Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

Abstract

BACKGROUND:

Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.

METHODS:

Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.

RESULTS:

Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H (GZMB/H) was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).

CONCLUSIONS:

Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either GZMB or GZMH genes was associated with reduced survival.

• Authors: Yuxiang Ma, Xi Chen, Ao Wang, Hongyun Zhao, Qingguang Lin, Hua Bao, Yang Zhang, Shaodong Hong, Wanxiangfu Tang, Yan Huang, Yunpeng Yang, Xue Wu, Yang Shao, Wenfeng Fang, Li Zhang
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 3 (03 2021) ISSN: 2051-1426 [Electronic] England
• PMID: 33737344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• camrelizumab
• GZMB protein, human
• GZMH protein, human
• Granzymes

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Biomarkers, Tumor (genetics)
• Clinical Trials, Phase II as Topic
• DNA Copy Number Variations
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Dosage
• Granzymes (genetics)
• Humans
• Immune Checkpoint Inhibitors (adverse effects, therapeutic use)
• Male
• Middle Aged
• Nasopharyngeal Carcinoma (drug therapy, genetics, immunology, secondary)
• Nasopharyngeal Neoplasms (drug therapy, genetics, immunology, pathology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Progression-Free Survival
• Retrospective Studies
• Time Factors
• Young Adult