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Clinical Trial
, 23 (19), 5687-5695

Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer

Affiliations
Clinical Trial

Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer

Cynthia X Ma et al. Clin Cancer Res.

Abstract

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection.Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

C.X. Ma reports receiving commercial research grants from and is a consultant/advisory board member for Novartis, Pfizer, and Puma Biotechnology. R. Bose is a consultant/advisory board member for Genetech. G. Kimmick reports receiving commercial research grants from BioNovo, Bristol-Myers Squibb, GlaxoSmithKlein, Novartis, and Puma Biotechnology. E. Winer is a consultant/advisory board member for Genetech, LEAP, and Tesaro. M. Naughton reports receiving speakers bureau honoraria from Genetech and Novartis. D. Tripathy is a consultant/advisory board member for Puma Biotechnology. M. Cobleigh is a consultant/advisory board member for Puma Biotechnology. C. Anders is a consultant/advisory board member for Angiochem, Eli Lilly, Genentech, Geron, Kadmon, Merrimack, Nektar, Novartis, Sanofi, and to BBB. K.C. Banks holds ownership interest (including patents) in Guardant Health. R.B. Lanman holds ownership interest (including patents) in Guardant Health. R. Bryce and A. Lalani are employees of PUMA Biotechnology. D.F. Hayes reports receiving commercial research grants from Puma Biotechnology, reports receiving other commercial research support from AstraZeneca, Janssen, and Pfizer, and holds ownership interest (including patents) in OncImmune. K. Blackwell is a consultant/advisory board member for Puma Biotechnology. M.J.C. Ellis is an employee of and holds ownership interest (including patents) in Bio-classifier LLC, and is a consultant/advisory board member of AstraZeneca, Novartis, Pfizer, and Puma Technology. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
HER2 mutations identified by tumor DNA sequencing at Central and other laboratories. Each circle (lobular) or square (ductal) represents a single patient except in a case of concurrent S310F and V842I mutations (indicated by *).
Figure 2.
Figure 2.
Antitumor activity of neratinib. A, Swimmer Plot of time to progression (TTP) for patients with HER2-activating mutations. Co-occurring mutations in TP53, CDH1, and PIK3CA by tumor DNA sequencing are indicated. B, Percentage change in target lesion at best response compared with baseline. Patients with measurable diseases are included. C, Representative CT images of a patient on study. Sixty-four-year old woman (Pt 9) with ER+/HER2 metastatic breast cancer, HER2 L755S, prior disease progression on fulvestrant, and exemestane plus everolimus in the metastatic setting, achieved a partial response on neratinib. D, ctDNA HER2 mutation variant allele frequency in response to neratinib. HER2 mutation VAFs at baseline, 4 weeks, and progression are plotted for individual patients (n = 11).
Figure 3.
Figure 3.
Variant allele frequency maps of ctDNA-detected mutations in individual patients in response to neratinib treatment. Variant allele frequencies (VAFs) of ctDNA-detected mutations over time are shown for the 11 patients with detectable HER2 mutation at baseline and with available blood samples at subsequent time points (n = 11 at 4 weeks, and n = 8 at progression). A includes four patients who achieved clinical benefit (CR in Pt 15, PR in Pt 9, SD ≥24 weeks in Pts 16 and 14). B, three patients who had best response of SD but lasted less than 24 weeks (Pt 2, Pt 6, and Pt 8). C, four patients who had PD as the best response (Pt 11, Pt 7, Pt 1, and Pt 12). Numbers at the bottom of each graph represent the VAFs of the HER2 mutation colored in yellow, which were also used to plot Fig. 2D. All ctDNA alterations are shown except for patients 14 and 6 due to space limits in the figure. The complete list of mutations and their VAFs is detailed in Supplementary Table S3.

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