In a retrospective cohort study reported in JAMA Oncology, Ricciuti et al found that patients with advanced non–small cell lung cancer (NSCLC) with higher tumor mutational burden (TMB) had better outcomes with PD-1/PD-L1 inhibitor treatment vs those with lower TMB across thresholds of PD-L1 expression.
Study Details
The study involved a total of 1,552 patients who received PD-1 or PD-L1 inhibitors without chemotherapy from the Dana-Farber Cancer Institute (n = 714), Memorial Sloan Kettering Cancer Center (MSKCC; n = 672), and Stand Up To Cancer/Mark Foundation (n = 166) data sets. Patient clinicopathologic and genomic data were collected between September 2013 and September 2020.
These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell–mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.— Ricciuti et al
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Key Findings
Analysis in the MSKCC cohort showed that TMB > 19.0 mutations per megabase (high TMB) vs ≤ 19.0 (low TMB) was associated with improved objective response rates, progression-free survival, and overall survival. The finding was confirmed in the other two cohorts. Among all patients, a total of 161 had high TMB and 1,391 had low TMB.
In the total population, objective response rates for high TMB vs low TMB patients by PD-L1 expression level were: 46.7% vs 8.7% for < 1% (P < .001); 50.0% vs 17.7% for 1% to 49% (P < .001); and 56.5% vs 38.1% for ≥ 50% (P = .02).
Median progression-free survival for high TMB vs low TMB patients by PD-L1 expression level was: 10.7 vs 2.1 months for < 1% (P < .001); 13.6 months vs 2.9 months for 1% to 49%; and 18.1 months vs 5.2 months for ≥ 50% (P < .001).
Median overall survival for high TMB vs low TMB patients by PD-L1 expression level was: 23.9 months vs 10.4 months for < 1% (P = .07); not reached vs 11.3 months for 1% to 49% (P < .001); and 47.7 months vs 21.4 months for ≥ 50% (P = .02).
Multiplexed immunofluorescence and transcriptomic profiling showed that high TMB levels were associated with increased CD8-positive, PD-L1–positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.
The investigators concluded, “These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell–mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.”
Mark M. Awad, MD, PhD, of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the National Cancer Institute and National Human Genome Research Institute. For full disclosures of the study authors, visit jamanetwork.com.
