TY - JOUR
T1 - Biomarker analysis of the phase III NALA study of neratinib + capecitabine versus lapatinib + capecitabine in patients with previously treated metastatic breast cancer
AU - Saura, Cristina
AU - Matito, Judit
AU - Oliveira, Mafalda
AU - Wildiers, Hans
AU - Brufksy, Adam M.
AU - Waters, Simon H.
AU - Hurvitz, Sara A.
AU - Moy, Beverly
AU - Kim, Sung Bae
AU - Gradishar, William J.
AU - Queiroz, Geraldo Silva
AU - Cronemberger, Eduardo
AU - Wallweber, Gerald J.
AU - Bebchuk, Judith
AU - Keyvanjah, Kiana
AU - Lalani, Alshad S.
AU - Bryce, Richard
AU - Vivancos, Ana
AU - Eli, Lisa D.
AU - Delaloge, Suzette
N1 - Funding Information:
This work was supported by Puma Biotechnology Inc. (no grant number is applicable). The funders of the study designed the trial, were responsible for data collection, data integrity and analyses, and interpretation of the data with oversight from the authors. The manuscript was written with input from authors, and with review and input from the sponsor. The lead and senior authors were responsible for the final decision regarding manuscript contents and submission. Puma Biotechnology Inc. funded the provision of editorial support provided by Miller Medical Communications.
Funding Information:
We thank the Independent Data Monitoring Committee, study investigators, research staff, clinical research organizations, and other vendors, as well as the patients who participated in the NALA trial. We would like to acknowledge statistical programming support provided by Yan Yan (Puma Biotechnology). We thank Jeff Sperinde and Weidong Huang (Monogram Biosciences) for additional support for HERmark and p95 assay design and execution. We thank Sandra Bernard (Targos GMBH) for oversight of clinical sample management. We thank Lee Miller and Deirdre Carman (Miller Medical Communications Ltd) for writing/editorial support. This work was supported by Puma Biotechnology Inc. (no grant number is applicable). The funders of the study designed the trial, were responsible for data collection, data integrity and analyses, and interpretation of the data with oversight from the authors. The manuscript was written with input from authors, and with review and input from the sponsor. The lead and senior authors were responsible for the final decision regarding manuscript contents and submission. Puma Biotechnology Inc. funded the provision of editorial support provided by Miller Medical Communications.
Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/11/15
Y1 - 2021/11/15
N2 - Purpose: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS. Patients and Methods: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models. Results: Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR ¼ 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR ¼ 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3þ vs. 2+, HR ¼ 0.67 (0.54-0.82); H-score ≥240 versus <240, HR ¼ 0.77 (0.63-0.93); HERmark positive vs. negative, HR ¼ 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with LþC [IHC 3+, HR ¼ 0.64 (0.51-0.81); H-score ≥ 240, HR ¼ 0.54 (0.41-0.72); HERmark positive, HR ¼ 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR ¼ 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2, HR ¼ 0.91 (0.61-1.36)]. Conclusions: PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.
AB - Purpose: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS. Patients and Methods: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models. Results: Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR ¼ 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR ¼ 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3þ vs. 2+, HR ¼ 0.67 (0.54-0.82); H-score ≥240 versus <240, HR ¼ 0.77 (0.63-0.93); HERmark positive vs. negative, HR ¼ 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with LþC [IHC 3+, HR ¼ 0.64 (0.51-0.81); H-score ≥ 240, HR ¼ 0.54 (0.41-0.72); HERmark positive, HR ¼ 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR ¼ 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2, HR ¼ 0.91 (0.61-1.36)]. Conclusions: PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.
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U2 - 10.1158/1078-0432.CCR-21-1584
DO - 10.1158/1078-0432.CCR-21-1584
M3 - Article
C2 - 34380637
AN - SCOPUS:85118966876
SN - 1078-0432
VL - 27
SP - 5818
EP - 5827
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -
