Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

Abstract

Purpose: To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

Methods: TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).

Results: From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P = .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in R0 resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).

Conclusion: The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC.

FIG 1.

CONSORT diagram. ^aPatients included in the intention-to-treat population. ^bPatients included in the safety population. FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, and irinotecan.

FIG 2.

Response parameters according to the treatment arm: (A) ORR and disease control rate and (B) early tumor shrinkage. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. CR, complete response; DCR, disease control rate; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, and irinotecan; NE, not evaluable; OR, odds ratio; ORR, objective response rate; PD, progression disease; PR, partial response; SD, stable disease.

FIG 3.

Subgroup analyses of the objective response rate according to clinical characteristics of the intention-to-treat population. The control group indicates FOLFOX plus panitumumab; the experimental group indicates mFOLFOXIRI plus panitumumab. ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, and irinotecan; OR, odds ratio.

FIG 4.

Deepness of response. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, and irinotecan.

FIG 5.

Kaplan-Meier estimates of progression-free survival in the intention-to-treat population. The control group indicates FOLFOX plus panitumumab; the experimental group indicates mFOLFOXIRI plus panitumumab. FOLFOX, fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, and irinotecan.