Negative hyperselection of resistance mutations for panitumumab maintenance in RAS wild-type metastatic colorectal cancer (PanaMa phase II trial, AIO KRK 0212).

BACKGROUND:We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a FU/FA maintenance as pre-specified analysis of the randomized PanaMa trial. METHODS:Mutations (MUT) were identified using targeted next generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and immunohistochemistry. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpression were negatively hyperselected and correlated with median progression-free (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS:202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: Hyperselection WT: 162 (80.2%); MUT: 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared to hyperselection MUT mCRC (7.5 vs. 5.4 months; HR=0.75 (95%CI 0.52 - 1.07), P=0.11), OS (28.7 vs. 22.2 months; HR=0.53 (95%CI 0.36 - 0.77), P=0.001), and higher ORR (35.8% vs. 25.0%, P=0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR=0.66 (95%CI 0.47 - 0.93), P=0.02) and numerically also for OS (36.9 vs. 24.9 months; HR=0.91 (95%CI 0.61 - 1.36), P=0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P=0.06) and OS (P=0.009). CONCLUSIONS:Extended molecular profiling beyond RAS may have the potential to improve of the patient selection for anti-EGFR containing maintenance regimens.