15. The method of any one of claims 12 to 14, wherein the endocrine therapy agent is letrozole or fulvestrant.

16. The method of any one of claims 12 to 15, wherein the subject is administered the endocrine therapy agent and subsequently administered PF-07220060.

17. The method of claims 1 to 16, wherein the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection.

18. The method of claims 1 to 17, wherein the subject has been previously treated with a CDK4/6 inhibitor.

19. The method of claims 1 to 18, wherein the subject has been previously treated with an endocrine therapy agent.

20. The method of claims 1 to 19, wherein the subject has been previously treated with a CDK4/6 inhibitor in combination with an endocrine therapy agent.

21. The method of claim 20, wherein the endocrine therapy agent is a non-steroidal aromatase inhibitor.

22. The method of claims 1 to 21, wherein the subject has been previously received a treatment targeting estrogen receptor 1 (ESR1), phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT1, phosphatase and tensin homolog (PTEN), or breast cancer gene (BRCA).

23. The method of claims 1 to 21, wherein the subject has been previously treated with one prior line of systemic therapy comprises a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.

24. The method of claims 1 to 22, wherein the subject has been previously treated with two prior lines of systemic therapy, wherein one of the two prior lines of systemic therapy comprises a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor, and the other one of the two prior lines of systemic therapy comprises a treatment targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA.

25. The method of claims 1 to 21, wherein the subject has not received any prior systemic therapies but has been previously treated with an adjuvant therapy comprising a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.

26. The method of any one of claims 1 to 25, wherein the subject is a mammal.

27. The method of any one of claims 1 to 26, wherein the subject is suffering from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer.

28. The method of any one of claims 1 to 27, wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+), hormone receptor negative (HR-), human epidermal growth factor receptor 2 negative (HER2-), human epidermal growth factor receptor 2 positive (HER2+), HR+/HER2-, ER-/HR+, ER+/HER2-and triple negative breast cancer (TNBC).

29. The method of any one of claims 1 to 27, wherein the cancer is NSCLC, prostate, colorectal cancer, liposarcoma, or tumors characterized by amplification or overexpression of CDK4 and/or CCND1.

30. A method of treating cancer comprising administering to a subject in need thereof the following steps: (a) withholding dose until toxicity is Grade < 2 or has returned to baseline, and

(b) resuming treatment with PF-07722060 at starting dose level or reduced by one dose level.