Session cochair Dr. George Fisher of the Stanford (Calif.) Cancer Center, maintained that the "door has been closed now" on potential benefit of anti-EGFR therapy in subsets of patients with KRAS-mutated colorectal cancer. "It’s hard for me to imagine that any mutations short of the very rare ones ... might be appropriate for EGFR inhibitors," he said in an interview.
Dr. George Fisher
However, even if inhibition of signaling in the EGFR pathway in these patients is not efficacious, there still might be a role for EGFR binding as it relates to antibody-dependent cell-mediated cytotoxicity, Dr. Fisher added. "There are a number of groups still working on that, and that would theoretically work even in KRAS mutants."
Panitumumab is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer. Its label indicates that it is not recommended for patients having common KRAS mutations.
The three trials included in the analysis tested addition of panitumumab to FOLFOX4 in the first-line setting (the PRIME trial, 301 patients), to FOLFIRI in the second-line setting (701 patients), and to best supportive care in the third-line setting (463 patients). In the new analysis, the investigators assessed the prognostic and predictive impact of six common KRAS mutant alleles: G12D, G12V, G13D, G12C, G12A, and G12S.
"Baseline demographics and clinical features were generally balanced between all mutant KRAS allele subgroups," Dr. Peeters noted.
In cross-trial analyses in which researchers looked just at the control arms to assess prognostic impact of the mutant alleles, none of the six alleles were consistently associated with better progression-free survival or overall survival, compared with all other mutant alleles.
When researchers looked at both arms in the trials to assess predictive impact of the mutant alleles, none of them were consistently associated with differential progression-free survival or overall survival if patients received added panitumumab instead of the control treatment.
In a single trial, G12V was associated with better overall survival and G13D was associated with poorer overall survival if patients received added panitumumab instead of the control treatment of FOLFOX4 alone, with a significant interaction term seen for each allele (P = .037 and P = .002, respectively).
In a pooled analysis of all three trials, only one mutant allele (G12) was significantly associated with overall survival, with poorer overall survival seen for patients having this allele if they received added panitumumab instead of the control treatment alone.
(The investigators also evaluated data from the CRYSTAL and OPUS trials, which tested addition of cetuximab to chemotherapy, and found that neither the G12V nor the G13D mutant allele significantly predicted benefit from the antibody in these trials.)
Dr. Peeters reported that he is a consultant to and receives honoraria and research funding from Amgen. Dr. Fisher reported that he owns stock in Seattle Genetics and receives research funding from Exelixis, FibroGen, Genentech, GlaxoSmithKline, Ispen, Merck, Newlink Genetics, Novartis, and Sanofi Aventis.