N. V. Kotha1, L. Vitzthum2, A. L. Chin1, S. Jackson1, A. Pratapneni1, M. L. Le-Budka1, E. Brown1, K. Barnick1, H. A. Wakelee3, M. Das3, K. J. Ramchandran3, N. Myall4, S. Padda5, C. M. Marquez1, L. Million1, M. Diehn2, B. W. Loo Jr6, J. W. Neal3, and M. F. Gensheimer1; 1Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 2Department of Radiation Oncology, Stanford University, Palo Alto, CA, 3Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 4Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, 5Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, 6Department of Radiation Oncology, Stanford University, Stanford, CA
Purpose/Objective(s): For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects, or address the most threatening tumors while the immunotherapy provides benefit for the remaining disease. In the Radical RADiotherapy and Immunotherapy for metastatic Cancer of the Lung (RRADICAL) trial (NCT03176173), we posited that the addition of high-dose RT to ICI therapy could prolong progression-free survival (PFS).Materials/
Methods: In this non-randomized single arm phase 2 trial, 45 patients with metastatic NSCLC who received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Imaging after initiation of ICI had to show partial response or stable disease (per RECIST 1.1) or modest progression (per investigator). Patients received high-dose RT to 1-4 extracranial tumors and continued the ICI until disease progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks from enrollment, comparing to a historical control rate of 35%. Secondary endpoints included toxicity, overall survival (OS), and local control. The exact binomial and log-rank tests were used. Results: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% were poly-metastatic, and 82% were on pembrolizumab. Of 81 treated tumors, the most common dose received was 40 Gray in 10 fractions (n=41). 46% of patients had one tumor treated; the most common treatment site was lung. All visible tumors were treated in 21 (48%) patients. Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median time from enrollment to last dose of the same immunotherapy drug was 6.1 months (IQR 2.7-12.8 mo). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICItreatment alone achieved durable responses with addition of radiotherapy, up to 56 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. Conclusion: Adding high-dose radiotherapy to immunotherapy in metastatic NSCLC improved 24-week PFS compared to historical controls receiving ICI therapy alone, indicating that this is a promising strategy for further study. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease in this setting. However, many patients progressed in other non-radiated sites soon after study RT, highlighting the need for better biomarkers for patient selection for aggressive local therapy.
