The addition of the multi-tyrosine kinase inhibitor sorafenib(Drug information on sorafenib) (Nexavar) to a gemcitabine(Drug information on gemcitabine)/cisplatin regimen failed to improve overall survival among patients with advanced nonsquamous non–small-cell lung cancer (NSCLC), according to a new randomized phase III trial.
Platinum-based combination chemotherapy is the standard treatment for these patients, but most will progress in spite of therapy. “It might be reasonable to evaluate whether the addition of a targeted agent that inhibits mediators of tumor cell growth and angiogenesis to standard cytotoxic chemotherapy can prolong survival,” wrote researchers led by Luis G. Paz-Ares, MD, PhD, of the Hospital Universitario Virgen del Rocio in Seville, Spain.
The phase III NSCLC Research Experience Utilizing Sorafenib (NExUS) trial enrolled 904 patients, with 772 available for the final analysis. Of these, 385 received gemcitabine/cisplatin along with sorafenib 400 mg twice daily, and 387 received gemcitabine/cisplatin and matching placebo. Results were published online before print on July 30 in the Journal of Clinical Oncology.
The median overall survival was 12.4 months in the sorafenib group compared with 12.5 months in the placebo group, yielding a hazard ratio of 0.98 (95% CI, 0.83-1.16; P = .401). However, the progression-free survival was 6.0 months in the sorafenib group and 5.5 months in the placebo group, for an HR of 0.83 (95% CI, 0.71-0.97; P = .008). No patient achieved a complete response, and the overall response rates did not significantly differ between the sorafenib and placebo groups.
The median time to tumor progression was 6.1 months in the sorafenib group vs 5.5 months in the placebo group, for an HR of 0.73 (95% CI, 0.60-0.88; P < .001).
The researchers could not firmly establish why the sorafenib group fared better with regard to progression-free survival and yet not in terms of overall survival. “Analyses of post-progression therapy did not provide sufficient evidence to establish whether the small imbalances between groups could have confounded the overall survival outcomes in relation to the progression-free survival results,” the authors wrote. Furthermore, a secondary analysis based on radiologic assessments in 168 sorafenib and 188 placebo patients did not show significant differences between the groups with regard to progression-free or overall survival.
There were more grade 3 and 4 adverse events in the sorafenib group (50.1% of patients vs. 28.1%), and there were five drug-related grade 5 adverse events in the sorafenib group compared with two in the placebo group.
The authors noted that other phase III trials have failed to show improved survival with molecularly targeted agents added to chemotherapy in NSCLC, though erlotinib and gefitinib(Drug information on gefitinib) have demonstrated efficacy as monotherapies. “Studies using novel biomarker-based approaches may guide the selection of individualize targeted therapies,” they wrote. And though sorafenib has shown promise as a monotherapy in phase II trials and phase III studies are underway, they added that “in the absence of data delineating biomarkers that can predict the efficacy of sorafenib plus chemotherapy of subpopulations of these patients, further development of these combinations may not be warranted.”
Patients had a median age of 60 years in the sorafenib group and 58 years in the placebo group; most patients were male, white, and were past or present smokers. Most patients in both groups presented with an ECOG performance status of 1, and about 80% of patients in each group had adenocarcinomas.