Drug Interactions between oxaliplatin and panitumumab

GENERALLY AVOID: Coadministration of panitumumab with oxaliplatin-based chemotherapy may negatively affect the clinical outcome in patients with mutant RAS metastatic colorectal carcinoma (mCRC) and those with ECOG (Eastern Cooperative Oncology Group) 2 performance status. The mechanism of interaction has not been described. In a phase 3 study consisting of 1183 subjects, of which 656 had wild-type KRAS and 440 had mutant KRAS (exon 2) mCRC, a significant shortening of progression-free survival (PFS) was observed in subjects with mutant KRAS tumors who received panitumumab in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as first-line therapy compared to those who received FOLFOX alone (median 7.4 vs 9.2 months). A trend toward shortened overall survival (OS) time was also observed in the mutant KRAS mCRC population for panitumumab and FOLFOX relative to FOLFOX alone (median 15.5 vs 19.2 months). In the same study, an exploratory covariate analysis according to ECOG status in subjects with wild-type KRAS mCRC showed that patients with ECOG 2 performance status (n=40) had increased toxicity and significant shortening of PFS (median 4.8 vs 10.8 months) and OS (median 7.0 vs 25.8 months) when given panitumumab plus FOLFOX compared to patients with ECOG 0 or 1 performance status (n=616). Moreover, PFS and OS were shortened in the ECOG 2 patients given panitumumab plus FOLFOX versus FOLFOX alone (median 4.8 vs 7.5 months and 7.0 vs 11.7 months, respectively). A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) mCRC from the phase 3 study identified additional RAS (KRAS [exons 3 and 4] or NRAS [exons 2, 3, 4]) mutations in 17% (n=108) of patients. A shortening of PFS and OS was also observed in the patients who received panitumumab in combination with FOLFOX (n=51) versus FOLFOX alone (n=57). In elderly patients overall, an increased number of serious adverse events were reported for panitumumab in combination with FOLFOX compared to chemotherapy alone (52% vs 37%). The most increased serious adverse event was severe diarrhea.

MANAGEMENT: Panitumumab should not be used in combination with oxaliplatin-based chemotherapy in patients with mutant RAS mCRC or in whom RAS mCRC status is unknown. RAS mutational status should be determined using a validated test method by an experienced laboratory. For patients with ECOG 2 performance status, assessment of risks versus benefits is recommended prior to initiation of panitumumab in combination with oxaliplatin-based chemotherapy for the treatment of mCRC. A positive benefit-risk balance has not been documented in this population.

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