Irreversible and Reversible EGFR Inhibitors Are Directly Compared in NSCLC

Small-molecule reversible inhibitors of human epidermal growth factor receptor 1 (EGFR/HER1), such as erlotinib and gefitinib, are commonly used for the treatment of advanced non–small-cell lung cancers (NSCLC), which frequently harbor activating EGFR mutations. Second-generation EGFR inhibitors can irreversibly block receptor activity by covalently binding the ATP-binding pocket, and thus may lead to more potent kinase inhibition and antitumor activity. Ramalingam and colleagues conducted an open-label phase II trial to compare progression-free survival (PFS) in patients with advanced NSCLC who were randomized to receive dacomitinib, a pan-HER irreversible inhibitor targeting EGFR, HER2, and HER4, or erlotinib as a second- or third-line therapy. Dacomitinib led to a significant improvement in PFS compared with erlotinib (2.86 vs. 1.91 months), particularly in wild-type KRAS tumors regardless of EGFR status (3.71 vs. 1.91 months). However, there was no improvement in PFS among patients with EGFR-mutant tumors (7.44 vs. 7.44 months), raising the possibility that the overall improvement in PFS in patients treated with dacomitinib is attributable to permanent blockade of multiple HER family receptors instead of EGFR alone. Overall, compared with erlotinib, dacomitinib also significantly increased the objective response rate (17.0% vs. 5%, including 1 complete response), clinical benefit response rate (29.8% vs. 14.9%), and median duration of response (16.56 vs. 9.23 months), and had a favorable, but non–statistically significant effect on overall survival (9.53 vs. 7.44 months). Dacomitinib was generally well tolerated, with manageable dermatologic and gastrointestinal side effects, and improved patient-reported outcomes pertaining to quality of life and disease-related symptoms. Collectively, these results suggest that irreversible pan-HER inhibitors may be an effective alternative to single-target, reversible HER inhibitors in advanced NSCLC and have led to initiation of a phase III study.

Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non–small-cell lung cancer. J Clin Oncol 2012 Jul 2 [Epub ahead of print].

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