A phase II study of BIBW 2992, a novel irreversible dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in patients with adenocarcinoma of the lung and activating EGFR mutations after failure of one line of chemotherapy (LUX-Lung 2)

Abstract

8013 Background: EGFR mutations are associated with exquisite sensitivity to EGFR TKIs in NSCLC. A phase II trial evaluating the efficacy of BIBW 2992 (Tovok), a novel, potent, irreversible, dual EGFR and HER2 TKI with preclinical activity in cell lines harboring activating (H3255, IC50=0.7 nM) and resistant (H1975, IC50=99 nM) EGFR mutations, is reported. Methods: Objective response rate is the primary endpoint of this 2-stage trial. Based on 16 or more unconfirmed PRs in an interim analysis of the first 40 2nd line patients (pts) completing 1 course (28 days), accrual will continue to a total of 120 1st and 2nd line pts (expected completion of accrual by May 2009. Data on 2nd line pts only are presented). Eligible pts have stage IIIB/IV lung adenocarcinoma, EGFR mutation in exons 18–21 (tested by direct sequencing), measurable disease, ECOG PS 0–2 and adequate end organ function. Pts receive 50 mg BIBW 2992 qd until progression. Tumor assessments are performed every 4 weeks for 12 weeks, then every 8 weeks. Results: Since Oct 2007, samples from 289 pts (222 from Taiwan and 67 from the US) have been sequenced. 100 had detectable EGFR mutations including del19 (n=39), L858R (n=45) and others (n=16). 69 pts have started treatment. The trial was moved to stage 2 after 21 of the first 38 treated pts had objective response at 28 days. Of 55 evaluable 2nd line pts, 29 (53%) had PR, and 23 (42%) had SD. Median follow up is 5.1 months. Most common related AEs were diarrhea and skin-related AEs, reported in 87% and 88% of pts, respectively. 27 pts (42.9 %) had dose reduction to 40 mg and 7 pts (11%) to 30 mg but only 1 pt permanently discontinued due to AEs. Diarrhea and rash were main causes of dose reduction. Conclusions: In the 2nd line setting, BIBW 2992 shows efficacy in NSCLC harboring EGFR activating mutations. Diarrhea and skin disorders, the most frequently observed AEs, are manageable with supportive care and dose reduction. Updated response and disease control rates and preliminary progression-free survival data will be presented. An international Phase III trial program investigating BIBW 2992 in NSCLC, LUX-Lung, is now recruiting. [Table: see text]