Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic ROS1-Rearranged Lung Cancers

• Main Authors: Noura J. Choudhury, MD, Jaime L. Schneider, MD, PhD, Tejas Patil, MD, Viola W. Zhu, MD, PhD, Debra A. Goldman, MS, Soo-Ryum Yang, MD, Christina J. Falcon, MPH, Andrew Do, BS, Yunan Nie, MD, Andrew J. Plodkowski, MD, Jamie E. Chaft, MD, Subba R. Digumarthy, MD, Natasha Rekhtman, MD, PhD, Maria E. Arcila, MD, Alexia Iasonos, PhD, Sai-Hong I. Ou, MD, PhD, Jessica J. Lin, MD, Alexander Drilon, MD
• Format: Article
• Language: English
• Published: Elsevier 2021-07-01
• Series: JTO Clinical and Research Reports
• Subjects: Non–small cell lung cancer; ROS1 fusion; Immune checkpoint inhibitors; Tumor mutational burden; PD-L1
• Online Access: http://www.sciencedirect.com/science/article/pii/S2666364321000461
• ISSN: 2666-3643

Introduction: ROS1 fusions are oncogenic drivers in 1% to 3% of NSCLCs. The activity of immune checkpoint inhibitor (ICI) monotherapy or in combination with chemotherapy (chemotherapy with ICI [chemo-ICI]) in these tumors and their immunophenotype have not been systematically described. Methods: In this multi-institutional retrospective study, tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) were evaluated in patients with ROS1-rearranged NSCLC. Time-to-treatment discontinuation (TTD) and objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) were calculated for patients treated with ICI or chemo-ICI in the metastatic setting. Results: A total of 184 patients were identified. Among 146 assessable cases, PD-L1 expression was less than 1% in 60 (41%), 1% to 49% in 35 (24%), and greater than or equal to 50% in 51 tumors (35%). Of 100 (92%) TMB-assessable tumors, 92 had less than 10 mutations per megabase. TMB was significantly lower for ROS1-rearranged tumors (n = 97) compared with tumors with EGFR (n = 1250) or KRAS alterations (n = 1653) and all other NSCLC tumors (n = 2753) evaluated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (median TMB = 2.6 versus 3.5, 7.0, and 6.1 mutations per megabase, p < 0.001). Among patients treated with ICI, median TTD was 2.1 months (95% confidence interval [CI]: 1.0–4.2 mo; n = 28) and ORR 13% (2 of 16 RECIST-assessable; 95% CI: 2%–38%). Among patients treated with chemo-ICI, median TTD was 10 months (95% CI: 4.7–14.1 mo; n = 11) and ORR 83% (5 of 6 RECIST-assessable; 95% CI: 36%–100%). There was no difference in PD-L1 expression (p = 0.91) or TMB (p = 0.83) between responders and nonresponders. Conclusions: Most ROS1-rearranged NSCLCs have low PD-L1 expression and TMB. The activity of ICI in these tumors is modest. In contrast, chemo-ICI can achieve meaningful activity.