Tumor mutational burden (TMB) refers to the number of somatic gene mutations present in a tumor, which varies across different cancer types.1 It is hypothesized that these tumor mutations can result in proteins expressed by tumor cells that are recognized by the immune system, called neoantigens. A greater number of mutations can theoretically result in a greater number of neoantigens, and therefore more immune system activation. Taken together, a tumor harboring a high number of mutations — or a tumor with a high TMB — may be more likely to respond to immune checkpoint inhibitor (ICI) therapies because ICIs work by enhancing the immune response to tumor cells.
The development of TMB as a biomarker to predict benefit of ICIs is a robust area of research that has resulted in a recent approval by the US Food and Drug Administration (FDA) that relied on the characterization and measurement of TMB. In June 2020, the FDA approved the checkpoint inhibitor pembrolizumab (Keytruda®) for the treatment of children or adults with solid tumors that cannot be removed by surgery or that have metastasized provided those tumors harbor a high TMB (defined as ≥10 mut/Mb).2 This indication is only available to patients whose cancer has progressed during or after treatment with another therapy and who have no other reasonable alternative treatments.
The FDA’s approval of this indication allows certain patients access to an ICI who may not have been candidates for the receipt of pembrolizumab before. However, TMB is not a perfect predictor of benefit to ICIs, and challenges regarding its use remain.
TMB and Tumor Sensitivity to ICIs
A study of more than 100,000 human cancer genomes found that the level of TMB varies widely across cancer types.3 Focusing on 167 different cancer types that had larger sample sizes, adults with cancer carried a higher TMB than children with cancer. TMB was highest in skin cancers, including squamous cell carcinoma and melanoma, and cancers of the lung, bladder, cervix, and kidney. The lowest levels of TMB were found in myelodysplastic or myeloproliferative disorders and cancers of the bone or soft tissue, adrenal gland, and thymus. However, there was wide variability in TMB for each cancer type, meaning that some patients harbored very high or very low TMBs regardless of their specific disease type.
Retrospective studies found that response to ICI treatment and subsequent survival were associated with high TMB in certain cancers,4-6 leading to the initiation of clinical trials that prospectively assessed whether high TMB could identify patients who are more likely to benefit from ICI treatment.
Outcomes from use of an ICI combination, nivolumab plus ipilimumab, were shown to be associated with TMB among patients with non-small cell lung cancer (NSCLC).7 In the phase 3 CheckMate 227 trial, the group with high TMB were more likely to respond and had a longer PFS (median 7.2 months vs 3.2 months) than the group with low TMB. But TMB was not associated with response to, or survival from, treatment with nivolumab when used alone. However, because clinical benefit was derived from nivolumab plus ipilimumab when TMB was not assessed, this combination was approved for the treatment of NSCLC regardless of TMB level.8 For this ICI combination, patients with NSCLC must have at least 1% programmed death ligand-1 (PD-L1) expression.
However, the FDA approval was based on the retrospective analysis of the phase 2 KEYNOTE-158 trial, in which patients with different solid tumors were treated with pembrolizumab.9 Patients with tumors with high TMB vs low TMB were more likely to respond to treatment (28.3% vs 6.5%, respectively), but there was no difference in progression-free survival (PFS) or overall survival (OS) between the groups.
Challenges With TMB
Although the use of TMB to select pembrolizumab for a patient has been approved by the FDA, some experts have raised concerns about using TMB as a biomarker.1,10 TMB has been measured differently between studies, using different assays — for example, some enriching for certain mutations (and others not), the number of genes included in the assay, the type of mutations included — and different thresholds for defining “high” compared with “low” mutation burden.1 These differences can lead to variations in the scoring of TMB. In addition, the turnaround time for TMB is approximately 2 to 3 weeks, which could delay the start of treatment.10 The pembrolizumab indication includes the use of a specific test to evaluate TMB, which should theoretically help to limit challenges related to methodology between centers.
There have also been mixed results from trials about the utility of TMB. To date, no prospective clinical trials had demonstrated that selection of ICI treatment based on a high TMB over low TMB improves OS.1,10 Most studies have evaluated TMB in specific tumors types, whereas KEYNOTE-158 evaluated TMB retrospectively in 10 different tumor types, each with relatively low numbers. But, the KEYNOTE-158 trial only showed a benefit in response to pembrolizumab; there was no difference in PFS or OS in the TMB-high or -low groups.
These challenges highlight that using TMB to gauge patient eligibility for ICI therapy is complex. Oncologists can use FDA approval for an indication as a guide, but must also consider the patients’ specific cancer type and other treatments that are available, among other factors. Using TMB as a biomarker is not one-size-fits-all model.
Through its recent approval, the FDA acknowledged the characterization of “high TMB” as a way to identify patients who may benefit from pembrolizumab treatment. Although there have been multiple studies that have associated high TMB with response and clinical benefit to ICI therapies, many challenges and questions remain regarding the optimal use of TMB as a biomarker.
- Sholl LM, Hirsch FR, Hwang D, et al. The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. Published online June 6, 2020. doi:10.1016/j.jtho.2020.05.019
- US Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors [press release]. Published June 17, 2020. Accessed August 13, 2020.
- Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. doi:10.1186/s13073-017-0424-2.
- Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124–128. doi:10.1126/science.aaa1348
- Samstein RM, Lee C-H, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202-206. doi:10.1038/s41588-018-0312-8
- Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448. doi:10.1038/s41591-018-0134-3
- Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104. doi:10.1056/NEJMoa1801946
- US Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%) [press release]. Published May 15, 2020. Accessed August 13, 2020.
- Marabelle A, Fakih MG, Lopez J, et al. Association of tumor mutational burden with outcomes of select advanced solid tumors treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30(suppl 5; abstr 4445):v475-v532. doi:10.1093/annonc/mdz253.018
- Addeo A. Tumor mutation burden—from hopes to doubts. JAMA Oncol. 2019;5(7):934-935. doi:10.1001/jamaoncol.2019.0626