Adding Cetuximab to Chemotherapy Improves Outcomes in Patients with KRAS G13D Mutation
Although epidermal growth factor receptor (EGFR) monoclonal antibodies were initially indicated for the treatment of EGFR-expressing metastatic colorectal cancer (mCRC), studies conducted in patients with mCRC have failed to show benefits of the EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) for patients with KRAS mutations. However, approximately 40% of patients with CRC have one of the KRAS gene mutations, with the most frequent mutations seen with G12D (13%), G12V (9%), or G13D (8%). A recent analysis of previously published data indicates that adding cetuximab to first-line therapy benefits patients with the KRAS G13D mutation (Tejpar S, et al. J Clin Oncol. 2012;30:3570-3577).
This study evaluated PFS, OS, and response to therapy using pooled data from 1378 patients in the 2 randomized clinical trials, CRYSTAL and OPUS. Among the 533 patients (39%) with KRAS mutations, 83 (16%) had the G13D mutation, 125 (23%) had the G12V mutation, and 325 (61%) had other mutations.
Even though previous comparisons between patients with KRAS wild-type tumors and patients with KRAS mutations have not differentiated between subtypes of KRAS mutations, this new analysis of pooled data from previously published studies shows significant variations in treatment effects in terms of the response rate and duration of PFS in patients with the KRAS G13D mutation compared with all the other mutations (including KRAS G12V).
In the subgroups of patients with the KRAS G13D mutation, PFS improved significantly by adding cetuximab to standard chemotherapy, leading to a median PFS of 7.4 months with the combination compared with 6.0 months with placebo (HR, 0.47; P = .039); similarly, tumor response rate was 40.5% versus 22.0%, respectively (odds ratio [OR], 3.38; P = .042). However, there was no significant difference in OS; median OS was 15.4 months with the combination versus 14.7 months with chemotherapy alone (HR, 0.89; P = .68) in patients with the G13D mutation. Patients with the G12V mutation and other mutations did not benefit from the combination. Of note, patients with the KRAS G13D mutation who received chemotherapy alone had worse outcomes than those with other mutations receiving chemotherapy alone (response rate, 22.0% vs 43.2%; OR, 0.40; P = .032).
This analysis of first-line chemotherapy with or without cetuximab provides evidence for significant heterogeneous treatment effects in patients with different KRAS mutations: adding cetuximab to first-line chemotherapy for patients with improved PFS and the KRAS G13D mutation is associated with improved clinical outcomes, including prolonged tumor response rate.