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

Area of Science:

• Oncology
• Radiation Oncology
• Clinical Pharmacology

Background:

• Extensive-stage small cell lung cancer (ES-SCLC) treatment typically involves induction chemotherapy followed by consolidative thoracic radiation therapy (TRT).
• Preclinical models suggest PARP inhibitors can enhance the radiosensitizing effects of radiation in lung cancer.
• Investigator-initiated studies are crucial for exploring novel therapeutic combinations in challenging cancers.

Purpose of the Study:

• To determine the safety and maximum tolerated dose (MTD) of concurrent olaparib and low-dose TRT in patients with ES-SCLC.
• To evaluate the efficacy of this combination in terms of local recurrence, progression-free survival (PFS), and overall survival (OS).

Main Methods:

• A single-arm, open-label, multi-institutional Phase I study was conducted.
• Patients received oral olaparib concurrently with low-dose TRT (30 Gy/10 fractions) after induction platinum/etoposide chemotherapy.
• Olaparib dose escalation started at 50mg twice daily, with primary endpoints focused on safety and MTD.

Main Results:

• The MTD of olaparib in combination with TRT was determined to be 200mg twice daily.
• Three dose-limiting toxicities (Grade 3) were observed: pneumonitis/pneumonia, esophagitis, and abdominal pain.
• The 12-month local recurrence rate was 27%, with median PFS of 3.6 months and median OS of 17.7 months.

Conclusions:

• The study successfully identified a recommended Phase II dose of 200mg twice daily for olaparib plus concurrent low-dose TRT.
• The combination demonstrated an acceptable safety profile with no unexpected toxicities.
• This regimen warrants further investigation in Phase II trials for ES-SCLC patients.