Cetuximab Misses ORR End Point in RAS Wild-Type, BRAF V600E+ mCRC

Sebastian Stintzing, MD

The chemotherapy regimen of FOLFOXIRI plus bevacizumab (Avastin) was found to be preferred in terms of antitumor activity compared with FOLFOXIRI plus cetuximab (Erbitux) in patients with RAS wild-type, BRAF V600E–mutant metastatic colorectal cancer, according to findings from the FIRE-4.5 trial that were presented during the 2021 ASCO Annual Meeting.¹

Results showed that FOLFOXIRI plus cetuximab (49.2%) did not induce a higher objective response rate (ORR) when compared with FOLFOXIRI plus bevacizumab (60.0%), according to the findings of the FIRE-4.5 trial (NCT04034459).

Sebastian Stintzing, MD, with the department of Hematology and Oncology at the Charité-Universitätsmedizin Berlin Department of Haematology-Oncology in Munich, Germany, presented findings from the FIRE-4.5 trial.

FIRE-4.5 is the first prospective and randomized study investigating the efficacy of the mFOLFOXIRI regimen (which consists of 150 mg irinotecan, 85 mg oxaliplatin, 400 mg folinic acid, and 3000 mg 5-fluorouracil) in combination with either 400 mg cetuximab or 7.5 mg/kg bevacizumab as first-line treatment for patients with RAS wild type, BRAF V600E mutant mCRC.

ORR was the primary endpoint. Secondary endpoints included PFS, overall survival (OS), and toxicity. Investigators initiated the study hypothesizing that adding bevacizumab to FOLFOXIRI could achieve an ORR of at least 60% while adding cetuximab could achieve an ORR by at least 82.5%.

Investigators enrolled 109 patients, 36 to the bevacizumab arm and 73 to the cetuximab arm in Germany, France, and Austria; 107 patients were included in the intent-to-treat (ITT) population. Investigators also analyzed patients in the “according to protocol” (ATP) group, those who had at least 3 cycles of treatment and at least 1 follow-up scan.

The ORR in the ATP population was 49.2% in the cetuximab arm (n = 59) and 60% in the bevacizumab arm (n = 30; P = 0.33), with an odds ratio (OR) of 1.55 (80% CI, 0.87-2.78). The disease control rate (DCR) in this same population was 81.4% in the cetuximab arm and 90.0% in the bevacizumab arm (OR, 2.06; 95% CI, 0.53-8.04; P = .29).

PFS in the ATP population was 6.3 months for patients in the cetuximab arm and 10.1 months for patients in the bevacizumab arm (HR, 2.03; 95% CI, 1.15-3.59; P = 0.01). The OS in the ATP population was 15.2 months for patients in the cetuximab arm and 17.1 months for patients in the bevacizumab arm (HR, 1.35; 95% CI, 0.61-3.00; P = 0.46).

In the ITT population, the ORR was 40.3% in the cetuximab arm and 51.4% in the bevacizumab arm (OR, 1.57; P = 0.28). The DCR was 66.7% in the cetuximab arm and 77.1% in the bevacizumab arm (OR, 1.67; P = 0.27). PFS was 6.0 months in the cetuximab arm and 8.3 months in the bevacizumab arm (HR, 1.75; P = .03). OS was 14.6 months in the cetuximab arm and 16.8 months in the bevacizumab arm (HR, 1.16; P = .67).

There were no new or unexpected toxicities in this trial and the hematologic toxicities were balanced between the two treatment arms, Stintzing said. In the ITT cetuximab arm (n = 72), 20.9% of patients experienced grade 3 or higher neutropenia. In the bevacizumab arm (n = 35), 25.7% of patients experienced grade ≥3 neutropenia.

For non-hematologic toxicities, 69.4% of patients in the ITT cetuximab arm experienced a grade 3 or higher toxicity compared with 82.9% of patients in bevacizumab arm. The most common toxicities were diarrhea (18.1%) and nausea (11.1%) in the cetuximab arm and diarrhea (20.0%) and pain (17.1%) in the bevacizumab arm.

Investigators observed grade 3 or higher treatment-related skin disorders grade ≥3 with cetuximab (18.1%), but not in the bevacizumab arm.

Reference

Stintzing S, Heinrich K, Tougeron D, et al. Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: the phase 2 FIRE-4.5 (AIO KRK-0116). J Clin Oncol. 2021: 39(suppl 15): abstr 3502. doi:10.1200/JCO.2021.39.15_suppl.3502