Mutation Burden Does Not Predict Immune Checkpoint Blockade Across All Cancers

By Marilynn Larkin

March 26, 2021

NEW YORK (Reuters Health) - An analysis of more than 10,000 tumors from more than 30 cancer types revealed that high tumor mutation burden (TMB-H) is not a reliable predictive biomarker of immune checkpoint blockade (ICB) in all solid tumors.

"TMB-H has been proposed as a predictive biomarker for response to ICB, largely due to the potential for tumor mutations to generate immunogenic neoantigens," Dr. Daniel McGrail of the University of Texas MD Anderson Cancer Center in Houston and colleagues write. "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."

Earlier work by the team showed that high TMB was associated with increased immune activation in only certain cancer types, Dr. McGrail told Reuters Health by email. "So, when the FDA approved an immune checkpoint inhibitor for treating advanced cancers with high TMB, we thought it was important to look more closely at the predictive accuracy of TMB in a broader group of cancers."

"Our previous observations were mirrored in this analysis," he said. "In cancers where high TMB corresponded with immune activation, such as melanoma and lung cancer, we observed that high TMB could accurately predict response to immunotherapy. However, for many common cancers, such as those of the breast, brain, or kidney, where TMB was not associated with immune activation, high TMB failed to predict response."

"Current evidence does not support the use of high TMB as a pan-cancer biomarker for immune checkpoint inhibition," he concluded.

As reported in Annals of Oncology, the team analyzed data from more than 10,000 patient tumors spanning 31 cancer types from The Cancer Genome Atlas (TCGA) to assess the correlation between predicted neoantigen load and CD8 T-cells.

Associations between TMB with ICB treatment outcomes were analyzed by both objective response rates (ORRs) and overall survival (OS).

In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors had a 39.8% ORR to ICB - significantly higher than that observed in low TMB (TMB-L) tumors (odds ratio, 4.1).

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, and showed a significantly lower ORR relative to TMB-L tumors (OR, 0.46).

Bulk ORRs were not significantly different between the two tumor types. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable.

Summing up, the authors state, "Taken together, current evidence fails to support the use of TMB-H as a biomarker for ICB treatment in all tumor types, including the FDA-approved threshold of 10 mut/Mb. Future studies should focus both on improving cancer type-specific assessment of TMB from targeted sequencing and cancer type-specific activity of ICB in TMB-H tumors before broad clinical implementation."

Dr. Peter Lee, Chair of the Department of Immuno-Oncology at City of Hope in Duarte, California, commented by email to Reuters Health, "This is an important study to highlight the complexities of anti-tumor immunity and biomarkers. Clearly, one size does not fit all. There are at least two different types of cancer in relation to host immune response and ICB therapy efficacy."

"TCGA data are primarily from primary tumors, while ICB therapy is mainly given to patients with metastatic disease," he noted. "It is possible that the TMB of metastatic tumors may be higher than that of primary tumors."

Further, he added, "Colon cancers should be divided into microsatellite stable versus microsatellite instable. (In this study), all ICB treatments are lumped together. These may include anti-CTLA4, anti-PD1, anti-PDL1. Within each, there are several different antibodies. ICB may be given alone or in conjunction with chemotherapy."

SOURCE: https://bit.ly/2PocZPB Annals of Oncology, online March 15, 2021.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....