Sara Tolaney, MD, MPH
Associate Director, Susan F. Smith Center for Women’s Cancers
Director, Clinical Trials, Breast Oncology
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School
Biomarker Evaluation in the Phase 3 ASCENT Study of Sacituzumab Govitecan Versus Chemotherapy in Patients With Metastatic Triple-Negative Breast Cancer
San Antonio Breast Cancer Symposium. 2020 Dec 8-11. Virtual: Abstract GS3-06.
Title: Sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer (ASCENT): how important is Trop-2 expression?
Background: Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease with few effective treatment options. The current standard of care is sequential single-agent chemotherapy, which yields short progression-free survival (PFS) and overall survival (OS).1 Immune checkpoint inhibitors have been associated with efficacy, but the benefits have mostly been limited to patients with treatment-naïve PD-L1+ disease.2-5 More effective treatments are needed, particularly for patients with prior chemotherapy exposure.
Sacituzumab govitecan is an antibody-drug conjugate that consists of SN-38 (the active metabolite of irinotecan) conjugated to an anti-Trop-2 antibody via a cleavable linker.6 In patients with pre-treated mTNBC, sacituzumab govitecan has resulted in improved overall survival compared to chemotherapy.6-8 As a result, sacituzumab govitecan is FDA approved for mTNBC patients who received at least two prior lines of therapy for metastatic disease. However, it is not currently known if the efficacy is associated with the level of Trop-2 expression on the tumor.
In addition, TNBC tumors with BRCA1/2 mutations are deficient in homologous recombination repair of DNA double strand breaks. Pre-clinical models have suggested that BRCA1/2-deficient TNBC tumors are vulnerable to synthetic lethality from the combined effects of PARP inhibitors and sacituzumab govitecan.9 The effect of BRCA1/2 mutations on the efficacy of sacituzumab govitecan has not yet been explored in clinical trials.
Study Design: ASCENT is a randomized phase III trial that recruited 529 patients with mTNBC who had received at least two prior lines of therapy for metastatic disease (if patients recurred within one year of adjuvant therapy it counted as a prior line). The participants were randomized 1:1 to sacituzumab govitecan (10 mg/kg on days 1 and 8 of each 21-day cycle) or chemotherapy of physician’s choice (eribulin, vinorelbine, gemcitabine, or capecitabine). Patients with stable-treated brain metastases were eligible,but were limited to 15% of the study population.
The primary endpoint, PFS in patients without brain metastases (n = 468), was reported at ESMO 2020.7 The median PFS was 5.6 months in the sacituzumab govitecan arm versus 1.7 months in the chemotherapy arm (HR: 0.41; p < 0.0001). The median OS was also significantly longer in the sacituzumab govitecan arm (12.1 months) versus the chemotherapy arm (6.7 months; HR: 0.48; p < 0.0001). Furthermore, the objective response rate (ORR) was 35% with sacituzumab govitecan versus 5% with chemotherapy (p < 0.0001).
At SABCS 2020, Dr. Sara Hurvitz presented the results of an exploratory biomarker analysis of ASCENT10 that investigated the association of efficacy with Trop-2 expression and BRCA1/2 mutation status in the primary study population (patients without brain metastases). Trop-2 expression was assessed on primary or metastatic tumor tissue using a validated immunohistochemistry assay and expressed as an H-score, a numerical value from 0-300, representing a weighted average of percent staining. An H-score < 100 indicated low Trop-2, H-score 100-200 indicated medium Trop-2, and H-score 200-300 indicated high Trop-2 expression. The status of germline mutations in BRCA1/2 was also collected at baseline, if available.
Results: The Trop-2 expression level was assessed in 151 patients in the sacituzumab govitecan group: 56% had high Trop-2, 26% had medium Trop-2, and 18% had low Trop-2 expression. In the chemotherapy group, 139 patients were evaluated for Trop-2 expression: 52% had high Trop-2, 25% had medium Trop-2, and 23% had low Trop-2 expression. Treatment with sacituzumab govitecan yielded longer PFS than chemotherapy among all patients, irrespective of Trop-2 expression level. In patients with high Trop-2, the median PFS was 6.9 months on sacituzumab govitecan versus 2.5 months on chemotherapy. Among patients with medium Trop-2, the median PFS was 5.6 months on sacituzumab govitecan versus 2.2 months on chemotherapy. Patients with low Trop-2 expression achieved a median PFS of 2.7 months on sacituzumab govitecan versus 1.6 months on chemotherapy. The results were similar for overall survival, in which all patients derived benefit from sacituzumab govitecan.
Among patients treated with sacituzumab govitecan, treatment-related adverse events did not vary by Trop-2 expression level. The most common grade 3 or higher adverse events for patients with high Trop-2 expression were neutropenia (47% of patients treated with sacituzumab govitecan versus 32% of patients on chemotherapy), diarrhea (12% versus 0%), and anemia (10% versus 5%).
The germline BRCA1/2 mutation status was available for 149 patients on sacituzumab govitecan (16 were BRCA1/2-positive, 133 were BRCA1/2-negative) and 143 patients on chemotherapy (18 were BRCA1/2-positive, 125 were BRCA1/2-negative). The median PFS for BRCA1/2-positive patients was 4.6 months on sacituzumab govitecan versus 2.5 months on chemotherapy, and the median OS was 15.6 months versus 4.4 months, respectively. Among BRCA1/2-negative patients, the median PFS was 4.9 months on sacituzumab govitecan versus 1.6 months on chemotherapy, and the median OS was 10.9 months versus 7.0 months, respectively. Among BRCA1/2-positive patients, the ORR was 19% on sacituzumab govitecan versus 6% on chemotherapy. For BRCA1/2-negative patients, the ORR was 33% on sacituzumab govitecan versus 6% with chemotherapy.
Conclusions: The results of this biomarker analysis confirm that patients with pre-treated mTNBC can achieve clinical benefit with sacituzumab govitecan irrespective of Trop-2 expression level or BRCA1/2 mutation status. The highest efficacy outcomes were observed in patients with medium or high Trop-2 expression who were treated with sacituzumab govitecan versus chemotherapy of physician’s choice. However, it is important to recognize the small sample sizes of patients with germline BRCA1/2 mutations and low Trop-2 expression.