Safety overview and management of inavolisib alone and in combination therapies in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer (GO39374)
Valentina Gambardella, MK Accordino, Philippe L. Bédard, A. Cervantes, Erika Hamilton, Antoîne Italiano, Kevin Kalinsky, Ian E. Krop, Matheus Gabriel de Oliveira, Cristina Saura, P. Schmid, Nicholas C. Turner, Andréa Varga, A Fernandez-Saranillo, Yanling Jin, Stephanie Royer‐Joo, Ubong Peters, Noopur Shankar, Jennifer L. Schutzman, Dejan Juric, Komal Jhaveri
Abstract
BACKGROUND: Inavolisib is a potent and selective PI3Kα inhibitor that promotes degradation of mutated p110α. We report safety from a phase I/Ib dose-escalation/-expansion study (GO39374; NCT03006172) of inavolisib alone or in combination therapies in PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced breast cancer. PATIENTS AND METHODS: Patients received inavolisib [oral once daily (od)] alone, with letrozole (2.5 mg od) or fulvestrant (500 mg intramuscularly 4 weekly) ± palbociclib (125 mg od for 21/28 days); metformin was included in one arm. PRIMARY ENDPOINT: safety and tolerability. RESULTS: At data cutoff (1 January 2024), 190 patients had been treated, of which 179 (94.2%) had discontinued study treatment, mainly due to progressive disease [146 (76.8%)]. Treatment-related any-grade and grade 3-5 adverse events (AEs) occurred in 181 (95.3%) and 107 (56.3%) patients, respectively. Inavolisib-related AEs led to inavolisib withdrawal in 5 (2.6%) and dose reductions/interruptions in 103 (54.2%) patients. Hyperglycemia, diarrhea, stomatitis (grouped terms), and rash (grouped terms) occurred in 129 (67.9%), 124 (65.3%), 93 (48.9%), and 47 (24.7%) patients, respectively. Hyperglycemia, diarrhea, and stomatitis mainly occurred early in treatment, and were manageable with supportive measures (including oral antihyperglycemic agents, common antidiarrheal medications, and dexamethasone mouthwash, respectively) and/or inavolisib dose modifications (dose interruptions with or without dose reductions). Hyperglycemia remained frequent in patients with risk factors, despite early metformin treatment. Rash was mostly grade 1 and required no treatment. Patients treated for ≥1 year [n = 65 (34.2%)] demonstrated encouraging long-term tolerability. CONCLUSIONS: Inavolisib alone or in combination with HR-positive breast cancer therapies demonstrated a manageable safety and tolerability profile, which supports its ongoing development.