Analysis of KRAS/NRAS Mutations in a Phase 3 Study of Panitumumab With FOLFIRI Compared With FOLFIRI Alone as Second-Line Treatment for Metastatic Colorectal Cancer
Menée dans le cadre d'un essai de phase III évaluant l'ajout de panitumumab à une chimiothérapie FOLFIRI en traitement de deuxième ligne chez des patients atteints d'un cancer colorectal métastatique, cette étude analyse l'association entre la présence de mutations du gène RAS et la survie sans progression ou la survie globale
Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized, multicenter phase 3 study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).
Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.
Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population (PFS HR, 0.70 [95%CI=0.54‒0.91];P=0.007 versus 0.73 [95%CI=0.59-0.90];P=0.004; OS HR, 0.81 [95%CI=0.63‒1.03];P=0.08 versus 0.85 [95%CI=0.70‒1.04];P=0.12). Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group.
Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared to the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC.
Clinical Cancer Research , résumé, 2015