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.

• Authors: Daniele Rossini, Carlotta Antoniotti, Sara Lonardi, Filippo Pietrantonio, Roberto Moretto, Lorenzo Antonuzzo, Alessandra Boccaccino, Federica Morano, Marco Brugia, Carmelo Pozzo, Federica Marmorino, Francesca Bergamo, Emiliano Tamburini, Alessandro Passardi, Giovanni Randon, Sabina Murgioni, Beatrice Borelli, Angela Buonadonna, Mirella Giordano, Gabriella Fontanini, Veronica Conca, Vincenzo Formica, Massimo Aglietta, Roberto Bordonaro, Giuseppe Aprile, Gianluca Masi, Luca Boni, Chiara Cremolini
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 40 Issue 25 Pg. 2878-2888 (09 01 2022) ISSN: 1527-7755 [Electronic] United States
• PMID: 35666229 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Organoplatinum Compounds
• Oxaliplatin
• Panitumumab
• Irinotecan
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• ras Proteins
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Camptothecin (adverse effects)
• Colonic Neoplasms (drug therapy)
• Colorectal Neoplasms (drug therapy, genetics)
• Fluorouracil
• Genes, ras
• Humans
• Irinotecan (therapeutic use)
• Leucovorin
• Organoplatinum Compounds
• Oxaliplatin
• Panitumumab
• Prospective Studies
• Proto-Oncogene Proteins B-raf (genetics)
• Rectal Neoplasms (drug therapy)
• ras Proteins