Related Experiment Video
Updated: Aug 18, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Phase II study of olaparib plus durvalumab in EGFR-mutant NSCLC transformed to small cell lung cancer
Chirayu Mohindroo1,2, Nobuyuki Takahashi1, Samantha Nichols3
1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
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.
Insights
Combining olaparib and durvalumab showed minimal effectiveness in treating EGFR-mutant non-small cell lung cancer (NSCLC) that transformed into small cell lung cancer (SCLC). This combination therapy did not achieve the desired objective response rate in patients with this aggressive cancer type.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Histologic transformation of EGFR-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) represents an aggressive resistance mechanism.
- This transformation is associated with poor patient outcomes and limited therapeutic strategies.
- Preclinical and clinical evidence suggests combining PARP inhibition with immune checkpoint blockade may be beneficial.
Purpose of the Study:
- To evaluate the efficacy and safety of combining durvalumab with olaparib in patients with EGFR-mutant NSCLC transformed to SCLC.
- To determine the objective response rate (ORR) as the primary endpoint.
- To assess secondary endpoints including progression-free survival (PFS) and overall survival (OS).
Main Methods:
- An open-label, single-arm Phase II clinical trial was conducted.
- Patients received intravenous durvalumab (1500 mg every 28 days) plus oral olaparib (300 mg twice daily).
- The study was terminated early due to slow patient accrual.
Main Results:
- The objective response rate (ORR) was 0%, with one patient achieving stable disease (25% disease control rate).
- Median progression-free survival (PFS) was 1.75 months, and median overall survival (OS) was 9.33 months.
- The combination therapy was generally well-tolerated, with predominantly Grade 1-2 adverse events and no Grade 3 or higher treatment-related toxicities.
Conclusions:
- Olaparib plus durvalumab exhibited limited clinical activity in EGFR-mutant NSCLC transformed to SCLC.
- Despite a strong biological rationale, the combination did not demonstrate significant efficacy in this patient population.
- The study was terminated early due to slow accrual, limiting further investigation.
