Panitumumab was FDA approved in the United States in 2006 as monotherapy for the treatment of metastatic EGFR-expressing colorectal cancer after disease progression on or following fluorouracil(Drug information on fluorouracil) (5-FU)-, oxaliplatin(Drug information on oxaliplatin) (Eloxatin)-, or irinotecan(Drug information on irinotecan) (Camptosar)-containing chemotherapy regimens, based on a phase III trial that showed it prolonged disease-free survival, compared with best supportive care (Van Cutsem et al: J Clin Oncol 25:1658-1664, 2007).
Investigators at the GI cancers meeting reported results for panitumumab as a single agent and in combination with other agents in the first- and second-line metastatic treatment settings.
An interim analysis of the randomized open-label PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study showed that adding panitumumab to first-line chemotherapy-plus-bevacizumab (Avastin) regimens for metastatic disease offered no additional benefits in terms of progression-free or overall survival, while toxicity was increased.
In March 2007, the data monitoring committee recommended discontinuation of panitumumab dosing in the
PACCE study after the drug demonstrated no additional benefit but more toxicity.
PACCE evaluated bevacizumab(Drug information on bevacizumab) plus standard chemotherapy—irinotecan based or oxaliplatin based—with or without panitumumab 6 mg/kg every 2 weeks until disease progression.
FOLFOX/panitumumab
Results of the oxaliplatin-based (FOLFOX) comparisons in 823 patients (abstract 273) were presented at the meeting by Edith Mitchell, MD, professor of medicine, Thomas Jefferson University.
At a median follow-up of 12.2 months, progression-free survival was shorter in the panitumumab arm, dose intensity was lower, and toxicity was increased, “indicating that this combination has an unfavorable benefit-to-risk profile in unselected patients with metastatic colorectal cancer,” Dr. Mitchell reported.
Progression-free survival was 19.4 months in the panitumumab arm but has not been reached in the control arm, for a 43% increased chance of progression with panitumumab (see Table 1).
Grade 3-4 adverse events were also higher with panitumumab, especially skin toxicity (36% vs 1%).
“This was expected, but we also saw more grade 3-4 diarrhea (24% vs 13%), infections (18% vs 10%), dehydration (17% vs 6%), hypokalemia (10% vs 4%), and other toxicities in this arm,” she said.
FOLFIRI/panitumumab
J. Randolph Hecht, MD, associate professor of hematology/oncology, UCLA School of Medicine, presented the data for the irinotecan-based chemotherapy (FOLFIRI, Douillard regimen) comparisons in 230 patients (abstract 279).
He reported that the response rates appeared higher in panitumumab-treated patients (due to higher responses associated with wild type KRAS). However, no significant differences were observed in progression-free survival or overall survival (see Table 2).
“However, most patients withdrew due to nonprogressive events (59% on the panitumumab arm and 71% on the standard arm), similar to the oxaliplatin chemotherapy cohort. This limits the utility of progression-free survival as a valid endpoint in this study,” Dr. Hecht commented.
By local review, overall response rates by KRAS status were 70% in patients with wild type KRAS receiving panitumumab, compared with 59% receiving standard therapy, for an odds ratio of 1.71. Patients with mutant KRAS had similar response rates to either regimen, 41% and 44%, respectively. This analysis was not powered for statistical significance and is descriptive only, he said.
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Oncology NEWS International. Vol. 13 No. 3 Panitumumab effective in normal KRAS subset
By Caroline Helwick |
March 1, 2008
Does one study raise questions about another? CHARLES BLANKE, MD — Commenting on the panitumumab (Vectibix) studies presented at the 2008 GI Cancers Symposium, Dr. Blanke, professor of medicine, Oregon Health and Science University, called the findings “not really surprising, though disappointing.” PACCE was a well-conducted trial that showed a negative result when panitumumab was given with chemotherapy plus bevacizumab (Avastin) in the first-line setting, he said. The negative effect on progression-free survival may be partly related to the higher toxicity in the panitumumab arms. “The severe toxicity and death rates were doubled with antibody therapy, and this merits more scrutiny,” he said. The data raised other questions: • Should the US Intergroup CALGB 80405 study be closed? • Can KRAS be used to make decisions for the individual patient? In CALGB 80405, more than 2,000 patients will receive combination chemotherapy with either FOLFIRI or FOLFOX (physicians’ choice), then be randomized to receive bevacizumab, cetuximab (Erbitux), or both monoclonal antibodies. This study should help determine the relative benefit of chemotherapy plus either targeted agent or the combination in prolonging survival, and will provide safety data for using combinations of biologics, Dr. Blanke said. “I do not believe that we should close CALGB 80405 based on negative results with panitumumab plus chemotherapy,” he said. “The two antibodies are different agents with different binding affinities, and different effects on the target and ultimately on the cellular level.” Furthermore, cetuximab is supported by “a large amount of background efficacy data” for its combination with chemotherapy, and bevacizumab has shown a survival benefit in colorectal cancer, he pointed out. “And in early analyses, no danger signal has emerged for these combinations of therapeutic agents,” Dr. Blanke added. As for the utility of KRAS in selecting patients, “We cannot say anything definitively—yet,” he said. “Wild type patients had higher responses across the board, but can KRAS guarantee benefit from panitumumab? No. We don’t see a 100% response rate in wild type patients.” Dr. Blanke noted that some experts are already suggesting that patients with mutant KRAS be excluded from anti-EGFR antibody studies, “but this information is based mostly on small numbers and needs absolute validation in prospective trials,” he said. Meanwhile, in clinical trials, he said, “we should stratify patients according to KRAS mutational status and collect tissue for correlative analyses.” |
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