Sacituzumab Govitecan Alone or in Combination with Pembrolizumab for the Treatment of Hormone Receptor+, HER2-, and PD-L1+ Metastatic Breast Cancer

Summary

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.