Modified FOLFOXIRI Plus Panitumumab Improves Overall Survival in RAS/BRAF Wild-Type Metastatic Colorectal Cancer

Clinical Summary: 

• Design/Population: The phase 3 TRIPLETE trial randomized patients with previously untreated RAS/BRAF wild-type metastatic colorectal cancer to receive modified FOLFOXIRI plus panitumumab or FOLFOX plus panitumumab. Most patients had left-sided primary tumors and good performance status.
• Key Outcomes: Although the trial did not meet its primary endpoint of improved objective response rate and showed no benefit in progression-free survival or other secondary efficacy endpoints, updated analysis demonstrated a significant improvement in overall survival with modified FOLFOXIRI plus panitumumab. The intensified regimen was associated with greater gastrointestinal toxicity than the doublet regimen.
• Clinical Relevance: These long-term findings suggest that chemotherapy intensification with modified FOLFOXIRI plus panitumumab may improve overall survival in selected patients with RAS/BRAF wild-type metastatic colorectal cancer despite the absence of earlier efficacy advantages.

Veronica Conca, MD, University of Pisa, Italy, discusses the final overall survival analysis of the phase 3 TRIPLETE trial evaluating modified FOLFOXIRI plus panitumumab versus FOLFOX plus panitumumab as first-line treatment for patients with RAS/BRAF wild-type metastatic colorectal cancer.

The updated analysis demonstrated a clinically meaningful overall survival benefit despite no differences in objective response rate, progression-free survival, or other secondary endpoints. Ongoing translational analyses, including circulating tumor DNA studies, aim to better understand the biologic mechanisms underlying the survival benefit and identify patients most likely to benefit from treatment intensification. 

Transcript: 

Hi, I'm Veronica Conca. I'm a medical oncologist at Pisa University and the Azienda Ospedaliero-Universitaria Pisana.

In the Journal of Clinical Oncology, in January, we published the updated analysis and overall survival results of the phase 3 TRIPLETE study, which investigated intensifying first-line treatment in patients with RAS- and BRAF wild-type metastatic colorectal cancer. The study had previously not demonstrated an improvement in terms of objective response rate, which was the primary end point of the study.

Previously, the study also did not show any benefit from intensification of chemotherapy in terms of progression-free survival, early tumor shrinkage, depth of response, or R0 resection rate, at the cost of increased gastrointestinal toxicity. In the Journal of Clinical Oncology, we analyzed the final overall survival data.

The study enrolled patients with metastatic colorectal cancer that was RAS and BRAF wild type on tissue by local assessment. Patients had to have a good performance status and adequate bone marrow, liver, and renal function.

Patients were randomized 1:1 to receive either FOLFOX plus panitumumab or modified FOLFOXIRI plus panitumumab for 12 cycles, followed by maintenance with fluoropyrimidine plus panitumumab until disease progression. Baseline characteristics were well balanced between the 2 arms, with the majority of patients having synchronous metastases and good performance status. The median age was 70 years, and the majority of patients, 88%, had left-sided primary tumors.

At a median follow-up of 46 months, modified FOLFOXIRI plus panitumumab improved overall survival, with a median overall survival of 41.1 months compared with 33.3 months for FOLFOX plus panitumumab. So there was an increase of approximately 8 months in median overall survival, without differences across the clinical subgroups.

We also analyzed the other end points as part of this updated analysis. There were no differences in objective response rate, which was the primary endpoint, or in other secondary end points such as progression-free survival, R0 resection rate, depth of response, or early tumor shrinkage.

We also analyzed subsequent lines of therapy. A similar proportion of patients in both arms received subsequent therapy. The majority of patients in the FOLFOX plus panitumumab arm received irinotecan-based therapy after the TRIPLETE study, whereas most patients in the experimental arm received oxaliplatin-based therapy after TRIPLETE treatment. A similar proportion of patients in both arms received regorafenib and trifluridine/tipiracil, and a similar proportion also received another anti-EGFR treatment. So there were no relevant differences in subsequent lines of therapy.

There was also no difference in the percentage of patients who underwent non-palliative locoregional treatment, with 16% in both arms.So there is no clear explanation for this difference in overall survival. One hypothesis is that patients in the experimental arm had a lower disease burden at the time of disease progression compared with patients in the FOLFOX plus panitumumab arm.

In the future, we may be able to confirm this hypothesis by analyzing ctDNA at the time of disease progression. There are a number of translational analyses currently ongoing, including ctDNA analyses, to better understand this difference and to help us identify which patients with RAS- and BRAF wild-type metastatic colorectal cancer benefit most from this treatment.

This is a very effective and very powerful combination, but it is also associated with substantial toxicity, particularly diarrhea and neutropenia.

So these data, together with results from other phase 2 studies, may help clinicians identify the best treatment option for patients with RAS- and BRAF wild-type metastatic colorectal cancer, especially those with left-sided primary tumors.

Source: 

Conca V, Rossini D, Antoniotti C, et al. Upfront modified FOLFOXIRI plus panitumumab for RAS/BRAF wild-type metastatic colorectal cancer: Final results of the phase III TRIPLETE study. J Clin Oncol. Published online: January 8, 2026. doi: 10.1200/JCO-25-01337