NSABP FC-11: A phase II study of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (KRAS/NRAS/BRAF/PIK3CA) metastatic colorectal cancer based on HER2 status: amplified, non-amplified (wild-type), or mutated.

Background: Patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) treated with single-agent cetuximab (C) or panitumumab (P), have improved progression-free survival (PFS) and overall survival (OS) compared to best supportive care but an objective response rate (ORR) of only 13-17%. Preclinical and clinical data suggest that dual targeted therapy (e.g., neratinib [N] + C) may improve overall response rates in tumors that are wt for KRAS, NRAS, BRAF, and PIK3CA (quadruple-wt).

Methods: NSABP FC-11 is a multi-center, two-arm, phase II study in patients with quadruple-wt mCRC who had prior oxaliplatin and irinotecan treatment. Arm 1 treated patients with HER2 mutation, with or without prior C or P. Arm 2 treated HER2 non-amplified (14 evaluable) and HER2-amplified (1 evaluable) patients with N + C. The primary aim was PFS at cycle 6 (PFS6). Secondary aims included ORR, objective response, clinical benefit, and safety. Exploratory aims included molecular profiling for mutations, copy number, and RNA expression.

Results: Arm 1 closed early due to low accrual (n = 4) and is not reported. Arm 2 enrolled 21 patients; six discontinued treatment before first scan. Fifteen patients were evaluable with at least one follow-up scan with six demonstrating PFS6. With intention-to-treat (ITT) analysis, this cohort demonstrated an ORR/PFS6 of 28% (6/21). No grade 5 or otherwise unexpected adverse events were noted. Correlative molecular studies did not definitively define responders.

Conclusion: Arm 2 of FC-11 demonstrated an ORR/PFS6 of 28%, which compares favorably to single-agent treatment in this subset of patients.

Clinical trials registration: NCT03457896.