Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled MISSION trial randomized patients with advanced relapsed/refractory NSCLC, following 2 or 3 prior treatment regimens, to sorafenib 400 mg bid (n=353) or matching placebo (n=353) plus best supportive care. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and time-to-progression (TTP). EGFR and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Median PFS (2.8 versus 1.4 mo; HR 0.61; 95% CI 0.51-0.72, p<0.0001) and TTP (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with EGFR mutations, OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.
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