Cancer-specific TMB cutoffs may help guide ICI use
medwireNews: A high tumor mutational burden (TMB) is generally predictive of response to immune checkpoint inhibitor (ICI) therapy across multiple tumor types, but the universal cutoff of 10 mutations/Mb to signify a high burden may not be applicable for all tumors, researchers report.
“[T]he predictive value of a single cutoff value for TMB is limited and would likely be improved with cancer type-specific cutoffs,” say Luc Morris and colleagues from Memorial Sloan Kettering Cancer Center in New York, USA.
The researchers drew on data for 1678 patients with microsatellite-stable solid tumors who were given at least one dose of a PD-1 or PD-L1 inhibitor at their institution between 2015 and 2018. Sixteen cancer types were reported among the study participants, the most common being non-small-cell lung cancer (NSCLC) and melanoma, accounting for 39.5% and 12.8% of the cohort, respectively.
Next-generation sequencing showed that a quarter of patients had tumors with a high TMB based on the universal cutoff of 10 mutations/Mb, with the proportion of TMB-high tumors varying across cancer types, from 0% in kidney cancer to 53% in melanoma.
Overall, patients with a high TMB had numerically higher response rates than those with a low TMB in 11 of the 16 cancer types.
In particular, response rates were better with high versus low TMB in the NSCLC, melanoma, sarcoma, bladder cancer, head and neck cancer, SCLC, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and breast cancer cohorts. But the converse was true for the gastric, hepatobiliary, pancreatic, and kidney cancer cohorts, and also for mesothelioma, “although the numbers in these cohorts were small,” say the investigators.
“This heterogeneity may result from applying a single universal TMB cutoff to cancer types with variable TMB distributions and differing mechanisms of neoantigen presentation and immune surveillance across different tissues and anatomical sites,” they write in JAMA Oncology.
Morris et al therefore “recommend caution when considering this universal TMB cutoff for clinical decision-making, because response rates are not reliably higher with TMB above the cutoff value in all cancer types, and associations between this cutoff value and survival rates are unclear.”
They also devised tissue-specific cutoffs, which ranged from 1.90 mutations/Mb for hepatobiliary cancer to 20.80 mutations/Mb for melanoma; the proportion of patients with TMB-high tumors based on these individual cutoffs ranged from 17.8% in the NSCLC cohort to 79.2% in the hepatobiliary cohort.
Using these cutoffs, the response rates to ICI treatment were numerically higher with high versus low TMB for 14 of the 16 cancer types – all except mesothelioma and esophageal cancer.
But the researchers caution that this was an exploratory analysis and these tissue-specific cutoffs “should not be considered definitive optimized cutoffs until they are validated independently.”
And they conclude: “Further investigation will help define the ideal TMB cutoffs to guide decision-making in individual cancer types and evaluate whether expanded use of anti–PD-1 and PD-L1 drugs based on TMB is a cost-effective strategy.”
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