Bevacizumab, which is a humanized IgG1 monoclonal antibody targeting VEGF-A, showed the most promising results among VEGF-targeted agents. Although this agent, in combination with platinum-based chemotherapy, has been investigated in three phase II studies, the results were controversial.

A single-arm phase II study, Eastern Cooperative Oncology Group (ECOG) 3501, reported that the addition of bevacizumab to standard cisplatin and etoposide (EP) regimen followed by maintenance bevacizumab resulted in improved PFS and OS relative to historical controls who received EP regimen without bevacizumab: ORR of 63.5 %, 6 month PFS rate of 30.2 %, median PFS 4.7 months, and median OS of 10.9 months [20]. Another single-arm phase II study combining bevacizumab with carboplatin and irinotecan regimen reported more promising results, ORR of 84 % and median OS of 12.1 months [21]. A randomized phase II study, SALUTE, showed that the addition of bevacizumab to cisplatin or carboplatin plus etoposide regimen improved PFS (5.5 vs 4.4 months; HR: 0.53; 95 % CI, 0.32–0.86) with acceptable toxicity but failed to improve OS (9.4 vs 10.9 months, HR: 1.16; 95 % CI, 0.66–2.04) [22].

Cediranib is a potent and selective inhibitor of the VEGF receptors (VEGFR) 1, 2, and 3. A single-arm phase II study of cediranib for second-line therapy of SCLC reported that nine cases out of 25 had stable disease, but none had objective responses [23].

Vandetanib is a multi-targeted kinase inhibitor of mainly VEGFR, epidermal growth factor receptor (EGFR), and RET-tyrosine kinases. A randomized phase II study (NCIC CTG BR.20) examined the improvement in PFS with vandetanib as maintenance therapy after objective responses to platinum-based chemotherapy with or without radiation therapy [24]. Vandetanib failed to prolong PFS, but limited-stage (LD) patients treated with vandetanib tended to have longer OS in planned subgroup analyses (HR: 0.45; p = .07).

Sorafenib is a multi-targeted kinase inhibitor of VEGFR-2 and VEGFR-3, platelet-derived growth factor receptor (PDGFR), BRAF, KIT, FLT3, and RET. A single-arm phase II study (SWOG 0435) was conducted to evaluate the efficacy and safety of sorafenib in patients with SCLC who previously received platinum-based chemotherapy [25]. As the results were disappointing, the single-agent sorafenib was determined to be not recommended for SCLC.

Sunitinib is a multi-targeted kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, PDGFR, KIT, FLT3, RET, and colony-stimulating factor 1 receptor (CSF-1R). A single-arm phase II study was conducted to evaluate the efficacy and safety of sorafenib in previously treated patients with SCLC [26]. The efficacy was disappointing: ORR of 9 % (95 % CI, 1–28 %), median PFS 1.4 months (95 % CI, 1.1–1.7), and median OS 5.6 months (95 % CI, 3.5–7.7). Moreover, most of the patients were unable to tolerate sunitinib. Another single-arm phase II study evaluated the efficacy and safety of sunitinib as maintenance therapy following carboplatin and irinotecan regimen in patients with ED SCLC [27]. Sunitinib was well tolerated and showed encouraging results with 1-year OS of 54 % and median time to progression of 7.6 months.

A randomized phase II study (CALGB 30504, ALLIANCE) also evaluated the efficacy of maintenance sunitinib after cisplatin and etoposide regimen. Compared with placebo, sunitinib significantly improved PFS (2.1 vs 3.7 months; HR: 1.62; 95 % CI, 1.02–2.60, P = .02) [28]. The result supports the strategy of investigating the use of sunitinib in the maintenance setting and the future study.

Ziv-aflbercept is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGFR-1 and VEGFR-2 that are fused to the Fc portion of the human IgG1 immunoglobulin. The agent acts as a soluble decoy receptor that inhibits angiogenesis by targeting VEGF-A and VEGF-B [29]. A randomized phase II study (S0802) evaluated the efficacy of ziv-aflibercept with topotecan in patients with previously treated SCLC [30]. Ziv-aflibercept improved the 3-month PFS only in patients who had platinum-refractory SCLC (27 % v 10 %; P = .02) but increased toxicity. The addition of ziv-aflibercept to topotecan did not improve OS.

Thalidomide, a glutamic acid derivative, inhibits angiogenesis by repression of key angiogenic genes and downregulation of VEGF and basic fibroblast growth factor [31, 32], while the mechanism is not fully understood. Two phase III studies have been conducted to evaluate the efficacy of thalidomide in patients with SCLC. An intergroup phase III study (FNCLCC cleo04 IFCT 00–01) failed to show survival benefit of adding thalidomide to platinum-based chemotherapy following response to induction chemotherapy (median OS, 11.7 vs 8.7 months; HR, 0.74; 95 % CI, 0.49–1.12, P = .16), but some benefit was observed among patients with a performance (PS) of 1 or 2 in exploratory analyses (HR, 0.59; 95 % CI, 0.37–0.92, P = .02) [32]. Moreover, sensory neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33 % v 12 %, respectively). The other phase III trials evaluated thalidomide in combination with carboplatin and etoposide regimen [33]. The study also did not meet its primary endpoint of OS (10.5 vs 10.1 months; HR, 1.09; 95 % CI, 0.93–1.27, P = .28) and showed that thalidomide increased risk of thrombotic events.