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FOLFOXIRI plus cetuximab active, feasible for metastatic colorectal cancer
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A 4-month course of induction therapy with modified FOLFOXIRI and cetuximab produced significant activity and appeared feasible for patients with RAS and BRAF wild-type metastatic colorectal cancer, according to researchers in Italy.
“The triplet FOLFOXIRI (fluorouracil, oxaliplatin and irinotecan hydrochloride) plus bevacizumab is regarded by major guidelines as a safe and efficacious first-line therapeutic option for selected patients with metastatic colorectal cancer,” Alfredo Falcone, MD, Azienda Ospedaliera-Universitaria Pisana in Italy, and colleagues wrote. “...Preclinical data show that the selective pressure of [epidermal growth factor receptor (EGFR)] inhibitors might lead to the activation of proangiogenic pathways. Based on this finding, tumors treated with anti-EGFR agents may be more sensitive to antiangiogenic agents, thus providing a sound biological rationale for investigating the potential efficacy of the sequential administration of an anti-EGFR agent and an anti-vascular endothelial growth factor agent.”
The researchers performed a prospective, noncomparative, open-label randomized phase 2 trial of patients with untreated RAS and BRAF wild-type metastatic colorectal cancer (n = 143). The patients were recruited from 21 oncology units throughout Italy. Falcone and colleagues randomly assigned patients to receive an induction regimen of modified FOLFOXIRI and cetuximab every 2 weeks for up to eight cycles, followed by either cetuximab (n = 74) or bevacizumab (n = 69). Progression-free rate at 10 months served as the main outcome. Secondary outcomes included OS, PFS, response rate, adverse events and rate of metastases resection.
A total of 116 patients (81.1%) had RAS and BRAF wild-type disease. The median age was 59.5 years, and 34 (29.3%) were women.
The 10-month progression-free rate was 50.8% for the cetuximab arm and 40.4% (90% CI, 29.4-52.1) in the bevacizumab arm after a median follow-up of 44 months.
Patients demonstrated an overall response rate of 71.6% (95% CI, 62.4-79.5). The most common grade 3 or grade 4 adverse event included neutropenia (31%; n = 36), diarrhea (n = 21; 18%), skin toxic effects (n = 18; 16%), asthenia (n = 11; 9%), stomatitis (n = 7; 6%) and febrile neutropenia (n = 3; 3%).
“Neither of the two arms ... met the primary endpoint of demonstrating a relevant increase in [10-month progression-free rate] against literature data with doublets plus anti-EGFR,” the researchers wrote.
However, modified FOLFOXIRI plus cetuximab appeared to be a feasible first-line treatment, according to Falcone and colleagues. – by Andy Polhamus
Disclosures: Falcone reports grants from Amgen, F. Hoffman-La Roche and Merck Serono, as well as personal fees from Bayer, Celgene and Sanofi Aventis. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
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There has been great interest in defining the best first-line treatment option for metastatic colorectal cancer. At present the most commonly used regimen for upfront therapy in the United States is FOLFOX -/+ bevacizumab. Per NCCN guidelines, FOLFIRI -/+ bevacizumab is also acceptable and in certain settings FOLFOXIRI plus bevacizumab has shown a PFS benefit but with a significant increase in grade 3 to grade 4 toxicities. A pooled analysis showed both a PFS and OS benefit with FOLFOXIRI plus bevacizumab from conversion of liver-limited metastatic disease to resectability. All these regimens are active regardless of RAS/BRAF mutation status. There is good evidence from the CRYSTAL and FIRE3 trials that FOLFIRI plus cetuximab in the frontline setting is preferred for left sided RAS/RAF wild-type metastatic colorectal cancer tumors and the FOLFIRI/cetuximab regimen is not recommended for right-sided wild-type RAS/BRAF metastatic colorectal cancer tumors.
The MACBETH — a randomized phase 2 trial — looked at whether 4 months of FOLFOXIRI plus cetuximab in the frontline setting followed by randomization to cetuximab or bevacizumab maintenance might offer an advantage over other frontline therapy regimens for RAS/BRAF wild-type colorectal cancers. Although the results showed that the FOLFOXIRI plus cetuximab is not obviously superior to historical results with other regimens — the study did not meet its primary endpoint — the overall response rate (71.6%) was high with evidence the upfront FOLFOXIRI plus cetuximab regimen is active and allows patients to get to surgery. This high ORR occurred even with induction treatment duration reduced to 4 months, but perhaps might have impacted on the trial achieving its primary endpoint. Cetuximab maintenance appeared feasible with greater skin toxicity than with bevacizumab maintenance. However, bevacizumab was used as monotherapy in the maintenance setting, which was not optimal as it is typically combined with 5-fluorouracil in that setting. There was no information provided on right- vs. left-sided primary tumors among the treated patients. The dose of 5-fluorouracil infusion was 2400 mg/m2 over 48 hours and irinotecan (130 mg/m2) compared with the 5-fluorouracil dose that is commonly used with FOLFOXIRI (3200 mg/m2 5-fluorouracil) and the irinotecan dose (165 mg/m2), perhaps leading to lesser toxicity that would be expected by adding cetuximab. Overall, the toxicity profile of the modified FOLFOXIRI regimen in combination with cetuximab appeared comparable to the original FOLFOXIRI plus bevacizumab regimen. The study was not designed to compare the two maintenance arms, although the observed median OS was comparable. FOLFOXIRI plus cetuximab is feasible and can be considered in the frontline setting for wild-type RAS/BRAF metastatic colorectal cancer given the observed high ORR in the MACBETH trial, although more data are needed on differences between right- and left-sided primary tumors. FOLFOXIRI plus cetuximab probably should not be used to treat right-sided wild-type RAS/BRAF metastatic colorectal cancer tumors in the absence of more definitive data to address use in that setting. It is unclear what the optimal maintenance therapy is after that regimen and more studies are needed to address that as there is a paucity of studies looking at cetuximab or panitumumab in the maintenance setting and the present study was not designed to compare the maintenance regimens.
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