A Phase I Open-Label Study of Cediranib Plus Etoposide and Cisplatin as First-Line Therapy for Patients With Extensive-Stage Small-Cell Lung Cancer or Metastatic Neuroendocrine Non–Small-Cell Lung Cancer

• Published in: Clinical lung cancer 2024-11, Vol.25 (7), p.601-611
• Main Authors: Concannon, Kyle F., Glisson, Bonnie S., Doebele, Robert C., Huang, Chao, Marotti, Marcelo, Camidge, D. Ross, Heymach, John V.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Neuroendocrine - drug therapy; Carcinoma, Neuroendocrine - pathology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; cediranib; Cisplatin; Cisplatin - administration & dosage; Etoposide; Etoposide - administration & dosage; Female; Humans; Indoles; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Middle Aged; Neoplasm Staging; Neuroendocrine non-small-cell lung cancer; Quinazolines - administration & dosage; Quinazolines - therapeutic use; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - mortality; Small Cell Lung Carcinoma - pathology; Small-cell lung cancer; Survival Rate
• ISSN: 1525-7304; 1938-0690; 1938-0690
• DOI: 10.1016/j.cllc.2024.08.015

Small cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC). Patients received up to six 21-day cycles of etoposide (100 mg/m2, days 1-3) and cisplatin (80 mg/m2, day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose. Twenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage. Cediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity. Small cell lung cancer (SCLC) remains the deadliest lung cancer subtype and novel treatment paradigms are urgently needed. This study evaluates 22 patients with pulmonary neuroendocrine tumors, 18 with SCLC, treated with front-line chemotherapy plus the VEGF inhibitor cediranib. The median PFS was 8.9 months, and the regimen was well tolerated. These data support further evaluation of cediranib in SCLC.