FOLFIRI/cetuximab followed by cetuximab monotherapy inferior to standard of care in RAS/BRAF wild-type metastatic colorectal cancer

The phase III ERMES trial investigated whether cetuximab alone after 8 cycles of FOLFIRI plus cetuximab results in a non-inferior progression-free survival (PFS) as compared to continuous FOLFIRI plus cetuximab in first-line therapy of RAS/BRAF wild-type metastatic colorectal cancer. Unfortunately, the study did not demonstrate non-inferiority of maintenance with cetuximab alone. However, the higher-than-expected drop-out rate and subsequent reduced statistical power might have impaired the results.

The optimal intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type metastatic colorectal cancer (WT mCRC) once disease control is achieved, remains controversial. A maintenance strategy with anti-EGFR monotherapy could be a valuable option to preserve efficacy while sparing toxicity. ERMES is a phase III trial designed to test whether maintenance with cetuximab monotherapy after FOLFIRI plus cetuximab induction might represent a valid option in RAS/BRAF WT mCRC.

Study design

Patients with untreated RAS/BRAF WT mCRC were randomly assigned (1:1) to receive either FOLFIRI plus cetuximab until disease progression or toxicity (arm A) or FOLFIRI plus cetuximab for 8 cycles followed by cetuximab alone (arm B). Co-primary endpoints were non-inferior PFS in the modified per-protocol (mPP) population (patients treated beyond cycle 8) and lower incidence of grade ≥3 AEs for arm B compared to arm A. To test non-inferiority, 386 events were needed, and the upper HR boundary was set at 1.33. Secondary endpoints were PFS in the intent-to-treat (ITT) population (patients who received at least one dose), OS in mPP and ITT, objective response rate (ORR) and quality of life (QoL). Translational analyses on tissue sample and liquid biopsies were planned.

Results

From May 2015 to March 2020, 606 patients were randomised. Of them, 593 patients received at least one cycle of chemotherapy and were included in the mITT population. With a drop-out rate of approximately 40%, 154 patients received FOLFIRI plus cetuximab beyond cycle 8 in arm A and 183 patients received cetuximab monotherapy in arm B (mPP population of 337 patients). Median follow-up was 22.3 months. Despite the high drop-out rate, patient and disease characteristics were well balanced between both arms. With 291 events in the mPP population, the median PFS was 10.0 months in the experimental arm vs. 12.2 months in the control arm (HR[95%CI]: 1.30[1.03-1.64], p= 0.43). In subgroup analysis in the mPP population, the standard arm achieved a better performance in all subgroups. However, the quantitative interaction for primary tumour location in the sub-group analysis for PFS in mPP supports to investigate maintenance therapy with cetuximab monotherapy in left-site RAS/BRAF WT mCRC patients. In the ITT population, 503 events occurred with median PFS of 9.01 vs. 10.72 months (HR[95%CI]: 1.1[0.92-1.31], p= 0.305). Median OS was 36.6 in arm B vs. 30.7 months in arm A (HR[95%CI]: 0.81[0.6-1.09], p= 0.157) and 31.1 vs. 25.3 months (HR[95%CI]: 0.9[0.72-1.12], p= 0.327) in the mPP and ITT population, respectively. The ORR in the mPP population was 67.5% for arm A and 71.6% for arm B, with respectively 10.5% and 8.8% of complete responses. Grade ≥3 AEs were lower in arm B compared to arm A (39.9 vs. 44.2%): neutropenia (9.8 vs. 14.9%), febrile neutropenia (2.7 vs. 5.2%), diarrhoea (8.2 vs. 11%), oral mucositis (1.6 vs. 5.2%), fatigue (0.6 vs. 4.6%) and skin disorders (18 vs. 20.1%).

Conclusion

The ERMES trial does not demonstrate non-inferiority of maintenance with cetuximab monotherapy compared to FOLFIRI plus cetuximab until progression in terms of PFS in RAS/BRAF WT mCRC patients. As expected, patients enrolled in maintenance with cetuximab monotherapy experienced less grade ≥3 adverse events. OS analyses in mPP and mITT population showed a promising performance of the experimental arm, allowing to support the hypothesis that a de-escalation therapy has the potential to represent a valuable option for a selected RAS/BRAF WT population.

Reference

Orlandi A, et al. Phase III study with FOLFIRI/Cetuximab versus FOLFIRI/Cetuximab followed by Cetuximab (Cet) alone in first-line therapy of RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients: the ERMES Study (NCT02484833). Presented at ESMO 2022; Abstract LBA22.