Panitumumab

Dermatologic toxicities have been reported in 90% of patients receiving single agent panitumumab and were severe (grade 3 or higher) in 15% of patients; may include dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe skin toxicities may be complicated by infection, sepsis, necrotizing fasciitis, or abscesses. The median time to development of skin (or ocular) toxicity was 2 weeks, with resolution ~12 weeks after discontinuation. The severity of dermatologic toxicity is predictive for response; grades 2 to 4 skin toxicity correlates with improved progression free survival and overall survival, compared to grade 1 skin toxicity (Peeters 2009; Van Cutsem 2007). Monitor all dermatologic toxicities for development of inflammation or infection. Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported; bullous mucocutaneous disease (life-threatening/fatal) have been observed. Withhold treatment for severe or life-threatening dermatologic or soft tissue toxicities associated with severe/life-threatening inflammatory or infectious complications; dermatologic toxicity may require dose reduction or permanent discontinuation. Patients should minimize sunlight exposure and wear sunscreen and protective clothing/hat; sunlight may exacerbate skin reactions. Nail toxicity has also been reported.

May cause diarrhea; the incidence and severity of chemotherapy-induced diarrhea is increased with combination chemotherapy. Severe diarrhea and dehydration (which may lead to acute renal failure) has been observed with panitumumab in combination with chemotherapy. Gastric mucosal toxicity has also been reported.

Magnesium and/or calcium depletion may occur during treatment (may be delayed; hypomagnesemia occurred ≥8 weeks after completion of panitumumab) and after treatment is discontinued; electrolyte repletion may be necessary. Monitor for hypomagnesemia and hypocalcemia during treatment and for at least 8 weeks after completion. Hypokalemia has also been reported.

Severe infusion reactions (bronchospasm, dyspnea, fever, chills, and hypotension) have been reported in ~1% of patients; fatal infusion reactions have been reported with postmarketing surveillance. Discontinue infusion for severe reactions; permanently discontinue in patients with persistent severe infusion reactions. Appropriate medical support for the management of infusion reactions should be readily available. Mild to moderate infusion reactions are managed by slowing the infusion rate.

Keratitis and ulcerative keratitis (known risk factors for corneal perforation) have occurred. Monitor for evidence of ocular toxicity; interrupt or discontinue treatment for acute or worsening keratitis.

Pulmonary fibrosis and interstitial lung disease have been observed (rarely) in clinical trials; fatalities have been reported. Interrupt treatment for acute onset or worsening of pulmonary symptoms; permanently discontinue treatment if interstitial lung disease is confirmed. Patients with a history of or evidence of interstitial pneumonitis or pulmonary fibrosis were excluded from most clinical trials; consider the benefits of therapy versus the risk of pulmonary complications in such patients. Disease-related concerns:

Confirm absence of RAS mutation prior to treatment; patients with codons 12 and 13 (exon 2), codons 59 and 61 (exon 3), or codons 117 and 146 (exon 4) RAS (KRAS or NRAS) mutations are unlikely to benefit from EGFR inhibitor therapy. Panitumumab is not indicated in patients with RAS mutation-positive metastatic colorectal cancer or patients in whom RAS mutation status is unknown. Utilizing an anti-EGFR-directed antibody in patients whose tumors contain RAS mutations resulted in increased toxicity without clinical benefit. In a study of FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin) ± panitumumab, patients with a KRAS mutation who received panitumumab with FOLFOX4 experienced a significantly shortened progression-free survival (Douillard 2010). In addition, a subset analysis of patients with wild-type KRAS identified additional RAS (KRAS [exons 3 and 4] or NRAS [exons 2, 3, 4]) mutations; progression-free survival and overall survival were significantly shortened in patients with RAS mutations who received FOLFOX4 in combination with panitumumab (Douillard 2013). The American Society of Clinical Oncology (ASCO) provisional clinical opinion update recommends that all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy should be tested (in a certified lab) for mutations in both KRAS and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146); anti-EGFR monoclonal antibody therapy should only be considered in

In a study of bevacizumab with combination chemotherapy ± panitumumab, the use of panitumumab resulted in decreased progression-free and overall survival and significantly increased toxicity compared to regimens without panitumumab (Hecht 2009). Toxicities included rash/acneiform dermatitis, diarrhea/dehydration, electrolyte disturbances, mucositis/stomatitis, and an increased incidence of pulmonary embolism.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Patients >65 years of age receiving panitumumab plus FOLFOX experienced a higher incidence of serious adverse events including severe diarrhea.