P2.06-08 Phase I/II Study of Rucaparib and Pembrolizumab Maintenance in Stage IV NSCLC after Carboplatin, Pemetrexed, Pembrolizumab

Document Type

Conference Proceeding

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Publication Title

J Thorac Oncol


Introduction: Carboplatin, pemetrexed, and pembrolizumab (CPP) followed by pemetrexed and pembrolizumab (PP) maintenance is a standard of care (SOC) for non-squamous metastatic non-small cell lung cancer (NSCLC) with a progression-free survival (PFS) of 8.8 months. Up to 38% of sporadic NSCLCs harbor somatic mutations in genes of the homologous recombinant repair (HRR) pathway resulting in a “BRCAness” phenotype that predicts sensitivity to PARP inhibitors (PARPi). Treatment with PARPi upregulates PD-L1 expression, which is associated with pembrolizumab response. We therefore hypothesized that maintenance therapy with a PARPi plus pembrolizumab will improve PFS compared to SOC PP. Methods: This was a single arm, multi-site, investigator-initiated phase I/II study that enrolled treatment-naïve patients with stage IV non-squamous metastatic NSCLC eligible for CPP. Patients without progression after 4 cycles of CPP received maintenance with rucaparib 600 mg PO BID and pembrolizumab 200 mg IV every 21 days. The primary objective was efficacy assessed by PFS. Secondary objectives included overall survival (OS), safety, and objective response rate (ORR). This study was funded by both Merck and Clovis; NCT03559049. Results: From 12/24/2018 to 10/6/2022, we enrolled 25 patients, 11 of whom did not proceed with maintenance. Reasons for not receiving maintenance include progression on CPP (3/11), physician discretion (2/11), AE from CPP (2/11), study termination (2/11), patient passed (1/11, not due to study), and incorrect enrollment (1/11). Here we report the early results of the 14 patients who received at least one cycle of maintenance rucaparib and pembrolizumab. The median age was 59 and 64% were female; all patients had adenocarcinoma histology, and one patient had stable treated brain metastases. The study was closed to accrual and terminated early due to financial insolvency of Clovis. The median PFS from enrollment was 11.4 months and median OS was 37.6 months. The ORR from enrollment was 64% (9/14; 8 PR, 1 CR), 95% CI (0.35-0.87). There were no SAEs reported and the highest grade of AE was Grade 3, which occurred in 50% of patients. The most common treatment related Grade 3 AE was liver enzyme elevations (28.6%) followed by anemia/leukopenia (14.6%). Conclusions: This is the first study to examine an alternative maintenance strategy to PP in stage IV non-squamous NSCLC after CPP. While the overall number of evaluable patients is small, the results suggest that maintenance therapy with the combination of PARPi plus pembrolizumab has a manageable safety profile and shows promising efficacy that warrants investigation in a larger study (Phase 3 studies are ongoing). Sequencing data are being evaluated to understand molecular alterations associated with benefit to PARPi and pembrolizumab. Keywords: maintenance therapy, PARP inhibitor, checkpoint inhibitor

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Not assigned.





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