Phase II Study of Olaparib Plus Durvalumab in EGFR-Mutant NSCLC Transformed to Small Cell Lung Cancer
Chirayu Mohindroo, Nobuyuki Takahashi, Samantha Nichols, Danielle Pinkiert, Anish ThomasAbstract
Background
Histologic transformation of EGFR-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is an aggressive resistance mechanism associated with poor outcomes and limited treatment options. Preclinical and clinical data suggest a rationale for combining PARP inhibition with immune checkpoint blockade in this setting.
Methods
We conducted an open-label, single-arm phase II study of durvalumab 1500 mg intravenously every 28 days plus olaparib 300 mg orally twice daily in patients with EGFR-mutant NSCLC transformed to SCLC. The primary endpoint was objective response rate by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study was terminated early because of slow accrual.
Results
All enrolled patients were evaluable for efficacy and safety. Best overall response was stable disease in 1 patient and progressive disease in 3 patients, resulting in an objective response rate of 0% and disease control rate of 25%. Median PFS was 1.75 months and median OS was 9.33 months. Concurrent TP53 and RB1 alterations were identified in most patients, and all retained activating EGFR mutations, predominantly exon 19 deletions. Although formal criteria for hyperprogression were not met, 1 patient developed rapid multi-organ progression involving bone, liver, lung, and lymph nodes. Treatment was generally well tolerated with predominantly grade 1-2 adverse events and no grade 3 or higher treatment-related toxicities.
Conclusion
Olaparib plus durvalumab demonstrated limited clinical activity in EGFR-mutant NSCLC transformed to SCLC despite a strong biologic rationale. ClinicalTrials.gov identifier: NCT04538378.