Tumor Mutational Burden Associated With Responses, Immune Cell Infiltration in NSCLC

Increasing tumor mutational burden (TMB) levels appeared to be associated with immune cell infiltration and inflammatory T-cell mediated response, as well as increased sensitivity to PD-1 and PD-L1 blockade for patients with non–small cell lung cancer (NSCLC), according to a study published in JAMA Oncology.

Two TMB groupings were identified using a regression tree modeling objective response rate (ORR) in the discovery cohort, which were defined as either TMB low with 19.0 or fewer mutations per megabase or TMB high with 19.0 or more mutations per megabase. Inclusion the discovery cohort and 2 independent cohorts—Dana-Farber Cancer Institute and Stand Up 2 Cancer—were associated with increasing improvement ORR, progression-free survival (PFS), and overall survival (OS).

Patients who were TMB high and had a PD-L1 expression of 50% or higher had an ORR of 57%, a median PFS of 18.1 months, and OS of 47.7 months following treatment an immune checkpoint inhibitor. Those with low TMB who were PD-L1–negative had an ORR of 8.7%, median PFS of 2.1 months, and median OS of 10.4 months following treatment.

Patients treated at Dana-Farber Cancer Institute with immunotherapy who had high TMB, a high transversion-transition ratio of greater than or equal to 1 helped to identify improved PFS (HR, 0.41; 95% CI, 0.18-0.91; P = .03) and OS (HR, 0.44; 95% CI, 0.20-0.97; P = .04) in the population. In the population with low TMB, improved PFS (HR, 0.81; 95% CI, 0.67-0.97; P = .02) was found to be associated with high transversion-transition ratio, but not OS (HR, 0.85; 95% CI, 0.69-1.04; P = .12).

A total of 3591 NSCLC samples were collected via Dana-Farber Cancer Institute and underwent tumor genomic profiling. Patients had a median age of 66 years, and 78.3% had a history of tobacco use. Overall, 1552 patients with NSCLC received a PD-L1 blockade, 53.5% of whom were women and 86.8% had nonsquamous histologies. The median TMB was 9.8 mutations per megabase. Patients with stage II, III, and IV had higher TMB than those with stage I.

Investigators set out to examine the association between TMB and outcomes among patients who received an immune checkpoint inhibitor at Memorial Sloan Kettering Cancer Center (n = 672), Dana-Farber Cancer Institute (n = 714), and Stand Up 2 Cancer (n = 166). In each cohort, a significantly higher TMB was found in those who responded to immunotherapy.

In the Memorial Sloan Kettering Cancer Center cohort, those who had TMB of 19.0 or more had improved ORR to immune checkpoint inhibitors at 42.5% vs 18.0% for patients with a TMB less than 19.0 (95% CI, 12.7%-36.2%; P <.001). The population also had a longer PFS (HR, 0.38; 95% CI, 0.28-0.52; P <.001), and longer OS (HR, 0.46; 95% CI, 0.32-0.65; P <.001).

In the Dana-Farber Cancer Institute cohort, investigators confirmed that those with high TMB had a higher ORR following treatment with an immune checkpoint inhibitor at 44.9% vs 21.1% for those with low TMB. The group also experienced improved PFS (HR, 0.50; 95% CI, 0.37-0.67; P <.001) and OS (HR, 0.55; 95% CI, 0.39-0.77; P <.001). This was further validated in the Stand Up 2 Cancer cohort, in which investigators identified an ORR of 89.5% in patients with a high TMB z score vs 37.4% with a low TMB of 16.0 or less (P <.001).

It was confirmed that patients who had a high TMB z score had higher ORR at 49.1% vs 21.5% for those with low TMB (P <.001), as well as significantly longer median PFS at 11.4 months vs 2.8 months (HR, 0.40; 95% CI, 0.33-0.50; P <.001) and OS in 36.1 months vs 12.4 months (HR, 0.46; 95% CI, 0.37-0.50; P <.001), respectively. A meta-analysis combined the cohorts and further validated the association between high TMB and ORR (OR, 2.90; 95% CI, 1.78-4.70; P <.001), PFS (HR, 0.47; 95% CI, 0.36-0.61; P <.001), and OS (HR, 0.59; 95% CI, 0.44-0.79; P = .001).

Reference

Ricciuti B, Wang X, Alessi JV, et al. Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. Published Online July 16, 2022. doi:10.1001/jamaoncol.2022.1981