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.

• Authors: Priyanka Sharma, Vandana G Abramson, Anne O'Dea, Lauren Nye, Ingrid Mayer, Harsh B Pathak, Marc Hoffmann, Shane R Stecklein, Manana Elia, Sharon Lewis, Jecinta Scott, Jilliann A De Jong, Yen Y Wang, Rachel Yoder, Kelsey Schwensen, Karissa Finke, Jaimie Heldstab, Stephanie LaFaver, Stephen K Williamson, Milind A Phadnis, Gregory A Reed, Bruce F Kimler, Qamar J Khan, Andrew K Godwin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 14 Pg. 3896-3904 (07 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33602685 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Biomarkers, Tumor
• Drug Combinations
• Thiazoles
• Alpelisib
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Receptor, ErbB-2
• Paclitaxel

Topics

• Adult
• Aged
• Albumins (administration & dosage)
• Biomarkers, Tumor (blood)
• Breast Neoplasms (chemistry, drug therapy, genetics, 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)