Treatment Intensification With Modified FOLFOXIRI Plus Panitumumab Provides No Added Benefit in Colorectal Cancer

According to data from the phase 3 TRIPLETE trial, the intensification of upfront chemotherapy with modified FOLFOXIRI plus panitumumab did not provide any added benefit to treatment activity among patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC).

The current upfront option for patients with RAS/BRAF wild-type mCRC is the combination of either the FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) chemotherapy doublet, and an anti-epidermal growth factor receptor (EGFR) antibody, such as cetuximab or panitumumab. The TRIPLETE study aimed to determine whether the triplet option of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab, provided higher treatment activity than modified FOLFOX plus panitumumab for this patient population.

The phase 3 study enrolled 435 patients who were randomized in a 1:1 ratio to receive modified FOLFOX with panitumumab (n = 217; control group) or mFOLFOXIRI plus panitumumab (n = 218; experimental group). All patients received treatment for up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab maintenance until disease progression.

The data cutoff was March 7, 2022. The primary end point was objective response rate (ORR) defined as the percentage of patients achieving a complete response (CR) or partial response (PR) during the whole treatment. Secondary end points included safety, progression-free survival, early tumor shrinkage (ETS) rate, depth of response (DOR), R0 resection rate, and overall survival (not yet mature at the time of this analysis).

The ORR in the experimental group was 73% (n = 161) with 7% CR and 66% PR compared to 76% (n = 165) in the control group with 7% CR and 69% PR (odds ratio 0.87, 95% confidence interval [CI], 0.56 to 1.34, P = .526). There were no differences between the 2 groups with regard to ETS rate (57 vs 58%, respectively; P = .878), median DOR (48% vs 47%; P = .845), or R0 resection rate (25% vs 29%; P = .317).

In addition, there was no significant difference reported between the arms in terms of PFS, with a median PFS of 12.7 months in the experimental group vs 12.3 months in the control group (hazard ratio, 0.88; 95% CI, 0.70 to 1.11; P = .277).

Grade 3 to 4 adverse events (AEs) were reported in 69% of patients in the experimental group and 57% of patients in the control group. The most frequent grade 3 to 4 AEs were neutropenia, diarrhea, rash acneiform, stomatitis, hypokalemia, and fatigue.

The triplet option was associated with a higher occurrence of grade ≥3 AEs (particularly of diarrhea), even when reduced doses of irinotecan and fluoroutacil were utilized. Overall, 72 (33%) patients experienced severe AEs in the experimental group and 44 (21%) patients in the control group. There were 3 treatment-related deaths (1 due to sepsis, 2 due to diarrhea) in the experimental group. No deaths were reported in the control group.

“Our results do not support the use of the triplet in combination with anti-EGFRs and highlight that patients' selection according to RAS and BRAF mutational status and primary tumor location may optimize the efficacy of anti–EGFR-based first-line treatments,” concluded study authors.

Source:

Rossini D, Antoniotti C, Lonardi S. 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. J Clin Oncol. Published online: June 6, 2022. doi:10.1200/JCO.22.00839.