TY - JOUR
T1 - Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer
AU - Ma, Cynthia X.
AU - Bose, Ron
AU - Gao, Feng
AU - Freedman, Rachel A.
AU - Telli, Melinda L.
AU - Kimmick, Gretchen
AU - Winer, Eric
AU - Naughton, Michael
AU - Goetz, Matthew P.
AU - Russell, Christy
AU - Tripathy, Debu
AU - Cobleigh, Melody
AU - Forero, Andres
AU - Pluard, Timothy J.
AU - Anders, Carey
AU - Niravath, Polly Ann
AU - Thomas, Shana
AU - Anderson, Jill
AU - Bumb, Caroline
AU - Banks, Kimberly C.
AU - Lanman, Richard B.
AU - Bryce, Richard
AU - Lalani, Alshad S.
AU - Pfeifer, John
AU - Hayes, Daniel F.
AU - Pegram, Mark
AU - Blackwell, Kimberly
AU - Bedard, Philippe L.
AU - Al-Kateb, Hussam
AU - Ellis, Matthew J.C.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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 ¼ 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.
AB - 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 ¼ 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.
UR - http://www.scopus.com/inward/record.url?scp=85029886742&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-0900
DO - 10.1158/1078-0432.CCR-17-0900
M3 - Article
C2 - 28679771
AN - SCOPUS:85029886742
SN - 1078-0432
VL - 23
SP - 5687
EP - 5695
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -