Pemetrexed

Dual-Maintenance Therapy for Advanced Non–Small-Cell Lung Cancer.

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Progression-free survival was superior with bevacizumab plus pemetrexed versus bevacizumab alone after induction with bevacizumab, cisplatin, and pemetrexed.
Maintenance therapy has been shown to improve survival in patients with non–small-cell lung cancer (NSCLC). Recently, maintenance with single-agent pemetrexed versus placebo was associated with improved progression-free survival (PFS) and overall survival . To test a dual-maintenance strategy in this setting, investigators conducted an industry-supported, phase III, multicenter, randomized, open-label trial (AVAPERL) of maintenance bevacizumab with or without pemetrexed.

A total of 376 patients with advanced, nonsquamous NSCLC received induction therapy with intravenous bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) every 3 weeks for 4 cycles. The 253 responding patients were randomized to maintenance bevacizumab every 3 weeks or combination bevacizumab (7.5 mg/kg) plus pemetrexed (500 mg/m2) every 3 weeks.

At a median follow-up of 8.1 months, PFS from time of randomization (the primary endpoint) was superior with combination bevacizumab plus pemetrexed versus bevacizumab alone (median, 7.4 vs. 3.7 months; hazard ratio, 0.48; P<0.0001), as was PFS from time of induction (10.2 vs. 6.6 months; HR, 0.50; P<0.001). OS favored combination therapy but did not reach statistical significance. No new safety signals were identified, but toxicity was greater with combination therapy.

COMMENT

At ASC0 2013, updated results from the AVAPERL trial (Abstract 8014) indicated that OS also failed to reach statistical significance (median OS from randomization, 17.1 vs. 13.2 months; HR 0.87; P=0.29 and median OS from induction, 19.8 vs. 15.9 months; HR 0.88; P=0.32). The AVAPERL trial thus suggests that adding pemetrexed to maintenance bevacizumab improves PFS with a trend towards OS benefit. However, other randomized, phase III data presented at ASCO 2013 (Abstract 8004) indicate that dual maintenance provides no OS benefit. At present, the issue of optimal maintenance therapy in unselected nonsquamous NSCLC patients remains unknown. Treatment decisions are currently based on eligibility for bevacizumab treatment and patient preference for toxicity profiles.

Source: NEJM