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

Noura J Choudhury; Jaime L Schneider; Tejas Patil; Viola W Zhu; Debra A Goldman; Soo-Ryum Yang; Christina J Falcon; Andrew Do; Yunan Nie; Andrew J Plodkowski; Jamie E Chaft; Subba R Digumarthy; Natasha Rekhtman; Maria E Arcila; Alexia Iasonos; Sai-Hong I Ou; Jessica J Lin; Alexander Drilon

doi:10.1016/j.jtocrr.2021.100187

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

JTO Clin Res Rep. 2021 May 18;2(7):100187. doi: 10.1016/j.jtocrr.2021.100187. eCollection 2021 Jul.

Authors

Noura J Choudhury¹, Jaime L Schneider², Tejas Patil³, Viola W Zhu⁴, Debra A Goldman⁵, Soo-Ryum Yang⁶, Christina J Falcon⁷, Andrew Do², Yunan Nie³, Andrew J Plodkowski⁸, Jamie E Chaft^{1

9}, Subba R Digumarthy¹⁰, Natasha Rekhtman⁶, Maria E Arcila⁶, Alexia Iasonos⁵, Sai-Hong I Ou⁴, Jessica J Lin², Alexander Drilon^{1

9}

Affiliations

¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
² Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
³ Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado.
⁴ Department of Medicine, University of California Irvine, Irvine, California.
⁵ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
⁶ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
⁷ Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
⁸ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
⁹ Department of Medicine, Weill Cornell Medical College, New York, New York.
¹⁰ Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.

Abstract

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.

Keywords: Immune checkpoint inhibitors; Non–small cell lung cancer; PD-L1; ROS1 fusion; Tumor mutational burden.

Abstract

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