November 12, 2019
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Addition of panitumumab to FOLFOXIRI improves response rates in colorectal cancer subtype

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Adding panitumumab to FOLFOXIRI chemotherapy improved rates of overall response and secondary resection of metastases among patients with RAS wild-type metastatic colorectal cancer, according to results of the randomized phase 2 VOLFI trial published in Journal of Clinical Oncology.

Further research is needed to determine whether the regimen, which serves as a new first-line treatment option for selected and fit patients, extends survival, according to researchers.

“Chemotherapeutic doublet regimens combined with monoclonal antibodies represent the standard of care in untreated metastatic colorectal cancer,” Dominik P. Modest, MD, oncologist in the department of medical oncology and comprehensive cancer center at University of Munich, and colleagues wrote. “To further increase efficacy, a triplet regimen, consisting of fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) was developed.”

Previous trials have tested FOLFOXIRI in combination with monoclonal antibodies that target VEGF or EGFR. However, no known randomized trial had compared FOLFOXIRI alone with FOLFOXIRI plus an anti-EGFR or anti-VEGF monoclonal antibody, researchers wrote.

Modest and colleagues evaluated whether panitumumab (Vectibix, Amgen), which targets EGFR, would improve efficacy of FOLFOXIRI among patients with untreated RAS wild-type metastatic colorectal cancer.

The researchers randomly assigned patients to modified FOLFOXIRI in combination with 6 mg/kg panitumumab (n = 63; median age, 58 years; range, 31-76; 65.1% men) or standard FOLFOXIRI alone (n = 33; median age, 60 years; range, 32-77; 72.7% men).

The final modified FOLFOXIRI regimen consisted of 150 mg/m2 irinotecan, 85 mg/m2 oxaliplatin, 200 mg/m2 folinic acid and 3,000 mg/m2 fluorouracil within 48 hours.

The control group received standard FOLFOXIRI consisting of 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin, 200 mg/m2 folinic acid and 3,200 mg/m2 fluorouracil within 48 hours.

Researchers repeated the treatments in both groups every 2 weeks until disease progression, resectability or up to a maximum of 12 cycles.

Researchers considered modified FOLFOXIRI with panitumumab active if the objective response rate reached or exceeded 75%. Researchers compared the ORR of the combination group with an estimated ORR for FOLFOXIRI alone of 60%, based on historical data.

ORR served as the primary endpoint. Secondary endpoints included PFS, OS, secondary resection rate and toxicity.

Median follow-up was 44.2 months in the panitumumab group and 63.3 months in the FOLFOXIRI-only group.

Results showed an ORR of 87.3% among patients treated with modified FOLFOXIRI plus panitumumab — exceeding the 75% threshold — compared with 60.6% among patients treated with FOLFOXIRI alone (OR = 4.47; 95% CI, 1.61-12.38). The panitumumab group also demonstrated a higher rate of secondary resection (33.3% vs. 12.1%; P = .02).

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OS results showed a positive trend among patients treated with panitumumab (median, 37.5 months vs. 29.8 months); however, this did not reach statistical significance (HR = 0.67; 95% CI, 0.41-1.11).

PFS was identical in both groups (median, 9.7 months; HR = 1.07; 95% CI, 0.69-1.67).

Grade 3 and grade 4 adverse events occurred among 81.3% of patients in the panitumumab group and 66.7% of patients in the control group. Common adverse events included fatigue, nausea, diarrhea, peripheral neuropathy, dermatitis acneiform and mucositis.

The study’s young patient population may not support generalizability of the results, which cannot be extrapolated to unselected or older patients, researchers wrote.

“In clinical practice, this four-drug regimen might be best for younger patients with little or no comorbidity in the context of intended conversion therapy or clearly symptomatic disease,” Modest and colleagues wrote. “Taking into account the unfavorable long-term survival in patients with right-sided metastatic colorectal tumors receiving anti-EGFR monoclonal antibodies, the regimen is ideally used in patients with left-sided primary tumors. Future studies are required to determine whether the addition of panitumumab to modified FOLFOXIRI prolongs survival.” – by John DeRosier

Disclosures: Modest reports advisory/consultant roles with and honoraria or travel accommodations from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche, Servier and Taiho Pharmaceuticals, and research funding to his institution from Amgen, Merck Serono and Roche. Please see the study for all other authors’ relevant financial disclosures.