Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study
Study Overview
This clinical trial focused on metastatic colorectal cancer patients with RAS and BRAF wild-type status (1). It was a multicenter, open-label, randomized phase III noninferiority trial compared two treatment arms: one receiving fluorouracil, leucovorin, and irinotecan with cetuximab (FOLFIRI/Cet) until disease progression (arm A) and the other receiving FOLFIRI/Cet for eight cycles followed by cetuximab monotherapy (arm B). The study included 606 patients, with 300 in arm A and 306 in arm B.
The primary endpoints were progression-free survival (PFS) in the modified per-protocol (mPP) population and the incidence of grade 3-4 adverse events (AEs). The results showed that the PFS was 10 months for arm B and 12.2 months for arm A, not demonstrating noninferiority of maintenance with cetuximab alone. However, arm B exhibited a more favorable safety profile, with lower incidence of grade 3-4 AEs during the maintenance period compared to arm A (20.2% vs 35.1%).
In terms of overall survival (OS), arm B had a median OS of 35.7 months compared to 30.7 months in arm A in the mPP population, and 31.0 versus 25.2 months in the intention-to-treat population. Despite these findings, the study concluded that maintenance with single-agent cetuximab after induction with FOLFIRI/Cet cannot be recommended for all patients but could be an option in selected cases.
Epidemiology and Prognosis
The trial investigated metastatic colorectal cancer (mCRC) patients with RAS and BRAF wild-type status. Colorectal cancer is one of the most common cancers globally, with variations in incidence and mortality rates across different regions. In metastatic cases, prognosis is generally poor. For mCRC specifically, the median survival historically ranged from 6 to 12 months without treatment. However, advancements in therapy have improved median survival to over 30 months in some cases. The presence of RAS and BRAF wild-type status in patients has been associated with better responses to certain treatments, including anti-EGFR therapies like cetuximab, potentially improving outcomes. The prognostic significance of RAS and BRAF mutations lies in their association with resistance to these therapies, highlighting the importance of molecular profiling in treatment planning.
Standard Treatment
The standard treatment for metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type status often involves a combination of chemotherapy and targeted therapy. Typically, this includes a regimen of FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) in combination with anti-EGFR monoclonal antibodies like cetuximab or panitumumab. This trial aimed to explore the efficacy of maintenance therapy with cetuximab alone after an initial induction phase with FOLFIRI and cetuximab, potentially offering a less toxic treatment alternative while maintaining therapeutic effectiveness.
Clinical Implications
The trial's findings suggest that maintenance therapy with cetuximab alone after induction with FOLFIRI and cetuximab does not demonstrate noninferiority in progression-free survival compared to continuous treatment. However, it showed a more favorable safety profile with fewer high-grade adverse events. Clinically, this could mean that while continuous combination therapy may be more effective in controlling disease progression, cetuximab alone as maintenance could be considered for patients prioritizing quality of life or those with concerns about toxicity, particularly in the context of personalized treatment strategies. The study's impact lies in its potential to inform tailored treatment approaches in mCRC.
Reference
Pinto C, Orlandi A, Normanno N, Maiello E, Calegari MA, Antonuzzo L, Bordonaro R, Zampino MG, Pini S, Bergamo F, Tonini G, Avallone A, Latiano TP, Rosati G, Cogoni AA, Ballestrero A, Zaniboni A, Roselli M, Tamberi S, Barone C. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study. J Clin Oncol. 2024 Jan 5:JCO2301021. doi: 10.1200/JCO.23.01021. Epub ahead of print. PMID: 38181312.