A phase II trial of erlotinib for EGFR mutant NSCLC to prospectively assess biopsy feasibility and acquired resistance at disease progression

Background: Erlotinib is a first-line therapy for patients (pts) with advanced EGFR mutant non-small cell lung carcinoma (NSCLC). However, tumors develop acquired resistance; choice of further therapy, including third-generation EGFR inhibitors in development, often depends on the mechanism driving resistance. We performed a prospective trial to assess biopsy feasibility and resistance mechanisms in EGFR mutant pts with acquired erlotinib resistance. Methods: Advanced, EGFR TKI naïve EGFR mutant NSCLC pts were enrolled in a phase II trial of erlotinib. At study entry, eligible pts consented to undergo re-biopsy at progression. The primary endpoint was feasibility of re-biopsy and evaluation of acquired resistance. Re-biopsies underwent pathology review and genomic analysis. Secondary objectives included evaluating biopsy features and reason(s) why re-biopsy could not be performed. Results: Between 02/10 and 1/15, 60 EGFR mutant pts (44 women, 34 never- smokers) were enrolled (L858R (17); exon 19 deletion (38); other (5)). 16 pts remain on study. Median age (range): 62.5 years (34-90). Median PFS: 11.0 months. 44 pts discontinued therapy (39 for progression, 5 for adverse events); 31 (70%) underwent re- biopsy. 8 pts did not undergo re-biopsy because of pt refusal (3); clinical contraindication (3); sudden death (1); or discovery of germline T790M (1). 31 re-biopsies identified: T790M mutation (17, 55%); SCLC transformation (3, 10%); no T790M or SCLC (6, 19%); inadequate tissue (3, 10%). Re-biopsy targeted enlarging lesions (26) and stable lesions (5), with T790M identified in 5/5 stable lesions and 12/26 enlarging lesions. Genotyping was done on effusions (3/4), lymph node (8/8), lung lesion (15/17), peritoneal deposit (1/1), and bone (1/1). Conclusions: Repeat biopsy at disease progression on first-line EGFR- directed therapy is feasible in 70% of pts and yields clinically meaningful results for subsequent therapy. It may be possible to identify resistance mechanisms from biopsy of focally stable yet easily accessible sites of disease. However, non-invasive means of detecting acquired resistance will be important, as re-biopsy is not always possible.