Treatment with the drug sorafenib as a third or fourth line therapy does not result in improved overall survival among patients with advanced non-small cell lung cancer (NSCLC), according to findings released at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna. However, a post-hoc biomarker analysis of the trial data that was also presented suggests that patients with EGFR-mutant tumors may benefit.
Sorafenib is an oral inhibitor of several tyrosine protein kinases, which can be active in cancers. At the meeting, Dr Luis Paz-Ares from from Virgen del Rocio University Hospital in Seville, Spain, reported the findings of the phase III MISSION trial, a randomized, double-blind, placebo-controlled study of monotherapy administration of sorafenib in 703 patients who were randomly assigned to either oral sorafenib 400mg twice daily or placebo.
Median overall survival, the study's primary end-point, was similar in the two groups (248 vs 253 days; HR 0.99, p=0.4687) the researchers found, while median progression-free survival (HR 0.61; p<0.0001), time to disease progression (HR 0.54; p<0.0001), overall response rate (p<0.001) and diseases control rate (p<0,0001) were significantly greater in the sorafenib group.
"Treatment with sorafenib does not result in improved survival as compared to placebo as a third or fourth line treatment in advanced non-small cell lung cancer," Dr Paz-Ares said.
"There are data suggesting relevant anti-tumor activity of the drug, including progression-free survival in this clinical context," he added. "The fact that there is no significant impact on overall survival highlights the increasing importance of post-study therapies in lung cancer trials. In addition, one cannot exclude a potential overall survival benefit in some patient populations." Post-hoc biomarker analysis of MISSION trial suggests patients with EGFR mutant tumors may benefit from sorafenib To date, there is no specific biomarker that can help select patients for treatment with sorafenib. At ESMO 2012, Dr Tony Mok, professor in the Department of Clinical Oncology at the Chinese University of Hong Kong, reported data from an exploratory study which suggests that EGFR mutations may help to achieve this goal in patients with lung cancer.
The analysis was conducted using tumor and/or plasma mutation data from 347 patients who took part in the MISSION trial. EGFR and KRAs mutations were detected in 26% and 20% patients, respectively, and were well balanced between treatment arms, the researchers report.
Analysis of the interaction between EGFR mutation status and the effect of treatment on survival suggested that patients with EGFR mutations benefitted from sorafenib, while those with wild-type EGFR did not. Median overall survival was two-fold longer in patients with EGFR mutations receiving sorafenib versus placebo. There was no significant difference in overall survival between patients with wild type EGFR receiving sorafenib or placebo.
Similarly, researchers saw an interaction between EGFR mutation status and the sorafenib effect on progression-free survival. Those patients with mutated EGFR treated with sorafenib had better outcomes compared to placebo than patients with wild type EGFR.
KRAS mutation status, meanwhile, was not predictive of sorafenib efficacy.
"There are improvements in both overall survival and progression-free survival. The key is the positive interaction analysis, which is the essential test to validate the predictive value of a biomarker in a randomized study. The better overall survival could be partly influenced by the higher number of patients receiving EGFR tyrosine kinase inhibiting drugs after the study, but the improvement in progression-free survival is mostly attributed to the use of sorafenib," Dr Mok said.
"This is only an exploratory analysis thus cannot confirm the value of EGFR mutation. The biomarker population is of small size, and not necessarily representative of the overall population. But on the other hand, contrary to prior suggestions, we confirmed that KRAS is not a predictive biomarker for sorafenib," Dr Mok concluded.
Commenting on the data, Prof Rafael Rosell of the Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Spain, (who was not involved in the study) said: "This phase III MISSION trial shows that the administration of new treatments without selection of patients based on potential predictive markers dilutes the probable benefit of a targeted agent."
"A large subgroup of patients was genotyped for EGFR and KRAS mutations. Of great interest is that among the 26% of patients with non-small cell lung cancer that is driven by EGFR mutations, survival was twofold longer in those receiving sorafenib compared to those receiving placebo," Prof Rosell said. "This is an important finding since sorafenib inhibits BRAF, VEGFR and PDGFR. The inhibition of BRAF could be the main reason survival was longer in the subgroup of patients with EGFR mutations. BRAF and MEK inhibitors –-not yet explored— could provide additional benefit with EGFR TKIs in EGFR-mutant lung cancers."
"In my opinion, the significant benefit of sorafenib in the subgroup of patients with EGFR-mutant tumors is a great breakthrough that merits validation in a prospective study. The use of sorafenib in the second-line setting may provide benefit in patients progressing after treatment with EGFR tyrosine kinase inhibitors," Prof Rosell said. "It is also intriguing that in 20% of lung cancers driven by KRAS mutations, no benefit was observed with sorafenib. BRAF inhibitors can act on KRAS-mutated tumors, but we need to keep in mind that differences in predicting response can be found between chemotypes hitting the same target. The fact that sorafenib has no effect on KRAS mutations in this trial does not rule out the possibility that other BRAF inhibitors could be effective."
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