1O Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Exploratory biomarker analyses from phase III NALA trial

The irreversible pan-HER tyrosine kinase inhibitor neratinib had a significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized, phase 3 trial comparing neratinib + capecitabine (1500 mg, N+C) vs lapatinib + capecitabine (2000 mg, L+C) in 621 patients (pts) with HER2+ (either IHC3+ or IHC2+/FISH+) metastatic breast cancer (MBC) who received ≥2 prior HER2-directed regimens in the metastatic setting. Here we explore biomarker (PIK3CA or ERBB2 mutations, HER2 protein expression) associations with PFS changes. PIK3CA and ERBB2 mutations were evaluated by next-generation sequencing on either primary (67.4%, 283/420) or metastatic/lymph node samples (32.6%, 137/420) and confirmed by ddPCR pending tissue availability. HER2 protein expression was evaluated by central IHC, H-score, and HERmark. Hazard ratios (95% CI) for subgroups were estimated using unstratified Cox proportional hazards model. PIK3CA and ERBB2 mutations were detected at incidences of 35.0% (148/420) and 6.2% (26/420), respectively. PIK3CA mutations were associated with decreased PFS (wt vs mut: HR=0.81; 95% CI 0.64–1.02; p=0.077). ERBB2 mutation trended with better PFS, but sample size was limited (wt vs mut: HR=1.68, CI 0.97–3.29, p=0.086). Higher HER2 protein expression was prognostic of increased PFS when treatment arms were grouped (IHC3+ vs 2+: HR=0.67, CI 0.54–0.82, p<0.001; H-score above vs below median HR=0.77, CI 0.63–0.92, p=0.005; HERmark positive vs equivocal or negative HR=0.71, CI 0.52–0.98, p=0.006). Pts whose tumors had higher HER2 protein expression evaluated by any of the three methods appeared to have derived consistent benefit from N+C vs L+C (HER2 IHC3+: HR=0.64, CI 0.51–0.81, p<0.001; H-score ≥median (240): HR=0.54, CI 0.41–0.72, p<0.001; HERmark positive: HR=0.65, CI 0.50– 0.84, p<0.001). PIK3CA mutations associate with decreased PFS for pts enrolled in the NALA trial. Higher HER2 protein expression associates with increased PFS in the overall study population, and a greater benefit from N+C vs. L+C.