Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes

Abstract Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. In this study, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of central nervous system (CNS)–specific outcomes. Patients and Methods: This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was objective response rate (ORR). Secondary endpoints were safety, progression-free survival, and overall survival. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on days 1 to 7 of each 21-day cycle. In previously published cohort 1, olaparib was dosed on days 1 to 7; in cohort 2, olaparib was dosed continuously. Results: Sixty-six patients were enrolled across the two cohorts: 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, the best overall intracranial response was complete response in 6/15 patients, partial response in 4/15 patients, and stable disease in 3/15 patients for a CNS disease control rate of 87% (95% confidence interval, 59.5%–98.3%). Conclusions: Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses with regard to optimal dosing schedule will inform potential for future use of this combination in SCLC.