Results of a randomized phase IIb study estimating overall survival of pralatrexate versus erlotinib in platinum-pretreated NSCLC.

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7554 Background: Pralatrexate (PDX) is a folate analog targeting dihydrofolate reductase. A previous phase I trial in heavily pretreated patients (pts) with advanced NSCLC reported a 10% overall response rate, including 2 pts with durable complete response (26+ and 21+ months; Azzoli, ESMO 2009). Erlotinib (ERL), an EGFR tyrosine kinase inhibitor, is approved for use in NSCLC. The objectives of this study were to compare PDX with ERL in current and former smokers with advanced NSCLC after failure of platinum-based therapy. Methods: Pts were randomized 1:1 to PDX 190 mg/m² (230 mg/m² initially) IV on days 1 and 15 of a 28-day cycle or ERL 150 mg/d PO. The primary objective was to estimate overall survival (OS) of PDX vs ERL, including prespecified subgroups. Results: Baseline characteristics for the 201 enrolled pts were balanced except for histology; 29% vs 47% had squamous carcinoma and 61% vs 46% had nonsquamous carcinoma in the PDX and ERL arms, respectively. Efficacy: The hazard ratio (HR; 95% CI) for OS was 0.84 (0.61, 1.14). PDX OS benefit trend was greatest in pts with nonsquamous histology (n=107; HR=0.65). The activity of PDX was comparable to ERL in pts with squamous cell carcinoma (HR=1.06). An analysis adjusting for histology showed consistency with the overall results (HR=0.82). The median progression-free survival was 3.4 vs 2.8 months in the PDX and ERL arms (HR = 0.91). Safety: Safety profiles of both agents were consistent with those previously identified. The most common adverse event (AE) was mucositis with PDX (Grade 1, 2, 3, 4 = 11%, 34%, 20%, 3%) and rash with ERL (Grade 1, 2, 3, 4 = 28%, 28%, 8%, 0%). Grade 0 mucositis was required for retreatment. Only 1 dose reduction was allowed for AEs. In the PDX arm, 21% of pts discontinued due to mucositis; most discontinuations occurred in cycle 1. A landmark analysis of pts who remained on treatment at 30 days showed an OS benefit trend favoring PDX (HR= 0.61). Conclusions: Most pt groups with advanced NSCLC showed trends for greater OS benefit from PDX compared to ERL. Individualized dose-modification strategies and prospective mucositis management to maximize benefit and tolerability of pralatrexate will be key success factors in future trials.