COMMENTARY

Does Dacomitinib Offer Improvement Over Erlotinib in NSCLC?

Howard (Jack) West, MD

Disclosures

December 10, 2012

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

Ramalingam SS, Blackhall F, Krzakowski M, et al
J Clin Oncol. 2012;30:3337-3344

Next-Generation EGFR Inhibitors

The LUX-Lung 3 trial[1] compared afatinib, the irreversible inhibitor of the HER family, with standard chemotherapy in patients with previously untreated advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The question has emerged as to whether afatinib and the class of "next-generation EGFR inhibitors" provide a clinically significant benefit over the reversible and specific EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib.

Study Summary

The randomized phase 2 trial by Ramalingam and colleagues, which directly compared dacomitinib (PF-00299804) with erlotinib in previously treated but EGFR inhibitor-naive patients with advanced NSCLC, provides some helpful insight in a molecularly unselected patient population. The study is particularly relevant for most patients in North America who do not have an activating EGFR mutation.

The trial enrolled 188 patients who had received previous chemotherapy but not EGFR-based targeted therapy. The groups were well balanced except for baseline performance status score of 2 (19 in the dacomitinib group, 3 in the erlotinib group), presence of EGFR mutation (19 in the dacomitinib group, 11 in the erlotinib group), and number of patients receiving 2 previous chemotherapy regimens (40 in the dacomitinib group, 29 in the erlotinib group). Patients were randomly assigned (1:1) to dacomitinib at 45 mg orally daily or to erlotinib 150 mg orally daily. The primary endpoint of the trial was progression-free survival (PFS).

Efficacy across multiple parameters clearly favored dacomitinib. The response rate was 17.0% vs 5.3% (P = .011), and clinical benefit, combining objective responses with stable disease > 24 weeks, was 29.4% vs 14.9% (P =.014), with a duration of response also favoring dacomitinib (16.6 vs 9.2 months). PFS was statistically superior for dacomitinib (median, 2.9 vs 1.9 months; hazard ratio [HR], 0.66; P = .012). Of importance, the benefit in PFS was seen across nearly all clinically and molecularly defined subgroups, including KRAS mutation-positive patients (median, 3.7 vs 1.9 months; HR, 0.55; P =.006), KRAS and EGFR wild-type (median, 2.2 vs 1.8; HR, 0.61; P = .043), and EGFR mutation-positive patients (although 7.4 months for both groups, the HR of 0.46 favored dacomitinib, P = .098). Overall survival (OS) was not statistically significantly different between the 2 groups, but the median OS was 2 months longer in the dacomitinib group (9.5 vs 7.4 months; HR, 0.80; P = .205).

The leading challenge was the higher toxicity with dacomitinib. Dacomitinib was associated with more diarrhea (73% vs 48%), dermatitis acneiform (64% vs 57%), stomatitis (29% vs 11%), paronychia (26% vs 8%), and several other less common side effects. More patients assigned to dacomitinib required dose reduction (41% vs 17%), and more patients required withdrawal of treatment (7 vs 2 patients).

Viewpoint

This agent certainly has promise if the toxicity issues can be addressed. The fact that this agent appears likely to be meaningfully superior to erlotinib for a broad NSCLC population, and particularly for patients with a KRAS mutation and/or EGFR wild-type, suggests that it could prove to be a valuable treatment option. We await the results of an ongoing phase 3 randomized, double-blind study of dacomitinib vs erlotinib, and I suspect that it will be important for clinicians to learn how to manage the side effects proactively before it is embraced as an appealing treatment approach in the palliative setting for previously treated advanced NSCLC.

Abstract

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