Sorafenib Fails to Improve Survival as Third- or Fourth-line Treatment of Advanced Non–Small Cell Lung Cancer

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Third- or fourth-line therapy with sorafenib (Nexavar) failed to extend overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to the main results of the phase III MISSION trial. However, a post hoc biomarker analysis of MISSION suggested that patients with EGFR-mutant tumors may benefit from sorafenib in this setting. Both studies were presented at the 2012 European Society for Medical Oncology (ESMO) Congress in Vienna.


MISSION was a phase III, double-blind, placebo-controlled study conducted in 33 countries that randomly assigned 703 patients with advanced, relapsed/refractory, heavily pretreated NSCLC to third- or fourth-line therapy with either oral sorafenib monotherapy at 400 mg twice daily or placebo. All patients got best supportive care.

The study did not meet its primary endpoint of improved overall survival, which was similar in both groups: 248 days for sorafenib vs 253 days for placebo. However, median progression-free survival, time to disease progression, overall response rate, and disease control rate were significantly improved by the addition of sorafenib.

Median progression-free survival was 84 days for sorafenib vs 43 days for placebo (P < .0001). Median time to progression was 89 vs 43 days, respectively (P < .0001). Overall response rate was 4.9% vs 0.9 (P < .001), and disease control rate (response plus stable disease) was 47% vs 25% (P < .0001).

At baseline, demographic factors and prior treatments were well balanced in the two arms. Minor differences were more females in the sorafenib group (47% vs 41%) and more never-smokers (46% vs 38%). Fewer patients in the sorafenib arm were treated with additional therapies postprogression (44% vs 56%).

A higher rate of adverse events was reported in the sorafenib arm: 99% vs 91%. Serious adverse events were reported in 39% vs 32%, respectively.

Although sorafenib had relevant antitumor activity, lead author Luis Paz-Ares, MD, Virgen del Rocio University Hospital, Seville, Spain, said, “The fact that there is no significant overall survival highlights the increasing importance of poststudy therapies. In addition, one cannot exclude a potential overall survival benefit in some patient populations.”

Biomarker Analysis

A post hoc companion biomarker analysis of MISSION explored the effect of EGFR and KRAS mutation status on progression-free and overall survival, and findings suggested that EGFR-mutated status may be a predictive factor for sorafenib response. This conclusion was based on a positive interaction analysis for both progression-free and overall survival, explained lead author Tony Mok, MD, Chinese University of Hong Kong.

Median overall survival was twice as long in patients with mutated EGFR receiving sorafenib vs placebo (423 vs 197 days, hazard ratio [HR] = 0.48, P = .002). In contrast, there was no significant difference in overall survival between patients with wild-type EGFR receiving sorafenib or placebo (253 vs 256 days, HR = 0.92, P = .559).

That said, Dr. Mok noted, “In the EGFR analysis, overall survival outcome could be biased by much greater use of poststudy EGFR tyrosine kinase inhibitors [43% in the sorafenib arm vs 18% in the placebo arm].”

KRAS mutation status did not appear to predict response to sorafenib, based on a negative interaction analysis for both progression-free and overall survival. Sorafenib treatment had a more favorable effect on progression-free survival than placebo in patients with both mutated and wild-type KRAS tumors.

“We do not see KRAS as having a predictive value for sorafenib as third- or fourth-line therapy,” Dr. Mok stated.

Samples were obtained from 357 patients; 107 provided tissue samples and 346 provided plasma samples. Samples were positive for EGFR mutations in 26% and for KRAS mutations, in 20%.

 “This is a retrospective exploratory analysis with a small sample size. It is hypothesis-generating, and results should be interpreted with caution,” Dr. Mok said. During the question-and-answer session, he said that it is not clear why EGFR-positive patients appeared to benefit from sorafenib. “We need to learn more,” he concluded. ■

Disclosure: Dr. Mok has been a consultant to and speaker for AstraZeneca, Roche, Pfizer, Boehringer Ingelheim, Lilly, Merck Serono, Taiho, BeiGene, and Eisai. Dr. Paz-Ares has been an advisor for Lilly.


1. Paz-Ares L, Hirsh V, Zhang L, et al: Monotherapy administration of sorafenib in patients with non-small cell lung cancer: Phase III, randomized, double-blind, placebo-controlled MISSION trial. 2012 ESMO Congress. Abstract LBA33. Presented September 29, 2012.

2. Mok TSK, Paz-Ares L, Wu Y-L, et al: Association between tumor EGFR and KRas mutation status and clinical outcomes in NSCLC patients randomized to sorafenib plus best supportive care (BSC) or BSC alone: Subanalysis of the phase III MISSION trial. 2012 ESMO Congress. Abstract LBA9. Presented September 29, 2012.

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