Study of Sacituzumab Govitecan With Atezolizumab/Durvalumab as Maintenance Therapy for Extensive-Stage Small Cell Lung Cancer

Small Cell Lung Cancer (SCLC) is a high-grade neuroendocrine tumor, accounting for nearly 15% of all lung cancers. It is characterized by rapid doubling time, high vascularity, apoptotic imbalance, and early widespread hematogenous metastasis. More than two-thirds of the patients present with extensive stage and only one-third of them present with limited stage confined to the chest. Prognosis continues to be poor with a 3yr relative survival rate of 13%. Despite high response rate with platinum-based chemotherapy, the median survival is limited in patients with advanced SCLC due to early recurrence. The addition of atezolizumab to platinum doublet in the extensive stage has shown only marginal improvement in both progression free survival (PFS) (5.2 months vs 4.3 months) and median overall survival (OS) (12.3 months vs 10.3 months) Similar results were observed with the addition of Durvalumab (median OS- 12.9 months vs 10.5 months). Therefore, there is a significant need to develop strategies that can sustain the response of platinum-based chemotherapy and thus prolong PFS and OS in advanced SCLC patients.

Transmembrane glycoprotein Trophoblast cell surface antigen 2 (TROP-2) is expressed at membranous and/ or cytoplasmic levels in many epithelial solid tumors including SCLC and is associated with poor prognosis. It plays an important role in carcinogenesis and tumor progression. Sacituzimab govitecan (SG) is an anti-TROP-2 antibody-drug conjugate composed of a humanized monoclonal antibody coupled with a toxic payload, SN-38, an active metabolite of irinotecan with a hydrolyzable linker. The antitumor activity/ efficacy of SG in SCLC was first noticed in first in human studies with \>30% reduction of target lesions even after progression on prior topoisomerase I inhibitor. SG was evaluated in a phase I/II dose expansion/ escalation cohort to assess safety and efficacy in relapsed and refractory SCLC following 2 median prior therapies with a primary endpoint of objective response, assessed by imaging. A dose of 10mg/kg was determined to be dose-maximized efficacy and safety. Key treatment-related adverse events reported were neutropenia (57.8%) and diarrhea (56.2%). Patients with homozygous UGT1A1 allele status had an increased risk of neutropenia. Other common side effects reported were nausea/ vomiting, abdominal pain, anorexia, constipation, fatigue, anemia, and alopecia. Overall response rates of 14% (7/50) based on ITT (intention to treat) and 17% (6/36) for patients in the 10 mg/kg dose group, with a median duration of response of 5.7 months. Stable disease is noted in 42% of patients (21/50). In an open-label, multicohort Phase 2 study (TROPiCS-03), SG was evaluated in a second-line setting in patients who progressed after chemotherapy/immunotherapy in SCLC. Among 43 patients enrolled, the overall response rate was 41.9%, with a median PFS of 4.4 months (95% CI 3.81-6.11) and a median OS of 13.6 months (95% CI 6.57-14.78). All patients had treatment-related adverse events, and no AE led to treatment discontinuation.