High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types

D J McGrail; P G Pilié; N U Rashid; L Voorwerk; M Slagter; M Kok; E Jonasch; M Khasraw; A B Heimberger; B Lim; N T Ueno; J K Litton; R Ferrarotto; J T Chang; S L Moulder; S-Y Lin

doi:10.1016/j.annonc.2021.02.006

High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types

Ann Oncol. 2021 May;32(5):661-672. doi: 10.1016/j.annonc.2021.02.006. Epub 2021 Mar 15.

Authors

D J McGrail¹, P G Pilié², N U Rashid³, L Voorwerk⁴, M Slagter⁵, M Kok⁶, E Jonasch², M Khasraw⁷, A B Heimberger⁸, B Lim⁹, N T Ueno⁹, J K Litton⁹, R Ferrarotto¹⁰, J T Chang¹¹, S L Moulder⁹, S-Y Lin¹²

Affiliations

¹ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: djmcgrail@mdanderson.org.
² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, USA.
⁴ Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁵ Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
⁶ Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷ The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, USA.
⁸ Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, USA.
⁹ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
¹⁰ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
¹¹ Department of Integrative Biology and Pharmacology, The University of Texas Health Sciences Center at Houston, Houston, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA.
¹² Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: sylin@mdanderson.org.

Abstract

Background: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers.

Patients and methods: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936).

Results: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10^-16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable.

Conclusions: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.

Keywords: biomarker; immune checkpoint blockade; tumor mutation burden.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor
Humans
Immune Checkpoint Inhibitors*
Male
Mutation
Neoplasms* / drug therapy
Neoplasms* / genetics
Treatment Outcome

Substances

Biomarkers, Tumor
Immune Checkpoint Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding