EGFR Mutation Status Might Predict Sorafenib Benefit in NSCLC

Tony S. Mok, MD

Results of the phase III MISSION trial presented at the 2012 ESMO Congress showed that third- or fourth-line treatment with sorafenib did not improve overall survival (OS) in patients with advanced non—small cell lung cancer (NSCLC). A post-hoc biomarker analysis of MISSION suggested that patients with EGFR-mutant tumors may benefit from treatment with sorafenib, but KRAS mutation status was not predictive of response.

“Mutated EGFR is a potent predictor for gefitinib. There was a hint in the biomarker analysis that it may be predictive for sorafenib, but interpret these data with caution,” said lead author Tony S. Mok, MD, Chinese University of Hong Kong. “The sample size is small, it was a subgroup analysis, and an exploratory analysis only.”

MISSION was a multinational, doubleblind, placebo-controlled, randomized phase III trial comparing sorafenib plus best supportive care versus best supportive care alone as third- or fourth-line therapy in an unselected population with NSCLC. The study enrolled 703 patients who were randomized 1:1 to either 400 mg of oral sorafenib twice daily or placebo.

Median overall survival was comparable between the sorafenib and placebo arms (248 vs 253 days; P = .4687), and thus the trial failed to reach its primary endpoint. Statistically significant improvements with sorafenib were demonstrated with several secondary endpoints, including median progression-free survival (PFS; P <.0001), time to disease progression (P <.0001), overall response rate (P <.001), and disease control rate (P <.0001).

Although the primary results were negative, the researchers conducted a mutational analysis involving 347 patients to determine if some patients might benefit from sorafenib. In the analysis subgroup, EGFR mutations were detected in 26% and KRAS mutations in 20%, and were well balanced between the two study arms.

The EGFR mutation analysis included 44 patients from the sorafenib group and 45 from the placebo group who had mutated EGFR in tumor or plasma, and 122 in the sorafenib group and 136 in the placebo group with wild-type EGFR.

EGFR Mutational Subanalysis

of Phase III Mission Trial

Treatment

Median

PFS (mo)

Median

OS (mo)

EGFR-mutant tumors

Sorafenib (n = 44)

2.7

13.9

Placebo (n = 45)

1.4

6.5

P value

<.001

<.002

EGFR wild-type tumors

Sorafenib (n = 122)

2.7

8.3

Placebo (n = 136)

1.5

8.4

P value

<.001

<.559

Mo indicates months; OS, overall survival; PFS, progression-free survival.

A significant PFS benefit was observed for sorafenib in patients with mutated EGFR: median PFS was 2.7 months with sorafenib versus 1.4 months with placebo (hazard ratio [HR] = .27; 95% CI, .16-.46; P <.001). PFS was also significantly better with sorafenib in wild-type EGFR patients versus the placebo group: median PFS of 2.7 months versus 1.5 months, respectively (HR = .62; 95% CI, .48-.82; P <.001).

However, median OS was significantly better in EGFR-positive patients who received sorafenib, but no difference was found between the study arms in the wild-type group. Median OS was 13.9 months with sorafenib versus 6.5 months with placebo for EGFR-positive patients (HR = .48; 95% CI, .30-.76; P <.002). In patients with wild-type EGFR, median OS was 8.3 months in the treatment arm versus 8.4 months with placebo (HR = .92; 95% CI, .70-1.21; P <.559).

The lack of benefit in the wild-type EGFR group suggests a potential benefit of EGFR mutational status as a biomarker, Mok noted.

Luis Paz-Ares, MD

With KRAS mutated or KRAS wild-type NSCLC, however, no significant PFS or OS benefit was observed for sorafenib.

“Based on current data, we hypothesize that EGFR mutation is a predictive biomarker for sorafenib in treatment of patients with advanced NSCLC. It is possible that the OS outcome was biased by the unbalanced use of poststudy tyrosine kinase inhibitor. KRAS mutation did not appear to influence response to sorafenib. A negative interaction was observed for both PFS and OS. Sorafenib resulted in more favorable PFS outcomes than placebo in patients with both KRAS mutant and wild-type tumors,” Mok said.

In a press conference at ESMO 2012, Luis Paz-Ares, MD, Hospital Virgen del Roc, Seville, Spain, commented on the next step for researchers. “There is no clear explanation for the benefit of sorafenib in the EGFR-mutated subgroup. We need to perform the rest of the biomarker analysis before doing a larger trial. This study is hypothesis-gathering.”

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. Presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA9.