Phase I Dose Escalation Trial Combining Olaparib and Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer

Abstract Purpose: Patients with extensive-stage small cell lung cancer (ES-SCLC) are commonly treated with induction systemic therapy and consolidative thoracic radiation therapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open label phase I study of concurrent olaparib with TRT. Patients and Methods: Patients without progression after induction platinum/etoposide +/- atezolizumab were treated with oral olaparib for 3 weeks and concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose started at 50mg twice daily and escalated in 50mg/dose increments in cohorts of 3 patients each. Primary objectives were the safety and maximum tolerated dose (MTD) of olaparib + TRT. Secondary objectives included in-field local recurrence rate, progression-free survival (PFS), and overall survival (OS). Results: Between 10/2018 and 03/2022, 24 patients with a median age of 68 years were treated (median follow-up: 11.4 months) with platinum/etoposide and 30 Gy/10 fractions TRT; 10 patients also received atezolizumab. The MTD of olaparib with TRT was 200mg twice daily. There were 3 grade 3 (G3) dose-limiting adverse events (AEs), including pneumonitis/pneumonia, esophagitis, and abdominal pain. The most common G2-3 treatment-related AEs were esophagitis (n=12) and pneumonitis/pneumonia (n=2). There were no G4 or 5 AEs. The 12-month cumulative incidence of local recurrence was 27%, median PFS and OS were 3.6 months and 17.7 months, respectively. Conclusions: This study defined a MTD and recommended phase II dose of 200mg twice daily olaparib with concurrent low-dose TRT, and the combination appeared safe without unexpected toxicities.