PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial

Abstract

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET.

Methods: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models.

Results: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309).

Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC.

Trial registration: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

Keywords: Breast cancer; Drug targets; Neratinib; PIK3CA; Predictive; Prognostic.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the institutional ethics committee at participating sites; the study was conducted in accordance with the 2008 Declaration of Helsinki. All patients (intention-to-treat [ITT] population) provided written informed consent; patients in the correlative cohort signed an optional consent form relating to primary tumor collection for exploratory biomarker analyses.

Consent for publication

Not applicable

Competing interests

SKLC received honoraria from Novartis, Hoffmann-La Roche, Pfizer, and AstraZeneca. MM received grants and personal fees from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, Pharmamar, and Lilly. BE received research funding from NanoString, Novartis, and Roche, and travel, accommodations, or expenses from AstraZeneca. SD received honoraria from Puma, Pfizer, AstraZeneca, Roche, and Lilly; consulting or advisory role from Puma, Pfizer, AstraZeneca, Roche, and Lilly; research funding from Puma, Pfizer, AstraZeneca, Roche, and Lilly; and travel and accommodations expenses from Pfizer, Roche, and AstraZeneca. BM acted in a consulting or advisory role (immediate family member) for Motus GI. HI received honoraria from Chugai, AstraZeneca, and Eisai, and consulting or advisory role for Chugai, Pfizer, Daiichi-Sankyo, AstraZeneca, and Lilly. GvM received research funding from Pfizer, Amgen, Roche, Teva, Novartis, AstraZeneca, Celgene, Myriad, AbbVie, and Vifor. JM received research funding from Roche, Macrogenics, and Puma Biotechnology Inc. CHB received grants and personal fees from GlaxoSmithKline, Roche, and Novartis outside the submitted work. MG received research funding from Sanofi-Aventis, Pfizer, Smith Medical, Novartis, Roche, GlaxoSmithKline, and personal fees from Novartis, Roche, GlaxoSmithKline, AstraZeneca, Nanostring Technologies, and Accelsiors. ND received research funding from Amgen and Genentech. SBK received research funding from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc., and Dongkook Pharma Co. Ltd. NR acted in a consulting or advisory role for New Century Health and Bristol-Myers Squibb and received research funding from Side-Out Foundation. JS II acted in a consulting or advisory role for BMS and Novartis. BZ, LDE, and ASL are employed by Puma Biotechnology, Inc. MB is employed by the International Drug Development Institute (IDDI) and holds stock of IDDI. YY was employed by Puma Biotechnology at the time of the research but is now employed by QED Therapeutics Inc. FAH, ZT, RS, EHJ, VH, GH, and AC declare that they have no competing interests.

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Figures

Fig. 1

PIK3CA mutations and PIK3CA amplifications in the correlative cohort. a Distribution of hotspot variants in PIK3CA mutation-positive subgroups. b Distribution of PIK3CA amplification or mutation status in the correlative cohort

Fig. 2

Kaplan-Meier plot of 5-year invasive disease-free survival for patients with PIK3CA-altered tumors (correlative cohort)

Fig. 3

Forest plot of neratinib vs placebo in PIK3CA-altered and hormone receptor subgroups. HRc, hormone receptor