Durvalumab in Combination with Olaparib in Non-Small Cell Lung Cancer

Division Of Basic Sciences - Nci

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Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) show variable clinical activity in individuals with advanced cancers. In the lung-MAP sub-study S1400G, talazoparib alone was not sufficiently active in squamous lung cancers with homologous recombinant repair deficiency. Combinations of PARPi with immune checkpoint inhibitors (ICIs) are under investigation since preclinical studies show an immunostimulatory effect of PARPi that can potentially increase responsiveness to ICIs. To test this hypothesis, we have evaluated the PARPi, Olaparib with the ICI, Durvalumab in individuals with advanced non-small cell lung cancer (NSCLC) who had received at least one prior platinum-based regimen. Among 15 evaluable participants, median PFS (mPFS) was 3.2 mo. (95% CI: 0.9-7.6). Among 14 subjects with known EGFR mutation status, mPFS was longer in 11 individuals with EGFR-WT tumors (5.7 vs. 0.9 mo.; p=0.001). DNA repair mutation (APC, BAP1, BRCA1, BRCA2, CHEK2, FANCI, FANCL and PALB2) status was known for 9 subjects; mPFS of subjects with (n=7) or without (n=2) DNA repair mutations was 3.2 vs. 18.1 mo. (p=0.68), respectively. Tumor PD-L1 expression > 50% (n= 3/10) and prior ICI therapy (n= 9/15) was associated with longer, albeit not statistically significant, mPFS: 7.6 vs. 1.8 mo.; p=0.22, and 5.7 vs. 1.8 mo.; p=0.39, respectively. Two (13%) partial responses, 7 (47%) stable disease and 6 (40%) cases of progressive disease were observed. Four (27%) subjects, including 3 previously treated with ICIs, achieved durable response or stability for up to 3 years. Treatment-related adverse events (TRAEs) were generally mild (grade 1 or 2). The most common TRAEs were anemia (40%), thrombocytopenia (27%), anorexia, fatigue, pain, and hypophosphatemia (each observed in 20%). Grade > 3 TRAEs occurred in 4 (27%) subjects (all hematologic). Immune-related AEs occurred in 4 (27%) individuals. Two subjects developed myelodysplasia after 12 and 36 mo. of treatment. Three (20%) subjects required dose reductions or discontinuation of Olaparib due to anemia. There were no treatment-related deaths. Taken together, a combination of Olaparib and Durvalumab has acceptable safety and modest efficacy in an unselected population with recurrent NSCLC. Sufficient clinical activity is not observed in individuals with EGFR-mutated tumors.