Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma

Purpose This multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity. Patients and Methods Patients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m2 plus BSC (P + BSC) every 21 days or BSC alone. Results The study enrolled 243 patients (123 on P + BSC arm and 120 on BSC arm). Median OS time was not significantly different between the arms (8.4 months for P + BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who responded to first-line therapy. Time-to-event measures significantly favored P + BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P + BSC and BSC arms, respectively (P < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P + BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P + BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P + BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities. Conclusion Second-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.