Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer

• Published in: Clinical cancer research 2021-07, Vol.27 (14), p.3896-3904
• Main Authors: Sharma, Priyanka, Abramson, Vandana G, O'Dea, Anne, Nye, Lauren, Mayer, Ingrid, Pathak, Harsh B, Hoffmann, Marc, Stecklein, Shane R, Elia, Manana, Lewis, Sharon, Scott, Jecinta, De Jong, Jilliann A, Wang, Yen Y, Yoder, Rachel, Schwensen, Kelsey, Finke, Karissa, Heldstab, Jaimie, LaFaver, Stephanie, Williamson, Stephen K, Phadnis, Milind A, Reed, Gregory A, Kimler, Bruce F, Khan, Qamar J, Godwin, Andrew K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Albumins - administration & dosage; Biomarkers, Tumor - blood; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Class I Phosphatidylinositol 3-Kinases - genetics; Drug Combinations; Female; Humans; Middle Aged; Mutation; Neoplasm Metastasis; Paclitaxel - administration & dosage; Receptor, ErbB-2 - analysis; Thiazoles - administration & dosage
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-20-4879

mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of mutation with outcomes. A total of 43 patients were enrolled (phase I, = 13 and phase II, = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; = 0.014). No pharmacokinetics interactions were detected. The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with -mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.