Intensified Chemotherapy Does Not Improve Efficacy With Panitumumab in mCRC

A stronger chemotherapy regimen that included irinotecan combined with the targeted EGFR inhibitor panitumumab (Vectibix) failed to show significant benefit over an active comparator plus panitumumab in patients with metastatic colorectal cancer (mCRC) with unmutated RAS and BRAF, according to results presented at the 2022 American Society for Clinical Oncology Annual Meeting.¹

In the phase 3 TRIPLETE study (NCT03231722), the mFOLFOX6 (modified folinic acid, 5-fluorouracil, oxaliplatin) regimen plus panitumumab had an objective response rate (ORR) of 76% versus 73% with mFOLFOXIRI (modified folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) plus panitumumab (odds ratio [OR], 0.87; 95% CI, 0.56-1.34, P = .526).

“The intensification of the upfront chemotherapy backbone with mFOLFOXIRI does not increase the ORR as compared with FOLFOX6 in combination with panitumumab in [patients with] RAS and BRAF wild-type mCRC,” said Chiara Cremolini, associate professor at the University of Pisa, Italy, in her presentation.

FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) plus one of the anti-EGFR monoclonal antibodies panitumumab or cetuximab (Erbitux) are upfront treatment options for mCRC with unaltered RAS and BRAF. The combined regimen of FOLFOXIRI has shown promising efficacy in early-stage trials, and a modified schedule of FOLFOXIRI plus panitumumab showed improved efficacy versus FOLFOXIRI alone in the phase 2 VOLFI trial (NCT01328171).²

The TRIPLETE trial enrolled 435 previously-untreated patients with wild-type RAS and BRAF whose mCRC was unresectable.1 Patients could not have received adjuvant oxaliplatin and could only receive adjuvant fluoropyrimidine monotherapy if 6 months passed between the end of adjuvant therapy and first relapse.

Stratification factors were ECOG performance status 0 or 1 versus 2, primary tumor location (right or left), and whether metastases were only in the liver. Patients were randomized 1:1 to receive induction therapy with panitumumab plus either mFOLFOXIRI or mFOLFOX6 for up to 12 cycles, followed by maintenance with 5-fluoruracil, folinic acid, and panitumumab until disease progression. The trial took place in 57 treatment centers from September 2017 to September 2021.

The median age in both arms was 59 years. In the FOLFOX arm, 43% of patients had a resected primary tumor, versus 51% in the FOLFOXIRI arm. Only 2% had received adjuvant chemotherapy in the mFOLFOX6 arm and only 6% in the mFOLFOXIRI arm.

The schedule of FOLFOXIRI was modified to have lower doses of 5-fluororacil and irinotecan due to the high rate of grade 3 and 4 gastrointestinal toxicities previously observed. Irinotecan was given at a dose of 150 mg/m², oxaliplatin at 85 mg/m², folinic acid at 200 mg/m², and 5-fluoruracil at 2400 mg/m² for 48-hour infusion. Panitumumab was given at 6 mg/kg in both arms.

The primary end point was ORR. Cremolini said in her presentation that this end point was justified for a phase 3 study. “First…we deem ORR a clinically relevant end point in the vast majority of mCRC cases. Second, due to the lack of reliable signs of efficacy for progression-free survival [(PFS) and] overall survival [OS] when assessing upfront chemotherapy plus anti-EGFR–based regimens.”

The end point was based on the expected comparator arm’s ORR of 60% and targeted an increase of at least 15% in the experimental arm. Secondary end points included early tumor shrinkage, depth of response, PFS, and OS.

In addition to the inferior ORR for mFOLFOXIRI, the complete response rate for both arms was 7%, while the partial response rate was 69% for mFOLFOX6 and 66% for mFOLFOXIRI. The percentage of patients with no macroscopic or microscopic residual tumor was 29% in the mFOLFOX6 arm versus 25% in the mFOLFOXIRI arm (OR, 0.81; 95% CI, 0.53-1.23; P = .317). The median change in depth of response was 48% with mFOLFOXIRI versus 47% with mFOLFOX6 (P = .845). Similarly, there was no difference in early tumor shrinkage.

At median follow-up of 26.5 months, the median PFS was 12.3 months for mFOLFOX6 versus 12.7 months for mFOLFOXIRI (HR, 0.88; 95% CI, 0.70-1.11; P = .277). OS results were not yet mature.

Subgroup analysis showed 2 distinct differences in ORR. “It seemed that especially female patients and those with right-sided primary tumor could derive more benefit from the use of the traditional control strategy instead of the experimental arm,” said Cremolini. ORR favored mFOLFOX6 with female patients (OR, 0.43; 95% CI, 0.21-0.88; P = .014) and with right-sided tumors (OR, 0.26; 95% CI, 0.08-0.85; P = .030). She noted that these findings did not correlate when analyzing outcomes by PFS.

The mFOLFOXIRI arm was associated with higher grade 3 or 4 adverse events, especially diarrhea at 23% versus only 7% in the comparator arm and neutropenia at 32% versus 20% in the comparator arm. Grade 3 or 4 skin rash was more frequent in the mFOLFOX6 arm at 29% versus 19% with mFOLFOXIRI.

The null hypothesis of a 60% ORR for the mFOLFOX6 comparator arm was significantly inaccurate. Cremolini suggested that the ORR of 76% could be explained by primary tumor location, as 88% of patients had left-sided tumors.

“In conclusion, FOLFOXIRI plus panitumumab should not be recommended as upfront therapy for RAS and BRAF wild-type mCRC patients,” Cremolini stated. “When the use of targeted agents is optimized in a clinically and molecularly [selected] population, there is no added value from the intensification of the associated chemotherapy backbone.”

_References:

_{1. Rossini D, Antoniotti C, Lonardi S, et al. 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. 2022;40(suppl 17):LBA3505. doi:10.1200/JCO.22.00839}

_{2. Modest DP, Martens UM, Riera-Knorrenschild J, et al. FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109). J Clin Oncol. 2019;37(35):3401-3411. doi:10.1200/JCO.19.01340}