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

Abstract

Purpose: This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods: Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.

Results: One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.

Conclusion: Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

Fig 1.

CONSORT diagram showing treatment assignment and patient disposition. (*) “Ongoing on study” refers to those patients who are either still receiving study treatment or are in the post-treatment follow-up period for adverse events (AEs), if any, and overall survival.

Fig 2.

(A) Kaplan-Meier plot of progression-free survival for all patients and (B) Forest plot for the subgroup analyses of progression-free survival. ECOG, Eastern Cooperative Oncology Group.

Fig 3.

Patient-reported outcomes for treatment-related adverse effects; mean change from baseline in (A) European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30: diarrhea, (B) EORTC QLQ lung module: sore mouth, (C) Dermatology Life Quality Index (DLQI) symptoms and feelings, and (D) DLQI total score. Higher scores indicate higher levels of symptoms or a higher degree of impairment of functioning; lower scores indicate fewer symptoms or a lower degree of impairment of functioning. Cycle 1 refers to cycle 1 days 10 to 14. Numbers below figures are n per cycle for each arm. EORTC scales are scored 0 to 100; DLQI total scores range from 0 to 30, and the DLQI subscale symptoms and feelings is scored 0 to 6. QD, once daily.

Fig A1.

Progression-free survival in (A) KRAS wild-type/EGFR any status, (B) KRAS wild-type and EGFR wild-type, and (C) EGFR mutant subgroups.

Fig A2.

Kaplan-Meier plot of overall survival for all patients. At the time of data cutoff (July 21, 2011), a total of 150 deaths (80%) had been observed (ie, 72 patients receiving dacomitinib and 78 patients receiving erlotinib), with 33 patients (18%) still being followed up and five lost to follow-up.

Fig A3.

C_trough concentrations in dose-compliant patients in the as-treated population for cycles 1 through 4 for (A) dacomitinib and (B) the active metabolite PF-05199265. The horizontal line in the interior of the box is at the median of the data. The height of the box is equal to the interquartile distance (the difference between third and first quartiles of the data). The whiskers (the lines extending from the top and bottom of the box) extend to the nearest value not beyond a standard span from the quartiles. The standard span is 1.5 times.