Efficacy of Upfront Panitumumab Plus Intensified Chemo Falls Short in Liver-Limited, Unresectable mCRC

Panitumumab (Vectibix) combined with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or modified FOLFOX6 (mFOLFOX6; leucovorin, fluorouracil, and oxaliplatin) did not elicit clinically meaningful responses in previously untreated patients with liver-limited, RAS/BRAF wild-type unresectable metastatic colorectal cancer (mCRC), failing to meet the primary end point of the phase 2 PANIRINOX-UCGI28 trial (NCT02980510; EudraCT 2016-001490-33), data from which were presented at the 2025 ESMO Gastrointestinal Cancers Congress.¹

In the per-protocol population, among patients with liver-limited disease who received panitumumab plus FOLFIRINOX (n = 66), the complete response (CR) rate was 27.3% (95% CI, 17.0%-39.6%), the overall response rate (ORR) was 90.9%, and the early tumor shrinkage rate was 86.4%. The median depth of response was –78.9% (Q1-Q3, –100% to –58.2%), and the R0 resection rate was 34.8%.

Among patients with liver-limited disease who received panitumumab plus mFOLFOX6 (n = 34), the CR rate was 23.5% (95% CI, 10.7%-41.2%), the ORR was 91.2%, and the early tumor shrinkage rate was 76.5%. The median depth of response was –72.4% (Q1-Q3, –100% to –44.6%), and the R0 resection rate was 38.2%.

“Given that and the rest of our results, we can’t support the use of an intensified chemotherapy backbone in combination with anti-EGFR [therapy] in this setting, regardless of the disease extension,” Thibault Mazard, MD, PhD, stated in the presentation.

Mazard is a medical oncologist specializing in gastrointestinal and head and neck cancer at the Institut du Cancer de Montpellier Val d’Aurelle in France.

Trial Design

The multicenter, open-label, noncomparative, randomized PANIRINOX-UCGI28 trial enrolled patients with unresectable mCRC who were deemed to have curative-intent disease. Patients needed to be previously untreated except for fluoropyrimidine in the adjuvant setting, be 18 to 75 years of age, have an ECOG performance status of 0 or 1, and have RAS/BRAF V600E wild-type disease according to Intplex circulating tumor DNA (ctDNA) analysis.

“PANIRINOX is the first interventional study [that] used [prospective] ctDNA analysis to assess patient eligibility for anti-EGFR treatment before first line,” Mazard noted.

Stratum 1 (n = 108) included patients with liver-limited disease. Stratum 2 (n = 111) included those with non–liver-limited disease. Patients in each stratum were randomly assigned 2:1 to receive FOLFIRINOX plus panitumumab for a maximum of 12 cycles (arms A) or mFOLFOX6 plus panitumumab for a maximum of 12 cycles (arms B).

The primary end point was CR rate, defined as the complete disappearance of metastatic lesions per RECIST 1.1 criteria and CEA level normalization (if applicable) after a maximum of 12 cycles of chemotherapy. Each CR needed to be confirmed and centrally reviewed. CR could be achieved with chemotherapy or a multimodal approach consisting of methods such as surgical resection, radiofrequency, cryoablation, and radiation therapy.

Results from stratum 2 were initially presented at the 2023 ESMO Congress.

Baseline Characteristics

From October 2017 to August 2023, 574 patients were assessed for eligibility across 22 centers. In total, 96.7% of patients had blood samples complying with quality control criteria, and 46.3% of patients had RAS/BRAF V600E–mutated disease. Accordingly, 219 patients were randomly assigned and selected for either stratum.

In the intention-to-treat (ITT) population of stratum 1, the median age was 60 years (range, 31-75) in arm A (n = 74) and 60 years (range, 34-73) in arm B (n = 34). Most patients in both arms were male (64% vs 74%), had primary left-sided tumors (85% vs 85%), and had synchronous metastases (94% vs 96%). Furthermore, 64% and 47% of patients in each respective arm had an ECOG performance status of 0.

Across both arms in the ITT population of stratum 2, the median age was 63 years (range, 32-80). Most patients were male (60%), had an ECOG performance status of 0 (57%), had primary left-sided tumors (78%), had synchronous metastases (86%), and had more than 1 Nb metastatic site (79%). Additionally, liver, lung, and peritoneal involvement was present in 68%, 56%, and 23% of patients, respectively.

Notably, across both strata, similar characteristics were reported in the per-protocol population.

Additional Efficacy Findings

“In stratum 1, the progression-free survival [PFS] and overall survival [OS] were superimposable between the arms,” Mazard explained. “In stratum 2, it was the same tendency for PFS, but when you look at the OS curves, the experimental arm [appeared] to do better.”

At a median follow-up of longer than 35 months, in the per-protocol population of stratum 1, the median PFS was 10.7 months (95% CI, 9.7-12.7) in arm A and 11.2 months (95% CI, 9.3-12.6) in arm B (HR, 0.86; 95% CI, 0.55-1.34; log-rank P = .5127). In the per-protocol population of stratum 2, the median PFS was 9.1 months (95% CI, 8.1-11.7) in arm A and 9.0 months (95% CI, 7.5-11.9) in arm B (HR, 0.98; 95% CI, 0.61-1.57; log-rank P = .9312).

Regarding OS, in the per-protocol population of stratum 1, the median OS was not reached (NR; 95% CI, 33.7 months-NR) in arm A and NR (95% CI, 28.2 months-NR) in arm B (HR, 0.97; 95% CI, 0.49-1.94; log-rank P = .9341). In the per-protocol population of stratum 2, the median OS was 34.7 months (95% CI, 26.4-NR) in arm A and 25.9 months (95% CI, 17.8-NR) in arm B (HR, 0.71; 95% CI, 0.39-1.30; log-rank P = .2639).

Safety Data

The most commonly observed grade 3 or higher treatment-related adverse effects in arms A vs B, respectively, were diarrhea (34% vs 12%), peripheral neuropathy (19% vs 9%), and skin toxicities (16% vs 22%).

ctDNA Analysis Findings

Investigators performed a ctDNA analysis that included treated patients from both arms of both strata (n = 216) and found no differences in response according to mutation allele frequency (MAF) vs total ctDNA concentration. At baseline, 138 patients were RAS/BRAF V600E wild-type. In this population, the CR rate was 19.6% (95% CI, 13.3%-27.2%), and the ORR was 79.7% (95% CI, 72.0%-86.1%). Additionally, 78 patients had a RAS/BRAF MAF of 0.5% or lower. In this population, the CR rate was 12.8% (95% CI, 6.3%-22.3%), and the ORR was 87.2% (95% CI, 77.7%-93.7%).

Furthermore, many patients had RAS/BRAF wild-type ctDNA at end of treatment (EOT). After a median of 189 days (range, 58-455) of treatment, among evaluable patients who had RAS/BRAF wild-type disease at baseline (n = 82), 78% had persistent wild-type disease, and 22% had RAS/BRAF-mutated disease. Among evaluable patients who had a RAS/BRAF MAF of 0.5% or lower (n = 50), 16% and 84% had RAS/BRAF-persistent and wild-type disease, respectively.

“Our findings…confirm the relevance of using ctDNA analysis to molecularly select patients before first-line [therapy], even if the identification of RAS or BRAF MAF with our method may not impact treatment activity.”

Disclosures: Mazard reported serving on advisory boards for Pierre Fabre, MSD, Servier, and Takeda; serving as an invited speaker for Pierre Fabre, Servier, and Astra Zeneca; participating in a writing engagement with Galapagos; serving as a coordinating principal investigator for Amgen; receiving travel grants from Pierre Fabre, Merck, Serono, Sanofi, MSD, Takeda, and Servier; and serving in an advisory role for Inca.

Reference

1. Mazard T, Ghiringhelli F, Nguyen L, et al. Panitumumab (P) + FOLFIRINOX or mFOLFOX6 in unresectable metastatic colorectal cancer (mCRC) patients (pts) with RAS/BRAF wild-type (WT) tumor status from circulating DNA (cirDNA): final results of the randomised phase II PANIRINOX-UCGI28 study. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 7MO.