Efficacy differences of pemetrexed by histology in pretreated patients with stage IIIB/IV non-small cell lung cancer: review of results from an open-label randomized phase II study.

INTRODUCTION: Recent pivotal phase III studies in patients with advanced non-small cell lung cancer (NSCLC) consistently showed greater survival benefit of pemetrexed in patients with nonsquamous cell carcinoma histology (nonsquamous histology) compared with those with squamous cell carcinoma histology (squamous histology). To confirm the efficacy differences of pemetrexed by histologic type, we conducted an additional subgroup analysis of data from a Japanese randomized phase II study evaluating the efficacy and safety of pemetrexed 500 mg/m2 (P500) and 1000 mg/m2 (P1000) in patients with advanced NSCLC previously treated with chemotherapy. The efficacy and safety results of original phase II study have already been reported (Ohe et al., Clin Cancer Res 2008;14:4206-4212).

METHODS: Objective response rates (ORRs), overall survival time, and progression-free survival time were analyzed by subgroup of histology, squamous, and nonsquamous, for the dose groups combined and separately.

RESULTS: A total of 216 patients were evaluable for efficacy. One hundred sixty-eight patients had nonsquamous and 48 had squamous histology. ORRs were 20.8% and 2.1% (p < 0.001); median survival times (MST) were 16.0 and 8.5 months (p < 0.001); and median progression-free survival times (PFS) were 3.1 and 1.6 months (p < 0.001) for nonsquamous and squamous histology, respectively. In patients who were randomized to the P500 group, ORR were 23.5% and 0% (p = 0.0062); MST were 19.4 and 7.9 months (p < 0.001); and PFS were 3.1 and 1.4 months (p < 0.001) for nonsquamous and squamous histology, respectively. In patients who were randomized to the P1000 group, ORR were 18.1% and 4.0% (p = 0.1113); MST were 13.5 months and 8.6 months (p = 0.0971); and PFS were 3.1 and 1.7 months (p = 0.0024) for nonsquamous and squamous histology, respectively. There were no clinically relevant differences in the incidence of toxicities between histology groups.

CONCLUSIONS: This study showed the difference of pemetrexed efficacy by histologic type, and this result supports the treatment-by-histology effect observed in the past pivotal phase III studies. Higher dose of pemetrexed resulted in similar outcomes both in patients with nonsquamous histology and squamous histology. Pemetrexed is not as effective as alternative therapies for previously treated squamous histology; however, pemetrexed should be the key agent for the treatment of patients with nonsquamous histology.