Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

Abstract

BackgroundAblative local treatment of all radiographically detected metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies demonstrated safety of combining stereotactic body radiation therapy (SBRT) with single agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. MethodsWe conducted a phase Ib clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with stereotactic body radiation therapy (SBRT) to a dose of 30 – 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until progression or toxicity. ResultsSeventeen patients were enrolled on study, with 15 patients receiving at least one dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during COVID 19 pandemic. Grade 3+ treatment related adverse events were seen in 6 patients (40%). Of these, only one was felt possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months while median OS has not yet been reached. ConclusionsDelivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared to historical studies of dual checkpoint immunotherapy alone. While not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared to immunotherapy or radiation alone in this patient population.