Panitumumab Plus FOLFOX for KRAS Wild-Type Metastatic Colorectal Cancer


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New Indication for Panitumumab

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Panitumumab (Vectibix) was recently approved by the U.S. Food and Drug Administration (FDA) for use in combination with FOLFOX (fluorouracil, leucovorin, oxaliplatin) in first-line treatment of patients with wild-type KRAS (exon 2) metastatic colorectal cancer as determined by an FDA-approved test.1 The therascreen KRAS test (Qiagen) was simultaneously approved as a companion diagnostic test. Panitumumab should not be used in patients with KRAS-mutant metastatic colorectal cancer or in those with unknown KRAS mutation status.

Panitumumab was first approved by the FDA in 2006, for use in epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer that has progressed on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

Supporting Trial

The new indication was supported by the open-label phase III PRIME trial, in which 656 patients with wild-type KRAS (of 1,183 enrolled patients) were randomly assigned to panitumumab at 6 mg/kg given over 60 minutes plus FOLFOX (n = 325) vs FOLFOX alone (n = 331) every 14 days.1,2 The trial excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified primary endpoint in the wild-type KRAS population was progression-free survival. Overall, patients had a median age of 61.5 years, 64% were male, 92% were white, 66% had colon cancer, 34% had rectal cancer, and Eastern Cooperative Oncology Group performance status was 0 in 56% and 1 in 38%.

Median progression-free survival was 9.6 months in the panitumumab/FOLFOX group vs 8.0 months in the FOLFOX group (hazard ratio [HR] = 0.80, P = .02). The objective response rate was 54% vs 47%. In an exploratory analysis, median overall survival was 23.8 vs 19.4 months (HR = 0.83, 95% confidence interval = 0.70–0.98).

How It Works

Panitumumab is an EGFR antagonist. The interaction of EGFR with its normal ligands results in phosphorylation and activation of intracellular proteins that regulate transcription of genes involved in cell growth and survival, motility, and proliferation. Signal transduction through EGFR results in activation of wild-type KRAS protein, whereas KRAS-mutant protein is continuously active and appears independent of EGFR regulation in cells with activating KRAS somatic mutations.

Panitumumab binds specifically to EGFR on both normal and tumor cells and competitively inhibits the binding of EGFR ligands. Preclinical studies show that binding of panitumumab prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases and thus results in inhibition of cell growth, induction of apoptosis, decreased production of proinflammatory cytokines and vascular growth factor, and internalization of EGFR. Studies in vitro and in vivo in animals have shown that panitumumab inhibits the growth and survival of selected tumor cell lines expressing EGFR.

How It Is Given

Panitumumab is given at 6 mg/kg via intravenous infusion over 60 minutes (≤ 1,000 mg) or 90 minutes (> 1,000 mg) every 14 days. The infusion rate should be reduced by 50% for mild infusion-related reactions and infusion should be terminated for severe reactions. The drug should be withheld or discontinued for severe or intolerable dermatologic toxicity.

For grade 3 dermatologic toxicity, one or two doses should be withheld with reinitiation at the original dose if toxicity resolves to less than grade 3 after the first occurrence, at 80% of the original dose if toxicity resolution occurs after the second occurrence, and at 60% of the original dose if resolution occurs after the third occurrence. The drug should be permanently discontinued if there is a fourth occurrence of grade 3 toxicity.

Safety Profile

In the phase III trial, the most common adverse events of any grade in patients receiving panitumumab/FOLFOX were diarrhea (62% vs 52% in the FOLFOX group), rash (56% vs 7%), anorexia (36% vs 26%), acneiform dermatitis (32% vs 0%), and hypomagnesemia (30% vs 8%). The most common grade 3 or 4 adverse events were diarrhea (18% vs 9%), rash (17% vs < 1%), acneiform dermatitis (10% vs 0%), and hypokalemia (10% vs 5%). Deep-vein thrombosis occurred in 5.3% vs 3.1% of patients.

Serious adverse reactions that occurred with ≥ 2% greater frequency in the panitumumab/FOLFOX group were diarrhea and dehydration. Adverse events leading to discontinuation of treatment in ≥1% of panitumumab/FOFLOX patients were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One case of grade 5 hypokalemia was observed. In clinical trials of panitumumab monotherapy in 725 patients, 3% had infusion reactions, with a grade 3 or 4 reaction occurring in three patients (< 1%).

The incidence of neutralizing antipanitumumab antibodies (excluding preexisting and transiently positive patients) was 0.8% in 1,123 patients receiving monotherapy and (excluding preexisting positive patients) 0.2% in 1,297 receiving panitumumab in combination with chemotherapy. No evidence of an altered safety profile was found in patients who developed antibodies.

Panitumumab carries a boxed warning for dermatologic toxicity and infusion reactions. It also carries warnings/precautions for dermatologic and soft-tissue toxicity; increased tumor progression, increased mortality, or lack of benefit in patients with KRAS-mutant disease; electrolyte depletion; infusion reactions; pulmonary fibrosis/interstitial lung disease; and ocular toxicities.

Panitumumab recipients should be monitored for dermatologic and soft-tissue toxicities and should limit sun exposure. They should have electrolytes monitored regularly and should be monitored for keratitis or ulcerative keratitis. Panitumumab should be interrupted or discontinued in patients with acute or worsening keratitis and discontinued in patients developing interstitial lung disease.

Animal data suggest that panitumumab can cause fetal harm. Physicians are encouraged to enroll pregnant patients in Amgen’s pregnancy surveillance program. Nursing mothers should discontinue nursing or discontinue panitumumab.

Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088). ■

References

1. VECTIBIX® (panitumumab) injection for intravenous infusion, Amgen Inc, May 2014. Available at http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf.

2. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 28:4697-4705, 2010.


 



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