Phase 1B Study of Oral Dual-Pi3K/Mtor Inhibitor Gdc-0980 in Combination with Carboplatin (Carbo)/Paclitaxel (Pac) ± Bevacizumab (Bev) and Cisplatin (Cis)/Pemetrexed (Pem) in Patients (Pts) with Advanced Solid Tumors and Nsclc

Abstract

ABSTRACT Aim: The PI3K signaling pathway is altered in many tumor types, including NSCLC. GDC-0980 has single-agent activity as well as preclinical cytotoxic synergy with taxane and platinum agents and antiangiogenic synergy with anti-VEGF agents. Methods: This Phase 1b study evaluated the safety and tolerability of GDC-0980 in combination with platinum-based chemotherapy (CT) and Bev in pts with advanced solid tumors (AST) or first-line advanced NSCLC: Arm A – Carbo (AUC 6) + Pac (200 mg/m2); Arm B – Carbo/Pac + Bev (15 mg/kg); Arm C - Cis (75 mg/m2) + Pem (500 mg/m2). On a 21-day cycle, CT regimens were administered on Day 1, and GDC-0980 PO QD on Days 1-14. Pharmacokinetic (PK) analyses were performed. Archival tumor tissue and blood samples for pharmacogenetic and ctDNA analyses were collected. Results: Sixty-five pts (28 in Arm A [17 NSCLC]; 18 in Arm B [10 NSCLC]; 19 in Arm C [12 NSCLC]) were treated with GDC-0980 20 to 40 mg. For AST cohorts in Arms A and B, the MTD of GDC-0980 was 25 mg (DLTs were febrile neutropenia, rash, and fatigue). For NSCLC cohorts in Arms A and C, the maximum administered dose (MAD) was 30 mg GDC-0980. At this dose, Grade 3/4 adverse events (AEs) in >10% of all treated pts were neutropenia (59%), rash (24%), febrile neutropenia and anemia (12%) in Arm A and neutropenia (33%), anemia and fatigue (25%), hypertension, infection, and pneumonitis (17%) in Arm C. Other high-grade AEs of interest were less common: hyperglycemia in Arm A (6%) and Arm C (8%) and rash (8%) in Arm C. Among NSCLC pts treated with 30 mg GDC-0980, objective responses were observed in 9 of 14 (64%) pts in Arm A and 4 of 12 (33%) pts in Arm C. Other pts with follicular thyroid, ovarian, and urothelial cancers (Arm A) and angiosarcoma (Arm B) also had objective responses. There were no apparent PK interactions. Biomarker analysis is ongoing. Conclusions: The safety profile of GDC-0980 30 mg in combination with Carbo/Pac or Cis/Pem is consistent with that of the individual agents, and AEs were manageable and reversible. These GDC-0980 combinations have demonstrated preliminary activity in first-line NSCLC. Disclosure: O. Hamid: Consultant to Genenech; W. Lin: Employee of Genentech, Inc.; B. O'keeffe: Employee of Genentech, Inc.; M.R. Lackner: Employee of Genentech, Inc.; J. Spoerke: Employee of Genentech, Inc.; J. Ware: Employee of Genentech, Inc. All other authors have declared no conflicts of interest.