A multicenter phase II study to evaluate efficacy and safety of gefitinib as the first-line treatment for Korean patients (pts) with advanced pulmonary adenocarcinoma harboring EGFR mutations

초록

Background: This study (D7913L00056) was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in pts with advanced pulmonary adenocarcinoma harboring EGFR mutations and to explore the molecular factors affecting the efficacy of gefitinib. Methods: Chemo-naïve pts with advanced (stage IIIB/IV/recurrent disease) pulmonary adenocarcinoma underwent direct DNA sequencing of tumor EGFR exons 18, 19 and 21. Pts with EGFR mutations received gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). The protocol planned to accrue 45 pts with EGFR mutations in a single stage. Results: Out of 147 screened pts, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (del 19, 29 pts, 64%) and L858R point mutations in exon 21 (L858R, 15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR by RECIST was 53.3% (95% CI, 38.8 to 67.9) and disease control rate (DCR) including stable disease was 86.7%. Progression free survival (PFS) at 12 months (mo) was 74.6% (95% CI, 58.8 to 85.1). Median PFS was not reached after median 10.1 mo follow-up. Treatment was well tolerated. Six pts experienced grade 3 toxicities including rash, pruritis, and anorexia. No grade 4 toxicities were reported. Subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in pts with del 19 than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 pts with progressive disease had an L858R mutation. No secondary resistant mutations such as T790M were found in those pts. In addition, PFS at 12 mo was significantly better in pts with del 19 than those with L858R (63.2% vs 23.8%, P=0.0034). Conclusions: Gefitinib as the first-line treatment for Korean pts with advanced pulmonary adenocarcinoma harboring EGFR mutations was very effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in pts with the del 19 mutation.