Tumor mutational burden (TMB) is a genomic biomarker with the potential to make a significant impact on the landscape of cancer immunotherapy. This emerging marker measures the number of mutations within a tumor genome and has already been shown to be associated with improved responses to checkpoint inhibitor immunotherapies in lung cancer, melanoma and bladder cancer.
We believe this is just the beginning for the role of TMB in cancer care. In a study published earlier this year, Foundation Medicine and our collaborators analyzed more than 100,000 human cancer genomes across hundreds of tumor types and found that a surprising number of cancers are actually TMB-high, meaning that the tumor harbors a high number of mutations. This could mean that TMB has the ability to predict immunotherapy response in a subset of patients for nearly every type of cancer, and we now have new data that support this hypothesis.
The first study evaluating the potential utility of TMB across diverse cancers
In the new study, Foundation Medicine and our collaborators at the University of California San Diego examined the relationship between TMB and response to immunotherapy in a diverse set of cancer types. Using retrospective analysis, this study found that patients with high TMB had better outcomes compared to patients with lower TMB.
The study included 151 immunotherapy-treated patients with 21 different cancer types who had undergone genomic profiling with FoundationOne®. Patients with high TMB responded nearly three times more frequently than patients with non-high TMB. Additionally, patients with high TMB survived an average of 12.8 months without their tumor growing, nearly four times longer than patients with non-high TMB. Most importantly, a significant improvement in overall survival was observed for high TMB patients compared to those with low-to-intermediate TMB.
Taking it one step further
Previous research has shown that melanoma and non-small cell lung cancer (NSCLC) often have high mutational load and exhibit the most robust responses to PD-1/PD-L1 blockade.1
To ensure our findings weren’t purely driven by the lung and melanoma samples, a key analysis of the study explored whether the predictive power of high TMB held across other tumor types even when those samples were excluded. When we repeated our retrospective analysis in the group of 63 patients with other tumor types, we found similar results. In those samples, high TMB independently predicted improved response rate and progression-free survival after immunotherapy; however significant improvement in overall survival was not achieved.
Although these findings are from retrospective analyses, they are still very encouraging and suggest that we’re moving in the right direction. TMB may indeed help predict response to immunotherapy across a diversity of tumor types, in addition to lung cancer and melanoma, and we remain committed to researching the pan-cancer potential of TMB.
The road ahead
While these data are promising, the study also found that TMB is not a perfect predictor of response. For example, 2 of 46 patients with low TMB responded to anti-PD-1/PD-L1 therapies, and 16 of 38 patients with high TMB did not achieve an objective response. In addition, TMB was not found to be predictive of response to combination therapy of anti-CTLA-4 and anti-PD-1/PD-L1 therapies in another small set of samples.
Given the complexity of cancer, we will almost certainly need multiple biomarkers to accurately predict a patient’s response to immunotherapy. We’ve previously presented research on new genomic biomarkers, such as STK11, which may further refine our ability to match immunotherapy to the right patients. Additional investigation of other genomic signatures through comprehensive genomic profiling will help validate their clinical utility.
There is a lot of work to do, and we’re excited about the potential of TMB and other genomic biomarkers to re-define the cancer immunotherapy landscape. Our FoundationeOne and FoundationOne Heme test reports include TMB, in addition to genomic profiling of hundreds of cancer-related genes, to help physicians and patients make more informed treatment decisions. Importantly, prospective trials in larger patient populations are underway to confirm TMB’s clinical utility in predicting immunotherapy outcomes.
Through dedicated research and continued efforts to obtain a more comprehensive understanding of cancer biology and treatment, we can help advance precision oncology for as many patients as possible.
See the full publication here: Goodman et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Molecular Cancer Therapeutics. 2017. DOI: 10.1158/1535-7163.MCT-17-0386
Alexandrov et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.