Reply to S. Debska-Szmich et al
Authors: Eric Van Cutsem, Frank Beier, Fortunato Ciardiello
Journal: Journal of Clinical Oncology (2015)

Our retrospective analysis of the CRYSTAL trial assessed the treatment effect of cetuximab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone in patients who carried predefined tumor mutations in RAS loci and in patients whose tumors were wild type at all RAS loci. We agree with Debska-Szmich et al that there were more pronounced treatment effects stemming from the addition of cetuximab to FOLFIRI in the RAS-evaluable population than in the KRAS exon 2 wild-type population. Indeed, this point was explicitly discussed in our publication. Furthermore, DebskaSzmich et al are correct to conclude that a similar trend was not observed in the RAS-evaluable population compared with KRAS exon 2 wild-type populations of the OPUS, FIRE-3, and PRIME studies. Because baseline characteristics were similar between the RASevaluable and KRAS exon 2 wild-type populations of the CRYSTAL study, there is no evidence of an obvious selection bias. In the absence of another empirical explanation for the observed difference in treatment effects, we are left to conclude that this difference arose by chance. We do not believe that generating additional efficacy data for the 236 patients whose tumors were KRAS wild type and who were not evaluable for RAS tumor mutation status would afford any relevant insights regarding this apparent selection bias. More important, the unexpected finding of more pronounced treatment effects in the RAS-evaluable population compared with the KRAS exon 2 wild-type population does not alter the principal conclusion of our retrospective analysis of the CRYSTAL trial—that molecular testing of tumors for all activating RAS mutations (as opposed to solely KRAS exon 2 tumor mutations) is essential before considering anti–epidermal growth factor receptor therapy. First, in the RAS wild-type population, the addition of cetuximab to FOLFIRI provided a significant benefit for all end points. Compared with the treatment outcomes in the other RAS mutant population (ie, patients included in the KRAS exon 2 wild-type population for whom RAS tumor mutations were identified during full RAS testing), efficacy outcomes in favor of cetuximab were considerably improved for all end points in the RAS wild-type population; in contrast, no beneficial effects resulting from the addition of cetuximab to FOLFIRI were observed in the other RAS mutant population. Second, these observations pertaining to the importance of RAS testing (v KRAS exon 2 testing) have been confirmed via retrospective assessments of RAS tumor mutation status in numerous other randomized clinical trials, including the OPUS, FIRE-3, PRIME, and PEAK studies. Thus, although we agree with Debska-Szmich et al that retrospective analyses are inherently challenging and that efficacy outcomes in RAS subgroups may be somewhat affected by selection bias, these concepts do not affect our principal conclusion. Therefore, we remain confident that molecular testing of tumors for all activating RAS mutations is essential before anti–epidermal growth factor receptor therapy is considered.