Cediranib, an oral VEGF receptor inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51, and increases sensitivity of tumors to PARP inhibitors in vitro. Olaparib, a PARP inhibitor, has demonstrated clinical efficacy in patients with various types of advanced solid tumors who carry a germline BRCA mutation.
Researchers explored the antitumor activity of cediranib combined with olaparib in patients with advanced solid tumors, including patients with small-cell lung cancer (SCLC). This multicenter, 2-stage, phase 2 study enrolled patients with metastatic SCLC who were previously treated with a minimum of 1 platinum-based chemotherapy regimen in the advanced setting. Patients were treated with cediranib 30 mg by mouth once daily plus olaparib 200 mg by mouth twice daily until disease progression or unacceptable toxicity. The primary end point of the study was objective response rate by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses.
A total of 25 patients were enrolled in this study, with a median age of 67 years (range, 46-79 years) and a median number of prior therapies of 2 (range, 1-5). Most (80%) were platinum-sensitive, and half (52%) had been treated with immunotherapy.
Among these patients, the overall response rate associated with cediranib plus olaparib was 28% (95% confidence interval [CI], 10%-46%). Among responders, the median duration of response was 3.8 months; 6 of 8 responding patients had an objective response that lasted more than 3 months and up to 10.3 months. The rate of disease control (complete response + partial response + stable disease) was 88% (95% CI, 75%-100%). Median progression-free survival was 4.1 months (95% CI, 2.3-6.2 months). Median overall survival was 5.5 months.
Grade 3/4 adverse events, irrespective of attribution, were observed in 12 of 25 patients (48%). Grade 3/4 adverse events that occurred in more than 10% of patients were hypertension (21%), fatigue (17%), and weight loss (13%).
Researchers concluded that the combination of cediranib and olaparib resulted in promising clinical activity in patients with platinum-pretreated SCLC, with an overall response rate of 28% in biomarker-unselected patients. In some patients, this regimen required prompt initiation of antihypertensives. Other adverse events were also manageable. Analyses of mutation status in homologous recombination DNA repair genes are ongoing to learn whether mutational status correlates with clinical activity.
Reference
- Kim JW, Hafez N, Soliman HH, et al. Preliminary efficacy data of platinum-pretreated small cell lung cancer cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors. J Clin Oncol. 2020;38:suppl (abstract 9065).