Cooperative Group Research Endeavors in Small-cell Lung Cancer: Current and Future Directions

Current and Future Directions

Randeep Sangha; Primo N. Lara, Jr.; Alex A. Adjei; Paul Baas; Hak Choy; Laurie E. Gaspar; Glenwood Goss; Nagahiro Saijo; Joan H. Schiller; Everett E. Vokes; David R. Gandara

Disclosures

Clin Lung Cancer. 2009;10(5) 

In This Article

Eastern Cooperative Oncology Group

Bevacizumab, a monoclonal antibody (MoAb) targeting VEGF, has shown to improve survival when combined with chemotherapy in patients with advanced NSCLC, as described in the ECOG 4599 trial.[24] Given these positive results, further evaluation of bevacizumab was felt to be warranted in SCLC because of its high degree of vascularization and VEGF expression.[25] ECOG 3501, a phase II trial of bevacizumab with cisplatin/etoposide in ESSCLC, has completed accrual. A 21-day cycle of intravenous (I.V.) cisplatin 60 mg/m2 day 1, etoposide 120 mg/m2 days 1-3 I.V., and bevacizumab 15 mg/m2 day 1 was administered for 4 cycles with maintenance bevacizumab given thereafter until PD or unacceptable toxicity. The primary endpoint was to detect an improvement in 6-month PFS from 16% to 33% in 66 patients. Updated survival analysis reported at the 2008 ILCC showed a 6-month PFS of 35% and a 1-year OS rate of 37%.[26] Median PFS and OS were 4.7 months and 11.1 months, respectively. Of the evaluable patients, there were no grade 3/4 hemorrhagic events, despite the known predisposition for SCLC to be centrally located. In another nonrandomized phase II study, CALGB 3036, 72 patients with previously untreated ES-SCLC received a maximum of 6 cycles of cisplatin 30 mg/m2 days 1 and 8 I.V., irinotecan 65 mg/m2 days 1 and 8 I.V., and bevacizumab 15 mg/m2 day 1 without maintenance therapy. The regimen was feasible, and the 1-year PFS and OS rates were 18.3% and 48.9% (median PFS, 7.1 months; median OS, 11.7 months), respectively.[27] VEGF and PDGF levels showed no correlation with response, PFS, or OS. Overall, these studies are forming the rationale for the industry to evaluate bevacizumab in the phase III setting.

The Hedgehog (Hh) pathway is an essential embryonic signaling cascade implicated as an oncogenic catalyst in a variety of malignancies. There is evidence supporting persistent activation of the Hh pathway in SCLC, and in cell lines treated with a potent Hh inhibitor, cyclopamine, significant growth inhibition has been observed.[28,29] GDC-0449 is an orally bioavailable synthetic inhibitor of Hh signal transduction and has shown safety and clinical benefit in a phase I clinical trial for patients with advanced solid tumors.[30] Similarly, inhibition of the insulin-like growth factor (IGF) pathway is a promising new target with therapeutic efficacy in a variety of tumor models. This pathway is thought to mediate chemotherapy resistance as well as resistance to certain novel agents in SCLC.[31,32] Cixutumumab (IMC-A12), a MoAb targeting the IGF type 1 receptor (IGF-1R), is in clinical development. ECOG is proposing an ECOG 1508 three-armed, randomized phase II trial to determine "proof of activity." Patients with ES-SCLC will be randomized to receive (1) cisplatin/etoposide alone, (2) cisplatin/etoposide plus GDC-0449, or (3) cisplatin/etoposide plus cixutumumab for a total of four 21-day cycles. PFS is the planned primary endpoint, and the statistical design will include 74 patients per arm to have 85% power to detect a 33% reduction in the HR for PFS, corresponding to a 50% improvement in median PFS from 5.0 months to 7.5 months. Extensive correlative analysis will be integrated within this trial, with particular emphasis on Hh ligand and IGF-1R expression.

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