medwireNews: High tumor mutational burden is associated with a better response to immune checkpoint inhibitors (ICIs) in people with non-small-cell lung cancer (NSCLC) across all levels of PD-L1 expression, US researchers report.
Mark Awad (Dana-Farber Cancer Institute [DFCI], Boston, Massachusetts) and colleagues also found that people with high TMB levels had “increased CD8-positive T-cell infiltration and distinct immune response gene expression signatures,” which they say could make TMB “a valuable biomarker for estimating immune checkpoint inhibitor efficacy.”
The researchers used next-generation sequencing to measure the TMB levels in tumor samples from 1552 patients (median age 66 years, 53.5% women) with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors without chemotherapy in three independent cohorts between 2013 and 2020.
Overall, the median TMB was 9.8 mutations/mb. Tumors with activating mutations in BRAF and KRAS and those without an identifiable driver mutation had the highest TMB, while those with EGFR mutations and chromosomal rearrangements in RET and ALK had the lowest TMB.
Awad et al report in JAMA Oncology that tumors from patients who responded to immunotherapy had significantly higher TMB than those from patients with stable or progressive disease.
They then calculated that a TMB Z score of 1.16, based on the three platforms used to measure TMB among the patients, was the optimal cutoff for defining high versus low TMB. This corresponded to the approximately 90th percentile for TMB or a measurement of 19.0 mutations/mb on the Memorial Sloan Kettering-IMPACT platform, 19.3 mutations/mb on the DFCI-OncoPanel, or 16.0 mutations/mb with whole exome sequencing.
In a pooled analysis of the three cohorts, the investigators observed that high TMB was associated with a significantly higher objective response rate than low TMB (49.1 vs 21.5%), as well as a significantly longer median progression-free survival (11.4 vs 2.8 months) and overall survival (36.1 vs 12.4 months).
Moreover, individuals with high TMB levels had significantly better outcomes than those with low TMB levels across all subgroups of PD-L1 expression, which suggests that “TMB can further stratify outcomes of immunotherapy for patients within each clinically relevant PD-L1 expression group,” Awad and co-authors remark.
Further analyses using multiplexed immunofluorescence and transcriptomic profiling showed that high TMB levels were associated with increased CD8-positive, PD-L1–positive T-cell infiltration and upregulation of innate and adaptive immune response signatures.
In addition, high-TMB tumors were significantly enriched for mutations in different genes to those enriched in low-TMB tumors, and the researchers highlight the fact that there was no significant co-occurrence of KRAS/STK11 mutations in nonsquamous high-TMB tumors, but significant co-occurrence of KRAS with KEAP1 and STK11 in the low-TMB cohort. The say this finding “is of interest given that concurrent KRAS/STK11 and KRAS/KEAP1 comutations have been shown to be associated with resistance to ICI in NSCLC.”
Awad and team conclude that “integration of TMB with PD-L1 expression may identify patients with the greatest likelihood of response to immunotherapy.”
They add that the findings “suggest that TMB should routinely be introduced as a stratification factor for immunotherapy clinical trials, to ensure that outcomes are associated with treatment interventions, rather than imbalances in TMB distributions.”
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JAMA Oncol 2022; doi:10.1001/jamaoncol.2022.1981