Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of <i>KRAS</i> and <i>BRAF</i> biomarker status with treatment outcome.

Abstract

3570 Background: The phase III CRYSTAL study showed that patients (pts) with KRAS wild-type (wt) tumors benefit from the addition of cetuximab to FOLFIRI as first-line treatment for metastatic colorectal cancer (mCRC). BRAF is a downstream effector of KRAS. Methods: Tumor KRAS and BRAF mutation status (wt or mutant [mt]) was determined for an expanded patient population using polymerase chain reaction and melting curve assays. Treatment arms were compared according to mutation status (log rank and Cochran-Mantel-Haenszel tests). Results: Of 1,198 pts in the primary analysis population, 1,063 (89%) were evaluable for KRAS mutation status; double the previous ascertainment rate. In pts with KRAS wt tumors, all efficacy endpoints were significantly improved in pts receiving cetuximab + FOLFIRI compared with FOLFIRI alone. Tumor BRAF status was evaluable in 625/666 pts with KRAS wt tumors. BRAF mutation was a marker of poor prognosis in both treatment arms (see Table). Conclusions: For all efficacy endpoints, including survival, this analysis confirms the value of KRAS mutational status as a predictor of treatment outcome in pts with mCRC receiving cetuximab plus FOLFIRI first-line. BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to FOLFIRI but the sample size may be too small to be conclusive. KRAS wt n=666 KRAS wt/BRAF wt n= 566 KRAS wt/BRAF mt n=59 FOLFIRI n=350 Cetuximab + FOLFIRI n= 316 FOLFIRI n=289 Cetuximab + FOLFIRI n=277 FOLFIRI n=33 Cetuximab + FOLFIRI n= 26 Median OS months ([95% CI) 20.0 (17.4–21.7) 23.5 (21.2–26.3) 21.6 (20.0–24.9) 25.1 (22.5–28.7) 10.3 (8.4–14.9) 14.1 (8.5–18.5) Hazard ratio (95% CI) 0.796 (0.670–0.946) 0.830(0.687–1.004) 0.908(0.507–1.624) p 0.0093 0.0549 0.7440 Median PFS months(95% CI) 8.4 (7.4–9.2) 9.9 (9.0–11.3) 8.8 (7.6–9.4) 10.9 (9.4–11.8) 5.6 (3.5–8.1) 8.0 (3.6–9.1) Hazard ratio (95% CI) 0.696 (0.558–0.867) 0.679 (0.533–0.864) 0.934 (0.425–2.056) p 0.0012 0.0016 0.8656 OR rate (%) (95% CI) 39.7 (34.6–45.1) 57.3 (51.6–62.8) 42.6 (36.8–48.5) 61.0 (55.0–66.8) 15.2 (5.1–31.9) 19.2 (6.6–39.4) Odds ratio (95% CI) 2.0693 (1.5154–2.8258) 2.1750 (1.5505–3.0511) 1.0842 (0.2644–4.4456) p <0.0001 <0.0001 0.9136 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA Merck KGaA/Merck Serono Amgen, Merck KGaA/Merck Serono, Merck Serono, Pfizer, Roche, sanofi-aventis Merck Serono, Pfizer, sanofi-aventis