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

Abstract

Purpose: PIK3CA 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).

Patients and methods: 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/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA 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 PIK3CA mutation with outcomes.

Results: A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 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/m2 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 PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.

Conclusions: The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

Conflict of interest statement

Conflict of interest statement: PS reports research funding to the institution from Celgene, Genentech, GlaxoSmithKline, Merck, and Novartis, as well as advisory board participation for Almac Diagnostics, AstraZeneca, Epic Biosciences, Exact Life Sciences, Immunomedics, Merck, Myriad Inc., Novartis, Pfizer, Puma Biotechnology, and Seattle Genetics. VGA reports advisory board participation for Daiichi Sankyo and Eisai. AO reports speaking and consulting for Pfizer, Puma Biotechnology, and Novartis, as well as speakers bureau participation for AstraZeneca and Daiichi Sankyo. IM reports research funding to the institution from Genentech and Pfizer, as well as advisory board participation for Abbvie, AstraZeneca, Cyclacel, Genentech, GlaxoSmithKline, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, Puma Biotechnology, and Seattle Genetics. MH reports consulting for Celgene, Janssen, and Pharmacyclics and speakers bureau participation for Janssen and Pharmacyclics. SKW and QJK each report research funding to the institution from Novartis. AKG is co-founder of Sinochips Diagnostics and is a consultant for Personal Genome Diagnostics (PGDx), NanoString, and Clara Biotech, Inc. All remaining authors declare no potential conflicts of interest.

©2021 American Association for Cancer Research.

Figures

Figure 1:. Antitumor activity of alpelisib plus nab-paclitaxel based on RECIST v1.1.

(A) Best percentage change from baseline in the sum of longest diameters of target lesions. (B) Longitudinal change from baseline in the sum of longest diameters of target lesions. (C) Durability of response. Panels A and B include patients who received at least one cycle of alpelisib and had available at least one post-baseline tumor assessment (N=39). Panel C includes all patients evaluable for response (N=42). Abbreviations: TNBC, triple-negative breast cancer.

Figure 1:. Antitumor activity of alpelisib plus nab-paclitaxel based on RECIST v1.1.

(A) Best percentage change from baseline in the sum of longest diameters of target lesions. (B) Longitudinal change from baseline in the sum of longest diameters of target lesions. (C) Durability of response. Panels A and B include patients who received at least one cycle of alpelisib and had available at least one post-baseline tumor assessment (N=39). Panel C includes all patients evaluable for response (N=42). Abbreviations: TNBC, triple-negative breast cancer.

Figure 1:. Antitumor activity of alpelisib plus nab-paclitaxel based on RECIST v1.1.

(A) Best percentage change from baseline in the sum of longest diameters of target lesions. (B) Longitudinal change from baseline in the sum of longest diameters of target lesions. (C) Durability of response. Panels A and B include patients who received at least one cycle of alpelisib and had available at least one post-baseline tumor assessment (N=39). Panel C includes all patients evaluable for response (N=42). Abbreviations: TNBC, triple-negative breast cancer.

Figure 2:. Kaplan-Meier estimates of progression-free survival.

(A) All evaluable patients. (B) All evaluable patients, by PIK3CA mutation status. Abbreviations: CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.