1. Fuerst, Mark L.

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A combination of doublet chemotherapy plus cetuximab is effective as first-line treatment for patients with RAS wild-type metastatic colorectal cancer (CRC). According to the National Comprehensive Cancer Network guidelines, RAS wild-type left-sided metastatic CRC patients should start with anti-epidermal growth factor receptor (EGFR) therapy. For example, cetuximab or panitumumab, plus doublet chemotherapy with leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) or folinic acid, fluorouracil, and irinotecan (FOLFIRI) as first-line treatment.

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"This has been shown to improve survival times in multiple Phase III studies when compared to bevacizumab plus doublet chemotherapy. In some cases, results of RAS mutational analysis may still be pending at the time of initiating systemic treatment," said Sebastian Stintzing, MD, Professor at the Charite Universitatsmedizin Berlin in Germany.


At the 2023 ASCO Gastrointestinal Cancers Symposium, Stintzing reported results from the randomized, controlled, open-label, Phase III FIRE-4 study (Abstract 100). This study tested the efficacy of early switch maintenance during first-line therapy (Part 1) and re-challenge with cetuximab (Part 2) in later-line treatment.


In Part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab. In Arm A, patients were randomized to continue therapy until progression or intolerable toxicity. In Arm B, patients received FOLFIRI plus cetuximab for 8-12 cycles, after which they received maintenance therapy with 5-fluorouracil-folinic acid plus bevacizumab. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong progression-free survival (PFS).


"One cycle of FOLFIRI without the admission of any antibody was allowed per protocol. When compared to patients treated with cetuximab from the first cycle, neither tumor response rates nor survival times were negatively impacted. Therefore, it may be feasible to start with doublet chemotherapy without any monoclonal antibody adding anti-EGFR antibodies or bevacizumab according to the RAS testing result in later cycles," said Stintzing.


Study Details

The trial randomized 672 patients and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 in Arm A and 329 in Arm B). Of those, 205 patients received 1 cycle of FOLFIRI alone before randomization.


In both arms, overall response rate was comparable for patients receiving cetuximab from the first cycle when compared to those receiving 1 cycle of chemotherapy only-Arm A with 58.7 percent versus 62.9 percent, and Arm B with 60.2 percent versus 55.6 percent. PFS was also not influenced in both arms (Arm A: 10.8 months vs. Arm B: 10.6 months; Arm B: 11.2 months vs. 11.4 months). Preliminary results also suggest that overall survival (event rate 38.3%) was not influenced by 1 cycle applied without cetuximab (Arm A: 33.7 months vs. 29.1 months; Arm B: 35.6 months vs. 28.9 months).


"Application of one initial cycle with chemotherapy alone did not influence the efficacy of a first-line strategy of FOLFIRI plus cetuximab," Stintzing noted. "If RAS mutational analysis is not timely available, a start with FOLFIRI alone adding cetuximab in Cycle 2 seems to be safe with respect of overall efficacy."


ASCO expert in gastrointestinal cancers Cathy Eng, MD, Professor of Medicine at Vanderbilt University Medical Center, commented: "The FIRE-4 trial demonstrates that 1 cycle of standard chemotherapy prior to randomization for a clinical trial does not negatively compromise the primary endpoint of PFS. The flexibility of this clinical trial design should be considered for any clinical trial that incorporates the standard of care. This approach will help reduce patient and provider concerns pending RAS status and improve patient enrollment to clinical trials."


Mark L. Fuerst is a contributing writer.