169P Phase I dose escalation trial combining olaparib and thoracic radiation therapy in extensive-stage small cell lung cancer

A standard for extensive-stage small cell lung cancer (ES-SCLC) is induction therapy followed by thoracic radiation therapy (TRT). PARP inhibitors including olaparib have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open label phase I study on concurrent olaparib with TRT. Patients with progression-free ES-SCLC after 4 to 6 cycles of platinum/etoposide ± atezolizumab, were treated with olaparib for 3 weeks with concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose escalation using the continuous reassessment method started at 50 mg twice daily, escalating at 50 mg/dose level. Patients were permitted to continue atezolizumab maintenance after completion of TRT per standard of care. The primary objective was the safety and MTD of olaparib+TRT. Secondary objectives were in-field local recurrence rate and progression-free (PFS) and overall survival (OS). Between 10/2018 and 03/2022, 24 patients were treated (median follow-up: 11.4 months [range: 2 to 48 months]). Median age was 68 years (range: 49 to 79 years); ECOG status was 0–1 for 13 and 2 for 11 patients, respectively. All patients were treated with platinum/ etoposide; 10 patients also received atezolizumab. All patients received 30 Gy/10 fractions TRT. The MTD of olaparib+TRT was 200 mg twice daily. There were 4 grade 3 (G3) dose-limiting adverse events (AEs), including pneumonitis, lung infection, esophagitis, and abdominal pain (each n = 1). Olaparib-related G2+ AEs included cough, dyspnea, dehydration, anorexia, dysgeusia, alopecia, and diarrhea (each n = 1). The most common G2+ TRT or olaparib+TRT-related AEs were esophagitis (n = 7), pneumonitis (n = 2), vomiting, dehydration, dyspepsia, maculo-papular rash, fever, and weight loss (each n = 1). There were no G4 or 5 AEs. No significant additional AEs were observed with atezolizumab maintenance. The 12-month cumulative incidence of local recurrence was 27%, median PFS was 3.6 months, and median OS was 17.7 months. This is the first report on the safety and MTD of olaparib with concurrent low-dose TRT. The MTD of olaparib was identified as 200 mg twice daily.