Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non–Small Cell Lung Cancer

Author:

Thummalapalli Rohit1ORCID,Ricciuti Biagio2ORCID,Bandlamudi Chaitanya3ORCID,Muldoon Daniel3ORCID,Rizvi Hira1ORCID,Elkrief Arielle1ORCID,Luo Jia2ORCID,Alessi Joao V.2ORCID,Pecci Federica2ORCID,Lamberti Giuseppe2ORCID,Di Federico Alessandro2ORCID,Hong Lingzhi4ORCID,Zhang Jianjun4ORCID,Heymach John V.4ORCID,Gibbons Don L.4ORCID,Plodkowski Andrew J.5ORCID,Ravichandran Vignesh6ORCID,Donoghue Mark T.A.6ORCID,Vanderbilt Chad3ORCID,Ladanyi Marc3ORCID,Rudin Charles M.1ORCID,Kris Mark G.1ORCID,Riely Gregory J.1ORCID,Chaft Jamie E.1ORCID,Hellmann Matthew D.1ORCID,Vokes Natalie I.4ORCID,Awad Mark M.2ORCID,Schoenfeld Adam J.1ORCID

Affiliation:

1. 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

2. 2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

3. 3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

4. 4Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas.

5. 5Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

6. 6Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

Abstract Purpose: We sought to identify features of patients with advanced non–small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR). Experimental Design: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR. Results: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched for LTR compared with STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared with non-LTR (P < 0.001), PD-L1 ≥ 50% did not enrich for LTR compared with STR (P = 0.181). Nonsquamous histology (P = 0.040) and increasing depth of response [median best overall response (BOR) −65% vs. −46%, P < 0.001] also associated with LTR compared with STR; no individual genomic alterations were uniquely enriched among LTR patients. Conclusions: Among patients with advanced NSCLC treated with ICIs, distinct features including high TMB, nonsquamous histology, and depth of radiographic improvement distinguish patients poised to achieve LTR compared with initial response followed by progression, whereas high PD-L1 does not.

Funder

National Institutes of Health

Conquer Cancer Foundation

Society for Immunotherapy of Cancer

Mark Foundation For Cancer Research

American Society of Clinical Oncology

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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