Panitumumab Not Inferior to Cetuximab in Overall Survival in Chemotherapy-Refractory Wild-Type KRAS Metastatic Colorectal Cancer
In the open-label noninferiority phase III ASPECCT trial reported in The Lancet Oncology, Price et al found that anti-EGFR monoclonal antibody treatment with panitumumab (Vectibix) produced a noninferior overall survival outcome vs cetuximab (Erbitux) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer.
Study Details
In the study, 999 patients (from centers in North America, South America, Europe, Asia, Africa, and Australia) with chemotherapy-refractory metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and wild-type KRAS exon 2 were randomly assigned between February 2010 and July 2012 to receive panitumumab at 6 mg/kg once every 2 weeks (n = 499) or cetuximab at an initial dose of 400 mg/m² and 250 mg/m² once a week thereafter (n = 500).
Patients had to have clinical or radiologic disease progression on or intolerance to irinotecan-based and oxaliplatin-based therapy and to have previously received a thymidylate synthase inhibitor (including fluorouracil [5-FU], capecitabine, raltitrexed, or 5-FU–uracil) and could not have received previous anti-EGFR therapy. The primary endpoint was overall survival assessed for noninferiority (retention of ≥ 50% of the cetuximab treatment effect, with a historical hazard ratio [HR] of 0.55 for cetuximab plus best supportive care vs best supportive care alone).
The panitumumab and cetuximab groups were generally balanced for age (median, 61 and 60.5 years), sex (63% and 64% men), ethnic origin (53% and 52% white, 44% and 46% Asian), median time from primary (25.3 and 27.0 months) and metastatic diagnosis (19.6 vs 19.8 months), ECOG performance status (0 in 31% and 33%, 1 in 61% and 59%, 2 in 8% in both), location of primary (colon in 59% and 65%), histologic type (no subtype in 39% and 38%, mucinous in 10% and 9%), prior bevacizumab (Avastin; 25% and 26%), liver-only metastatic disease (10% in both), and region (eg, North America, western Europe, Australia for 31% in both).
Noninferior in Overall Survival
Median follow-up was 41.4 weeks in the panitumumab group and 40.5 weeks in the cetuximab group. Postprogression therapy was used in 41% vs 42% of patients, including cytotoxic chemotherapy in 31% vs 33%, anti-EGFR monoclonal antibodies in 9% vs 10%, and anti-VEGF therapy in 7% vs 7%. Median overall survival was 10.4 months vs 10.0 months (HR = 0.97, 95% confidence interval [CI] = 0.84–1.11), with panitumumab meeting the noninferiority criterion (Z score −3.19, P = .0007). Panitumumab retained 105.7% (95% CI = 81.9%–129.5%) of the effect of cetuximab on overall survival.
There were no differences in overall survival in any predefined subgroups. There was no difference in progression-free survival (median, 4.1 vs 4.4 months, HR = 1.00, 95% CI = 0.88–1.14). Among patients with measurable disease, complete response occurred in < 0.5% vs 0% and partial response in 22% vs 20%.
Adverse Events
Adverse events of any grade occurred in 98% of patients in both groups. Grade 3 and 4 adverse events occurred in 36% and 7% of panitumumab patients vs 32% and 5% of cetuximab patients, and serious adverse events occurred in 30% vs 34%. Treatment-related adverse events led to treatment discontinuation in 3% vs 3% and to dose reduction in 35% vs 36%. The incidence of infusion reactions was lower in the panitumumab group (3% vs 13%, grade 3 or 4 in < 0.5% vs 2%).
Grade 3 or 4 hypomagnesemia occurred in 7% vs 3% of patients, and hypomagnesemia led to discontinuation of treatment in 1% vs < 0.5% and dose modification in 5% vs 3%. Grade 3 and 4 skin and subcutaneous tissue toxicity occurred in 12% and < 0.5% vs 10% and 0% of patients. Grade 5 adverse events occurred in 6% and 10% of patients, with most fatal adverse events being related to disease progression; the only fatal adverse event considered related to study treatment was lung infection in a cetuximab patient.
The investigators concluded, “Our findings show that panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. The authors suggested that given the consistency in efficacy and toxicity, “small but meaningful differences in the rate of grade 3-4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment.”
Timothy J. Price, MBBS, of The Queen Elizabeth Hospital, Woodville, Australia, is the corresponding author for The Lancet Oncology article.
The study was funded by Amgen Inc. For full disclosures of the study authors, visit www.thelancet.com.
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