Sunitinib: The Next Advance in Small-Cell Lung Cancer?
Authors: Natasha B. Leighl
Journal: Journal of Clinical Oncology (2015)

With the rapid evolution of targeted therapy in non–small-cell lung cancer (NSCLC), the pace of therapeutic progress in small-cell lung cancer (SCLC) has been disappointing. The 5-year survival for SCLC is estimated at 6% ( 3% in extensive stage), in contrast to an estimated 21% for NSCLC. Perhaps the most tangible progress has been the declining incidence of SCLC since the 1970s in some areas, for example a drop from 17% to 13% of current lung cancer cases in North America, attributed in part to changes in cigarette manufacture and consumption. However SCLC still exacts a significant toll, with more than 200,000 new cases estimated per year globally, and up to 90% dying within 1 to 2 years from diagnosis. The standard systemic treatment of SCLC has not changed in decades, although new agents have been developed as alternatives. Etoposide-platinum (EP) therapy remains standard for both limited (stages 1-3, one third of cases) and extensive stage (ES) disease (stage 4, two thirds). In ES-SCLC, irinotecan-platinum (IP) is an accepted alternative, standard in Japan. Prophylactic cranial irradiation in responding patients has resulted in improved survival in most studies, and a recent report suggests that thoracic irradiation in responding ES-SCLC patients may also prolong survival. On progression, second-line therapy yields response rates of 20% to 30%, with median survival times of 6 to 8 months in clinical trials. Cyclophosphamide, doxorubicin, and vincristine (CAV), topotecan and more recently amrubicin are all potential second-line options. Further improvement in systemic therapy has remained elusive, despite attempts to incorporate additional chemotherapy or targeted agents in the first-line, maintenance and relapsed/refractory setting. In the article that accompanies this editorial, Ready et al report the results of Cancer and Leukemia Group B (CALGB) 30504, a small randomized phase II trial of maintenance sunitinib versus placebo in 85 ES-SCLC patients with stable or responding disease after initial EP chemotherapy. While sunitinib has multiple targets, including vascular endothelial growth factor (VEGF), plateletderived growth factor, KIT, and FLT-3 receptor tyrosine kinases, VEGF-mediated signal transduction and angiogenesis are believed to be important targets in SCLC. Studies have demonstrated frequent tumoral expression of VEGF in SCLC, and an association between microvessel count and tumoral and circulating VEGF levels and patient outcome. Despite initial challenges with study design, namely the inability to safely combine sunitinib with concurrent EP chemotherapy, the ALLIANCE investigators successfully demonstrated better progression-free survival (PFS) with sunitinib maintenance compared with placebo (HR, 1.62; median 3.7 v 2.1 month; 95% CI, 1.02 to 2.60; P .022), and confirmed single-agent activity including a 7% complete response rate. There is also a statistically nonsignificant yet interesting improvement in median survival from random assignment, 6.9 months with placebo versus 9.0 months with sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; P .16). These findings have led the investigators to suggest a larger randomized phase II study of maintenance sunitinib with survival as the primary end point. Will sunitinib maintenance be the next step forward for SCLC? Or will it lead down another blind alley of failed VEGF and VEGF receptor (VEGFR) inhibitor trials in lung cancer? At least fifteen phase II or III studies of VEGF/VEGFR inhibitors have been conducted in SCLC, some showing single-agent activity. Bevacizumab has been the most extensively studied. SALUTE (A Study of Bevacizumab in Previously Untreated Extensive-Stage Small Cell Lung Cancer), a randomized phase II trial of bevacizumab added to EP chemotherapy, demonstrated better PFS, higher response, more toxicity but not better survival with the targeted agent. An interim analysis of the French Intergroup IFCT-0802 randomized phase II/III trial demonstrated no improvement in outcomes with bevacizumab added to EP in ES-SCLC, and the study has been halted. A similar study from the Italian Oncology Group for Clinical Research is ongoing, with results pending. Aflibercept, a soluble VEGF receptor, has been studied in a randomized phase II study from SWOG, and showed improved 3 month-PFS, but not better survival and increased toxicity when added to second-line topotecan. The NCIC Clinical Trials Group studied maintenance vandetanib (300 mg daily) in both limited and ES-SCLC patients with stable or responding disease after initial chemotherapy. The study was negative overall, with subgroup analysis suggesting benefit in those with limited but not extensive-stage disease. Sanborn et al recently reported results of Hoosier Oncology Group trial LUN06-113, a randomized phase II trial testing a lower dose of vandetanib (100 mg daily) concurrently with EP in 74 ES-SCLC patients but without vandetanib maintenance. There was no significant improvement in response, time to progression, nor survival. But the survival data from this negative trial are similar to the current CALGB results, with a median survival time from treatment start of 9.2 months in the EP arm and 13.2 months in the vandetanib/EP arm (HR, 0.797; 95% CI, 0.443 to 1.435; P .458). JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 15 MAY 2