Luis G. Paz-Ares, MD, PhD
The addition of sorafenib (Nexavar) to first-line gemcitabine/cisplatin does not appear to lengthen survival in patients with advanced, nonsquamous, non–small cell lung cancer (NSCLC), according to the results of the phase III NEXUS trial.
Luis G. Paz-Ares, MD, PhD, chairman of the Oncology Division at Seville University Hospital in Spain, and colleagues elsewhere randomized patients 1:1 to sorafenib (400 mg twice daily; n = 385) or matching placebo (n = 387) plus gemcitabine (1250 mg/m2
per day on days 1 and 8) and cisplatin (75 mg/m2
on day 1) for up to six 21-day cycles. Following the chemotherapy phase, patients with at least stable disease could continue receiving blinded maintenance therapy with sorafenib or placebo.
The study enrolled chemotherapy-naïve patients aged ≥18 years with unresectable stage IIIB to IV nonsquamous NSCLC who were deemed to be suited to treatment with gemcitabine/cisplatin. The primary endpoint was overall survival (OS).
The treatment protocol was revised to exclude patients with squamous cell histology a year after the trial was launched. The revision was made after interim results of the ESCAPE study demonstrated higher mortality rates in patients with squamous cell histology who were treated with sorafenib plus paclitaxel/carboplatin than paclitaxel/carboplatin alone.
Platinum-based combination chemotherapy remains the standard treatment for patients with advanced NSCLC, even though most patients with stage IIIB or IV disease worsen despite therapeutic intervention, the researchers wrote. Sorafenib, an oral multiple kinase inhibitor of tumor-cell proliferation and angiogenesis, has demonstrated activity in preclinical models of NSCLC, in phase I studies as single-agent therapy or combined with platinum-doublet therapy or gefitinib (Iressa), and in phase II trials as monotherapy or in combination with erlotinib (Tarceva) or gemcitabine in patients with advanced NSCLC.
The median OS in the NEXUS study was 12.4 months (95% CI, 10.9-13.7 months) in the sorafenib plus gemcitabine/cisplatin group and 12.5 months (95% CI, 11.0-13.6 months) in the placebo plus gemcitabine/cisplatin group (hazard ratio [HR] = 0.98; 95% CI, 0.83-1.16; P
The median progression-free survival by investigator assessment in the sorafenib and placebo groups was 6.0 months (95% CI, 5.5-6.8 months) and 5.5 months (95% CI, 5.1-5.7 months), respectively (HR = 0.83; 95% CI, 0.71-0.97; P
The two treatment groups had similar overall response rates and disease control rates.
Overall, grade 3 to 4 drug-related adverse events were higher in patients receiving sorafenib versus placebo (50.1% vs 28.1%, respectively). Further, the rates of grade 3 to 4 hand-foot skin reaction, fatigue, rash, and hypertension in the sorafenib group were at least twice those in the placebo arm.
Paz-Ares et al maintained that the identification of biomarkers would be essential for any further examination of sorafenib in advanced NSCLC. “In the absence of data delineating biomarkers that can predict the efficacy of sorafenib plus chemotherapy in subpopulations of these patients, further development of these combinations may not be warranted,” they noted.
Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non–small cell lung cancer. J Clin Oncol. 2012;30(25):3084-3092.