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

Cynthia X Ma; Ron Bose; Feng Gao; Rachel A. Freedman; Melinda L Telli; Gretchen Kimmick; Eric P. Winer; Michael Naughton; Matthew P. Goetz; Christy Russell; Debu Tripathy; Melody Cobleigh; Andres Forero; Timothy J Pluard; Carey Anders; Polly Ann Niravath; Shana Thomas; Jill Anderson; Caroline Bumb; Kimberly C Banks; Richard B Lanman; Richard Bryce; Alshad S Lalani; John D. Pfeifer; Daniel F. Hayes; Mark Pegram; Kimberly Blackwell; Philippe L Bedard; Hussam Al-Kateb; Matthew J C Ellis

doi:10.1158/1078-0432.CCR-17-0900

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

Cynthia X Ma, Ron Bose, Feng Gao, Rachel A. Freedman, Melinda L Telli, Gretchen Kimmick, Eric P. Winer, Michael Naughton, Matthew P. Goetz, Christy Russell, Debu Tripathy, Melody Cobleigh, Andres Forero, Timothy J Pluard, Carey Anders, Polly Ann Niravath, Shana Thomas, Jill Anderson, Caroline Bumb, Kimberly C BanksRichard B Lanman, Richard Bryce, Alshad S Lalani, John D. Pfeifer, Daniel F. Hayes, Mark Pegram, Kimberly Blackwell, Philippe L Bedard, Hussam Al-Kateb, Matthew J C Ellis

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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 HER2(mut) nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.Experimental Design: Tumor tissue positive for HER2(mut) 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 HER2(mut)).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2(mut) (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2(mut) cases were identified locally. Twenty-one of these 22 HER2(mut) 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 HER2(mut) 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 HER2(mut) variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusion: Neratinib is active in HER2(mut), nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2(mut) cancers for clinical trial participation. Clin Cancer Res; 1-9. ©2017 AACR.

Original language	English (US)
Journal	Clinical Cancer Research
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-0900
State	E-pub ahead of print - Jul 5 2017

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Journal Article

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10.1158/1078-0432.CCR-17-0900

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Ma, C. X., Bose, R., Gao, F., Freedman, R. A., Telli, M. L., Kimmick, G., Winer, E. P., Naughton, M., Goetz, M. P., Russell, C., Tripathy, D., Cobleigh, M., Forero, A., Pluard, T. J., Anders, C., Niravath, P. A., Thomas, S., Anderson, J., Bumb, C., ... Ellis, M. J. C. (2017). Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer. Clinical Cancer Research. Advance online publication. https://doi.org/10.1158/1078-0432.CCR-17-0900

Ma, CX, Bose, R, Gao, F, Freedman, RA, Telli, ML, Kimmick, G, Winer, EP, Naughton, M, Goetz, MP, Russell, C, Tripathy, D, Cobleigh, M, Forero, A, Pluard, TJ, Anders, C, Niravath, PA, Thomas, S, Anderson, J, Bumb, C, Banks, KC, Lanman, RB, Bryce, R, Lalani, AS, Pfeifer, JD, Hayes, DF, Pegram, M, Blackwell, K, Bedard, PL, Al-Kateb, H & Ellis, MJC 2017, 'Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-17-0900

@article{d0bb1a0caa9c41e1852e54ad57aa3798,

title = "Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer",

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 HER2(mut) nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.Experimental Design: Tumor tissue positive for HER2(mut) 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 HER2(mut)).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2(mut) (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2(mut) cases were identified locally. Twenty-one of these 22 HER2(mut) 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 HER2(mut) 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 HER2(mut) variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusion: Neratinib is active in HER2(mut), nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2(mut) cancers for clinical trial participation. Clin Cancer Res; 1-9. {\textcopyright}2017 AACR.",

keywords = "Journal Article",

author = "Ma, {Cynthia X} and Ron Bose and Feng Gao and Freedman, {Rachel A.} and Telli, {Melinda L} and Gretchen Kimmick and Winer, {Eric P.} and Michael Naughton and Goetz, {Matthew P.} and Christy Russell and Debu Tripathy and Melody Cobleigh and Andres Forero and Pluard, {Timothy J} and Carey Anders and Niravath, {Polly Ann} and Shana Thomas and Jill Anderson and Caroline Bumb and Banks, {Kimberly C} and Lanman, {Richard B} and Richard Bryce and Lalani, {Alshad S} and Pfeifer, {John D.} and Hayes, {Daniel F.} and Mark Pegram and Kimberly Blackwell and Bedard, {Philippe L} and Hussam Al-Kateb and Ellis, {Matthew J C}",

note = "{\textcopyright}2017 American Association for Cancer Research.",

year = "2017",

month = jul,

day = "5",

doi = "10.1158/1078-0432.CCR-17-0900",

language = "English (US)",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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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 P.

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 D.

AU - Hayes, Daniel F.

AU - Pegram, Mark

AU - Blackwell, Kimberly

AU - Bedard, Philippe L

AU - Al-Kateb, Hussam

AU - Ellis, Matthew J C

PY - 2017/7/5

Y1 - 2017/7/5

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 HER2(mut) nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.Experimental Design: Tumor tissue positive for HER2(mut) 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 HER2(mut)).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2(mut) (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2(mut) cases were identified locally. Twenty-one of these 22 HER2(mut) 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 HER2(mut) 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 HER2(mut) variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusion: Neratinib is active in HER2(mut), nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2(mut) cancers for clinical trial participation. Clin Cancer Res; 1-9. ©2017 AACR.

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 HER2(mut) nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.Experimental Design: Tumor tissue positive for HER2(mut) 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 HER2(mut)).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2(mut) (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2(mut) cases were identified locally. Twenty-one of these 22 HER2(mut) 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 HER2(mut) 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 HER2(mut) variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusion: Neratinib is active in HER2(mut), nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2(mut) cancers for clinical trial participation. Clin Cancer Res; 1-9. ©2017 AACR.

KW - Journal Article

U2 - 10.1158/1078-0432.CCR-17-0900

DO - 10.1158/1078-0432.CCR-17-0900

M3 - Article

C2 - 28679771

SN - 1078-0432

JO - Clinical Cancer Research

JF - Clinical Cancer Research

ER -

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

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