Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer
Cristina Saura, Judit Matito, Mafalda Oliveira, Hans Wildiers, Adam M. Brufksy, Simon Waters, Sara A. Hurvitz, Beverly Moy, Sung‐Bae Kim, William J. Gradishar, Geraldo Silva Queiroz, Eduardo Cronemberger, Gerald Wallweber, Judith D. Bebchuk, Kiana Keyvanjah, Alshad S. Lalani, Richard Bryce, Ana Vivancos, Lisa D. Eli, Suzette Delaloge
Abstract
Abstract 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 = 0.81; 95% confidence interval (CI), 0.64–1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97–3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54–0.82); H-score ≥240 versus <240, HR = 0.77 (0.63–0.93); HERmark positive vs. negative, HR = 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 L+C [IHC 3+, HR = 0.64 (0.51–0.81); H-score ≥ 240, HR = 0.54 (0.41–0.72); HERmark positive, HR = 0.65 (0.50–0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50–0.86) vs. p95 < 2.8 RF/mm2, HR = 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.