A phase I/II multisite study of rucaparib and pembrolizumab maintenance therapy in stage IV non-squamous non–small cell lung cancer after initial therapy with carboplatin, pemetrexed, and pembrolizumab.

Abstract

TPS9138 Background: Carboplatin, pemetrexed, and pembrolizumab (CPP) followed by pemetrexed and pembrolizumab maintenance is a standard of care (SOC) for non-squamous metastatic non-small cell lung cancer (NSCLC), based on results of the KEYNOTE-189 study. The progression free survival (PFS) on this study was 8.8 months. There is increasing data to support that certain sporadic tumors harbor somatic mutations in genes of the homologous recombinant repair (HRR) pathway resulting in a “BRCAness” phenotype rendering sensitivity to PARP inhibitors (PARPi). TCGA data suggest up to 38% of NSCLC have mutations in HRR pathway genes. Furthermore, treatment with PARPi is shown to upregulate PD-L1 expression, which is associated with pembrolizumab response in NSCLC. We therefore hypothesized that maintenance therapy with a PARPi and pembrolizumab will improve PFS compared to SOC pemetrexed and pembrolizumab. Methods: This is a single arm, multi-site, investigator-initiated phase I/II study that is enrolling treatment-naïve patients with stage IV nonsquamous metastatic NSCLC without any targetable driver mutations eligible for CPP. Patients without progression after 4 cycles of CPP then proceed to maintenance with rucaparib 600mg PO BID and pembrolizumab 200mg IV every 21 days. The primary objective is efficacy assessed by PFS and second objectives include overall survival, safety, tolerability, and objective response rate (ORR). Correlatives in this study include PD-L1 expression, tumor mutational burden (TMB), and measurements of HRR deficiency as assessed by homologous repair deficiency (HRD) and loss of heterozygosity (LOH) using established methods. Key exclusion criteria include untreated brain metastases and prior exposure to a PARPi or PD-1/PD-L1 inhibitor. The phase I cohort which consisted of 6 patients treated with the approved full doses of rucaparib and pembrolizumab was completed without dose limiting toxicity (DLT). Using a Bayesian decision-theoretic two-stage design, the first stage will enroll 38 patients. If predefined PFS parameters are met, an additional 17 patients, for a total of 55 patients, will be enrolled. To date, 21 patients have been enrolled. Clinical trial information: NCT03559049.