Summary

This phase II trial studies the effect of sacituzumab govitecan alone or in combination with pembrolizumab in treating patients with hormone receptor positive (HR+)/HER2 negative, PD-L1 positive breast cancer that has spread to other places in the body (metastatic). Sacituzumab govitecan is composed of a chemotherapy drug, called irinotecan, which is attached to an antibody, which are proteins normally made by the immune system that bind to substances that don’t belong in the body to prevent harm. The antibody in this study binds to certain types of cancer tumors, including HR+/HER2- tumors. Pembrolizumab is an immunotherapy, called an anti-PD-1 or a checkpoint inhibitor, and is an antibody (a type of human protein) designed to allow the body’s own immune system to seek out and destroy tumors. Giving sacituzumab govitecan alone or in combination with pembrolizumab may work better in delaying the worsening of HR+/HER2- breast cancers that are also positive for PD-L1.

Objectives

PRIMARY OBJECTIVE:
I. To compare the progression-free survival (PFS) of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone in patients with HR+/HER2- metastatic breast cancer (MBC).

SECONDARY OBJECTIVES:
I. To compare the PFS of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone in the subgroup of patients with PD-L1-positive HR+ / HER2- MBC.
II. To compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing other clinical outcome measures, including overall survival (OS), objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, duration of response (DOR), time to objective response (TTOR), time to progression (TTP), and clinical benefit rate (CBR), in all-comers (regardless of PD-L1 status) and in the subgroup of patients with PD-L1-positive HR+ / HER2- MBC.
III. To evaluate the safety and tolerability of sacituzumab govitecan and pembrolizumab compared to sacituzumab govitecan alone by monitoring adverse events, including immune-related adverse events.

CORRELATIVE/EXPLORATORY OBJECTIVES FOR ENROLLED PARTICIPANTS:
I. To explore tissue biomarkers of antitumoral immune activity and tumor genomic instability as predictors of response and resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone in patients with HR+/HER2- MBC.
Ia. To characterize baseline Trop-2 expression by histological assessment and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
Ib. To assess changes in Trop-2 staining, from baseline to on-treatment and at progression, and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
Ic. To characterize tumor-infiltrating lymphocytes (TILs), by histological assessment, at baseline and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
Id. To characterize the expression of markers of immune cell subsets (i.e. CD8 for cytotoxic T cells, CD68 for macrophages), inhibitory checkpoint pathway molecules (i.e. PD-1, PD-L1, TIM3, LAG3), and co-stimulatory pathway molecules (i.e. GITR, OX40) by immunohistochemistry (IHC) and/or immunofluorescence (IF).
Ie. To explore whether immunosuppressive and/or immune-stimulating immune marker profiles at baseline correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
If. To characterize mutational load and neoantigen burden at baseline and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, and OS).
Ig. To characterize ribonucleic acid (RNA) expression signatures of immune pathway activation and deoxyribonucleic acid (DNA) damage repair deficiency at baseline and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, and OS).
Ih. To explore whether changes in TILs, immunosuppressive and/or immune-stimulating immune marker profiles, mutational load, neoantigen burden, and RNA expression signatures, between paired biopsies from baseline and after 2 cycles of treatment, correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
Ii. To explore mechanisms of resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone in paired biopsies from baseline and at time of progression.
Ij. To explore whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel is correlated with patient outcomes (PFS, ORR by RECIST 1.1, and OS).
II. To explore blood biomarkers of antitumoral immune activity as predictors of response or resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone in patients with HR+/HER2- MBC.
IIa. To characterize serial changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) and in plasma over the course of study treatment.
IIb. To explore whether induction of changes in the immunosuppressive and/or immune-stimulating marker profile in PBMCs correlates with disease response to therapy (PFS, ORR by RECIST 1.1, OS).
IIc. To investigate whether there is an immune marker (i.e. PD-L1) in circulating PBMCs that correlates to tumor infiltrating lymphocyte (TIL) percentage in baseline tumor.
IId. To characterize serial changes of neoantigen burden in circulating tumor DNA and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
IIe. To explore serial changes in blood biomarkers as mechanisms of resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone.
III. To explore the structure and function of the gut microbiome as predictors of response or resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone in patients with HR+/HER2- MBC.
IIIa. To characterize structure and function of the gut microbiome at baseline and correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
IIIb. To explore whether changes in the overall diversity of gut microbiome, estimated by Shannon index, correlate with disease response to treatment (PFS, ORR by RECIST 1.1, OS).
IIIc. To explore correlates of resistance to sacituzumab govitecan plus pembrolizumab compared to sacituzumab govitecan alone in paired samples from baseline and at time of progression.
IV. To explore patient reported outcomes as measured by the following:
IVa. To assess and compare the impact of treatment on Health-Related Quality of Life (HRQoL) between treatment arms, using European Organization for the Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire version 30 (QLQ-C30) and the European Quality of Life (EuroQOL) EQ-5 dimension (D)-5 level (L) instruments.
IVb. To assess and compare the impact of treatment-related symptoms using a set of 16 relevant symptom concepts from the Patient-Reported Outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item library (decreased appetite, nausea, vomiting, constipation, diarrhea, abdominal pain, shortness of breath, cough, wheezing, rash, hair loss, itchy skin, hives, muscle aches, joint aches, and fatigue).

CORRELATIVE OBJECTIVES FOR PRE-SCREENED PARTICIPANTS:
I. To explore tissue biomarkers that characterize the immune microenvironment of HR+/HER2- MBC.
Ia. To characterize tumor-infiltrating lymphocytes (TILs) by histological assessment.
Ib. To characterize the expression of various biomarkers by immunohistochemistry (IHC) and/or immunofluorescence (IF).
Ic. To characterize the expression of markers of immune cell subsets (i.e. CD8 for cytotoxic T cells, CD68 for macrophages), inhibitory checkpoint pathway molecules (i.e. PD-1, PD-L1, TIM3, LAG3), and co-stimulatory pathway molecules (i.e. GITR, OX40) by immunohistochemistry (IHC) and/or immunofluorescence (IF).
Id. To characterize mutational load and neoantigen burden.
Ie. To characterize RNA expression signatures of immune pathway activation and DNA damage repair deficiency.
If. To explore the number and/or type of mutations identified using a next generation sequencing (NGS) panel or whole exome sequencing.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive sacituzumab govitecan intravenously (IV) over 1-3 hours on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1. Cycles with sacituzumab govitecan repeat every 21 days and treatment with pembrolizumab repeats every 21 days for up to 35 cycles (approximately 2 years) in the absence of disease progression or unacceptable toxicity. Additionally, patients who achieve a confirmed complete response (CR), have been treated for at least 24 weeks, had at least 2 treatments with pembrolizumab beyond the date when the initial CR was declared, and progress after stopping their initial treatment with either drug may be eligible for Second Course Phase Therapy.

ARM A (SECOND COURSE PHASE THERAPY): Patients receive sacituzumab govitecan intravenously (IV) over 1-3 hours on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to an additional 17 cycles (approximately 1 year) in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive sacituzumab govitecan IV over 1-3 hours on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 90 days and then every 6 months thereafter.

Eligibility

1. Participants must have histologically or cytologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation, i.e. visible chest wall disease or metastases on imaging meeting standard radiology criteria (i.e. lymph nodes larger than 1 cm in the short axis diameter)
2. Participants must have HR-positive, HER2-negative breast cancer (estrogen receptor [ER] > 1% and/or, progesterone receptor [PR] > 1%, HER2-negative per American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines) on local pathology review. If a patient has more than one histological result, the most recent sample will be considered for inclusion
3. Participants must have either progressed on or within 12 months of adjuvant endocrine therapy or have progressed on at least one line of endocrine therapy for metastatic disease, and be considered appropriate candidates for chemotherapy
4. Participants must have evaluable or measurable disease per RECIST 1.1. For instance, patients with bone only disease will be allowed to participate
5. Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline. Previously collected archival tissue will also be requested, if available, for all participants. A source of archival tumor tissue should be identified at time of registration. Participants must agree to a mandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible
6. Participants may have received 0-1 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to study treatment initiation. If a prior chemotherapy was given for less than 1 cycle, it will not be counted as a prior line. No prior irinotecan or topoisomerase I-containing antibody drug conjugates in the metastatic or neo/adjuvant setting are allowed. All toxicities related to prior chemotherapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade 1 or lower, unless otherwise specified, except alopecia can be any grade and neuropathy can be grade 2 or lower
7. Patients must have discontinued all biologic therapy at least 14 days prior to study treatment initiation. All toxicities related to prior biologic therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified
8. Targeted therapy (e.g., prior CDK 4/6 inhibitors) must have been discontinued >= 14 days prior to initiation of study therapy. All toxicities related to prior targeted therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified
9. Patients may have received prior radiation therapy. Radiation therapy must be completed at least 7 days prior to the initiation of study treatment (at least 7 days for stereotactic radiosurgery [SRS]), and all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
10. Previously treated brain metastases are permitted, with the following provisions: * Prior SRS should complete >= 7 days before study treatment initiation * Prior whole-brain radiotherapy (WBRT) should complete >= 7 days before study treatment initiation. * Any corticosteroid use for brain metastases must have been discontinued for >= 7 days prior to study treatment initiation.
11. Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment and also may initiate therapy with these agents on study if clinically indicated
12. The subject is >= 18 years old
13. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky > 60%)
14. Absolute neutrophil count >= 1,000/mcL
15. Platelets >= 100,000/mcL
16. Hemoglobin >= 9.0 g/dl
17. Institutional normalized ratio (INR)/prothrombin time (PT)/partial thromboplastin time (aPTT) =< 1.5 x upper limit of normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or aPTT is in therapeutic range of anticoagulant
18. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.0 x ULN in patients with documented Gilbert’s syndrome)
19. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN or =< 5 x institutional ULN for participants with documented liver metastases
20. Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 30 mL/min/ 1.73 m^2 for participants with creatinine levels above institutional ULN
21. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation. Childbearing potential is defined as participants who have not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus)
22. Women of childbearing potential (WOCBP) must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 180 days (6 months) after the last dose of study medication. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Hormonal contraceptives are contraindicated for HR+ breast cancer
23. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with pembrolizumab and 3 months after the last dose of study treatment
24. The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document