Safety and Tolerability of Extracranial Radiation Therapy and Immune Checkpoint Inhibitors Among Patients With Metastatic Non-Small Cell Lung Cancer

Abstract

Immune checkpoint inhibitors (ICPIs) are revolutionizing systemic management of non-small cell lung cancer (NSCLC). There is limited published data on the use of radiation therapy (RT) before, during, or after administration of these agents. The goal of this study was to assess safety and tolerability among patients receiving extracranial external beam RT within 6 months before or after enrollment on prospective clinical studies of ICPIs for metastatic NSCLC. A total of 213 patients with Stage 4 NSCLC were enrolled in prospective ICPI trials at our institution. For all patients, ICPIs were delivered until disease progression. Of these patients, we identified 29 patients who received palliative RT between February 2012 and December 2015 to 39 unique osseous or intrathoracic sites within 6 months before or after enrollment on one of 9 prospective clinical studies evaluating safety and/or efficacy of either single agent ICPI (n = 7 anti-PD-1, n = 8 anti-PD-L1) or combined ICPIs (n = 5 anti-PD-1/CTLA-4, n = 9 anti-PD-L1/CTLA-4). RT associated toxicities were defined qualitatively based on review of the clinical chart. Kaplan-Meier (KM) estimates of progression-free survival (PFS) and overall survival (OS) were calculated from date of ICPI initiation. Among patients treated with RT, the median age at time of ICPI study enrollment was 64 years (range 47-75) with 15 males included (52%). The majority of patients had an ECOG 1 performance status (79%) with a median of 4 metastatic sites (range 2-9). Eight lesions (21%) were treated concurrently with systemic treatment. The median interval between ICPI and RT administration was 2.4 months (range 0.2-5.6 months) in lesions treated with RT before or after ICPI. Median PFS and OS were 3.6 months (2.6, not reached-95% CI) and 8.7 months (5.2, 10.8-95% CI), respectively with a median PFS/toxicity follow-up of 5.6 months (range: 0.5-39.7 months). Ten lesions (26%) were treated to thoracic sites and 29 lesions (74%) were treated to osseous sites. The most common osseous dose and fractionation schedules were 30 Gy in 10 fractions (52%) and 20 Gy in 5 fractions (34%) (range: 8-45 Gy in 1-15 fractions). Response to osseous palliative radiation could be qualitatively assessed in 26 lesions; symptomatic improvement either partial or full was noted in 20 lesions (77%). Thoracic RT doses ranged between 10 to 70 Gy in 1 to 35 fractions. One patient experienced possible RT related grade 5 pulmonary toxicity 2 weeks following completion of RT (4 Gy x 5 to right hilum/lung), which was initiated 1 month after last dose of anti-PD-1 therapy. There were no other unexpected RT associated toxicities. In this analysis of RT among NSCLC patients treated on prospective clinical studies with ICPIs, RT directed at osseous metastases was well tolerated. Among patients treated with thoracic RT, there was 1 possible grade 5 RT associated toxicity. ICPI and RT for intrathoracic disease should be further studied to better understand safety and tolerability.