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Urology Times Journal

Vol 49 No 04
Volume49
Issue 04

High-TMB predicts immunotherapy response in bladder but not prostate cancer

A retrospective analysis led by researchers from The University of Texas MD Anderson Cancer Center found that high tumor mutation burden (TMB-H) is only a biomarker for clinical response to immune checkpoint inhibitors in some tumor types, according to findings published in the Annals of Oncology.1,2

Regarding the most common genitourinary cancers, the study showed that TMB-H status was predictive of clinical response to immune checkpoint inhibitors in patients with bladder cancer, but not in patients with prostate cancer.

“This study represents the most comprehensive analysis to date of TMB as a biomarker for response to immune checkpoint blockade,” lead author Daniel J. McGrail, PhD, postdoctoral fellow in Systems Biology at MD Anderson, stated in a press release. “Our results do not support applying high TMB status as a universal biomarker for immunotherapy response, suggesting that additional tumor type-specific studies are needed to clarify how best to apply TMB status in cancer types where it does not appear to be associated with outcomes.”

The anti–PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda) received a tumor-agnostic approval from the FDA in June 2020 for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.3

The approval was based on the phase 2 KEYNOTE-158 trial, which included 755 patients with evaluable TMB, 102 (13%) of whom had tumors that were classified as TMB-high. Results showed that the ORR with pembrolizumab in these patients was 29%, comprising a 4% complete response rate and a 25% partial response rate. Of note, there were solid tumor types not represented in the trial, including prostate, breast, and brain cancers.

“The FDA approval of pembrolizumab for patients with high TMB certainly provides an important option for many patients,” senior author Shiaw-Yih Lin, PhD, professor of Systems Biology, MD Anderson, stated in the press release. “However, we felt that it was important to look more closely at TMB status in a broader group of cancer types and establish approaches to harmonize TMB across various assays to enable clinicians to best utilize the recent FDA approval.”

For their analysis, the MD Anderson researchers used data from The Cancer Genome Atlas to examine over 10,000 tumors across 31 tumor types. They specifically assessed the interaction between TMB status and tumor immunogenicity, which they defined as “infiltration of immune cells (CD8+ T cells) into the tumor.” Across the 31 tumor types, there was a subgroup of cancers showing a strong relationship between TMB status and T cell infiltration, and a second subgroup in which the correlation between these 2 factors was not strong.

In tumors where the correlation was strong between T cell infiltration and TMB status (eg, bladder, lung, melanoma), clinical outcomes were improved in patients with TMB-H status. The ORR to immunotherapy was 39.8% among those who were TMB-H, which the researchers reported was significantly higher than the ORR in individuals with low TMB. 

In contrast, among tumors without a strong correlation between TMB status and T cell infiltration (eg, prostate, breast, and glioma), TMB status was not predictive of the success of immunotherapy. The ORR with immune checkpoint agents was 15.3% among patients in this subgroup with TMB-H status. This rate was lower than the ORR with immune checkpoint agents in patients with TMB low status.

“While TMB status does show value in predicting response to immune checkpoint blockade in several cancer types, this was not generalizable across all cancers,” McGrail stated. “For those cancer types where a high TMB does not appear to increase immunogenicity, additional prospective studies are needed to determine if TMB status can be an effective clinical biomarker and at what threshold.”

References

1. Study finds high tumor mutation burden predicts immunotherapy response in some, but not all, cancers. Published online March 15, 2021. Accessed March 24, 2021. https://bit.ly/2NPCmcD.

2. McGrail DJ, Pilié PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types [published online March 10, 2021]. Ann Oncol. doi: 10.1016/j.annonc.2021.02.006

3. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 16, 2020. Accessed March 24, 2021. bit.ly/3el8pck.

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