TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer

Abstract

BackgroundFOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer.MethodsThis is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, L-leucovorin 200 mg/m2, 5-fluoruracil 2400 mg/m2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria.DiscussionThe relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres.Clinical trial informationNCT03231722.

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

“…While doublet chemotherapy plus anti-EGFRs remains the preferred option in patients with left-sided RAS and BRAF wildtype mCRC, FOLFOXIRI-bevacizumab is a valuable option able to provide similar outcome results at the price of a moderate increase in toxicity, and may be adopted based on patients' preference, attitudes, expectations and compliance, potential impact on quality of life and psychosocial context. Present results underline the potential added value of the intensified upfront chemotherapy backbone also in this subgroup of patients, thus supporting the rationale for randomized trials currently ongoing that aim at comparing triplets plus anti-EGFRs and doublets plus anti-EGFRs as first-line therapy for unresectable mCRC patients [27,28].…”

FOLFOXIRI plus Bevacizumab Versus FOLFOX plus Panitumumab for Metastatic Left-Sided RAS/BRAF Wild-Type Colorectal Cancer: Which “Side” Are You On?

“…With regard to triplet chemotherapy plus anti‐EGFR, phase II data from VOLFI showed the addition of panitumumab to FOLFOXIRI significantly increased the overall response rate (87% vs. 60%, OR 4.47, p = .004) in patients with RAS wild type [5]. We await results from PANIRINOX and TRIPLETE, which are ongoing phase II and III trials comparing FOLFIRINOX + panitumumab versus mFOLFOX6 + panitumumab in RAS / BRAF wild‐type tumors [21, 22]. For now, if a triplet chemotherapy plus biologic is warranted, evidence remains more robust for FOLFIRINOX + bevacizumab.…”

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

“…In this respect, TRIPLETE, a multicenter randomized phase III trial, that is comparing FOLFOXIRI plus panitumumab versus FOLFOX6 plus panitumumab as initial therapy for fit patients with unresectable RAS and BRAF WT mCRC, is currently ongoing. 77 A potential intensification of first-line therapies with anti-EGFR drugs could be the combination of EGFR inhibitors and immune checkpoint inhibitors. Immunotherapy is generally of limited efficacy in mCRC.…”