Upfront modified FOLFOXIRI plus panitumumab (pan) versus FOLFOX/pan for unresectable <i>RAS</i> and <i>BRAF</i> wild-type (wt) metastatic colorectal cancer (mCRC) patients: Overall survival (OS) results from the phase III TRIPLETE study by GONO.

3512 Background: TRIPLETE (NCT03231722) is a phase III trial where unresectable RAS/BRAF wt mCRC patients (pts) were randomized 1:1 to first-line FOLFOX/pan (Arm A) or modified FOLFOXIRI/pan (Arm B). The study failed to demonstrate an improved overall response rate, primary endpoint of the study, in Arm B, and did not show any benefit from the intensification of the chemotherapy also in terms of progression-free survival (PFS), early tumor shrinkage, depth of response, R0 resection rate at the price of increased gastrointestinal toxicity. Here we report OS results. Methods: Eligible pts were stratified according to ECOG PS (0-1 vs 2), primary tumor location (right vs left), and liver-only metastases (yes vs no). OS was assessed from randomization to death from any cause. Survival curves were calculated using the Kaplan–Meier method and compared with the log-rank test stratified by the same factors as per randomization. Hazard ratios (HR) with 95% confidence interval (CI) were estimated using Cox regression models. Results: 435 pts (A/B: 217/218) were enrolled. Main pts' characteristics were median age 59/59 years, ECOG PS 0 80%/84%, synchronous metastases 88%/86%, liver-only disease 38%/39%, left-sided primary tumour 88%/88%; deficient MMR tumours 1%/3%. At a median follow up of 60.2 months (mos), 292 (67%, arm A/B: 71%/63%) OS events were collected. Significantly longer OS was observed in Arm B with a median OS of 41.1 vs 33.3 mos in Arm A (HR: 0.79; 95%CI: 0.63-0.99; p = 0.049). No molecular or clinical groups of interest emerged from the subgroup analyses. While no significant difference in PFS was confirmed (median PFS Arm A/B: 12.4/12.7 mos, p = 0.606), longer post progression survival (PPS) was reported in Arm B (HR: 0.73; 95%CI: 0.57-0.93; p = 0.012). The proportion of pts receiving subsequent lines of therapy was similar between arms (2 nd -line Arm A/B: 73%/71%, 3 rd -line: 52%/50%, 4 th -line: 33%/33%), and no differences were evident in the exposure to anti-EGFRs (Arm A/B 35%/38%) and oxaliplatin (26%/33%) after PD, while higher percentages of pts in ARM A received anti-angiogenics (59%/45%) and irinotecan (66%/56%). Similar percentages of pts received locoregional treatments with radical intent after PD (Arm A/B 16%/15%). Conclusions: Upfront modified FOLFOXIRI/pan provides a statistically significant and clinically meaningful survival advantage compared to standard FOLFOX/pan in pts with RAS/BRAF wt mCRC, with a 7.8 mos difference in median values, though in the absence of any significant difference in treatment activity and PFS. Clinical trial information: NCT03231722 .