No Survival Benefit With Pan-HER Tyrosine Kinase Inhibitor Dacomitinib vs Placebo in Pretreated Advanced NSCLC
In the phase III NCIC CTG BR.26 Trial reported in The Lancet Oncology, Ellis et al found that treatment with the irreversible pan-HER tyrosine kinase inhibitor dacomitinib was not associated with an overall survival benefit compared with placebo in patients with pretreated advanced or metastatic non–small cell lung cancer (NSCLC).
Study Details
In this double-blind trial, 720 patients from 75 centers in 12 countries were randomly assigned 2:1 between December 2009 and June 2013 to receive oral dacomitinib 45 mg once daily (n = 480) or placebo (n = 240) until disease progression or unacceptable toxicity. Patients had received three or fewer previous lines of chemotherapy and either gefitinib (Iressa) or erlotinib. The primary endpoint was overall survival in the intention-to-treat population. The study is completed, but follow-up is ongoing for patients on treatment.
The dacomitinib and placebo groups were generally balanced for baseline characteristics, including age (median, 64 and 66 years, 46% and 53% ≥ 65 years), sex (51% and 50% male), Eastern Cooperative Oncology Group performance status (0 or 1 in 75% and 76%), never smoker status (36% and 35%), histology (adenocarcinoma in 75% and 70%), ethnicity (60% white in both, 29% East Asian in both, 6% and 7% other Asian), previous chemotherapy regimens (2 in 60% and 62%, ≥ 3 in 12% in both), best response to previous EGFR tyrosine kinase inhibitor (complete or partial response in 13% in both), previous pemetrexed (Alimta) for advanced disease (59% and 53%), measurable disease (94% and 95%), EGFR status (mutant in 24% and 28%, wild-type in 49% and 48%, unknown in 27% and 24%), and KRAS status (mutant in 12% and 9%, wild-type in 46% and 50%, unknown in 42% and 41%).
Overall Survival, Other Outcomes
Median follow-up was 23.4 months for patients in the dacomitinib group and 24.4 months for those in the placebo group. Median overall survival was 6.83 months (95% confidence interval [CI] = 6.08–7.49) vs6.31 months (95% CI = 5.32–7.52; hazard ratio [HR] = 1.00, P = .506). Median progression-free survival was 2.66 vs 1.38 months (HR = 0.66, P < .0001) and objective response rates were 7% vs 1% (P = .001).
Postprogression therapy was received by 37% of the dacomitinib group and 41% of the placebo group, including pemetrexed in 9% and 6% and the EGFR tyrosine kinase inhibitor afatinib (Gilotrif) in 6% and 7%.
The effect of dacomitinib on overall survival was similar in patients with EGFR mutant tumors (HR = 0.98, 95% CI = 0.67–1.44) and in those with EGFR wild-type tumors (HR = 0.93, 95% CI = 0.71–1.21; P = .69 for interaction), but there was some evidence of a differential effect in patients with KRAS-mutant tumors (HR = 2.10, 95% CI = 1.05–4.22) vs KRAS wild-type tumors (HR = 0.79, 95% CI = 0.61–1.03; P = .08 for interaction).
Dacomitinib patients had significantly longer time to deterioration of cough (P < .0001), dyspnea (P = .049), and pain (P = .041).
Adverse Events
Serious adverse events occurred in 39% of the dacomitinib group vs 36% of the placebo group. The most common grade 3 or 4 adverse events were diarrhea (12% vs 0%), acneiform rash (10% vs < 1%), oral mucositis (3% vs 0%), and fatigue (3% vs 2%).
The investigators concluded: “Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor.”
Peter Ellis, PhD, of Juravinski Cancer Centre, Hamilton, is the corresponding author for the Lancet Oncology article.
The study was funded by the Canadian Cancer Society Research Institute and Pfizer. For full disclosures of the study authors, visit www.thelancet.com.
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