Tumor Mutational Burden May Help Predict Immunotherapy Response in Metastatic NSCLC

Response to immunotherapy and survival outcomes were found to be significantly associated with tumor mutational burden in patients with stage IV non-small cell lung cancer.

Tumor mutational burden (TMB) was associated with immunotherapy response and survival outcomes in patients with metastatic non-small cell lung cancer (NSCLC), according to study findings published in Oncotarget.

As immune checkpoint inhibitors have substantially improved clinical outcomes for some patients with metastatic NSCLC, determining which patients would most benefit from the drugs have generated inconsistent findings for biomarkers such as programmed death-ligand 1 (PD-L1).

“Improved patient selection would better identify patients who benefit from immunotherapy as well as spare patients predicted as non-responders from needless toxicity and cost,” noted researchers.

TMB measured by comprehensive genomic profiling (CGP) has emerged as a potential biomarker to predict a tumor’s sensitivity to immuno-oncology agents in a variety of advanced cancers. Moreover, high TMB has consistently been associated with improved clinical benefit among patients receiving immunotherapy for NSCLC, said the study authors.

Researchers sought to further assess the association of TMB with treatment response and survival outcomes in patients with metastatic NSCLC. They conducted a real-world multi-site study to evaluate clinical outcomes by TMB collected from tissue samples among patients diagnosed with stage IV NSCLC between 2012-2019 who were treated with immunotherapy containing regimens in the first-line setting and underwent CGP.

In the study, 667 patients with NSCLC of 9 US cancer centers were stratified by initial TMB mutations/megabase (mut/Mb) measures of greater than or equal to 10 mut/Mb (high; n = 272) and less than 10 mut/Mb (low; n = 395)

“The majority of patients received CGP from Foundation Medicine (64%), followed by Caris (20%), and Oncoplex (8%). Foundation Medicine was widely utilized by 6 (67%) of the participating cancer centers, while Caris was utilized by 2 (22%) institutions, and all other testing platforms were utilized by a single institution,” added researchers.

Compared with patients who had low TMB, those with high TMB were significantly associated with a positive smoking history (P < .01). Furthermore, lower TMB was associated with ALK (P = .01) and EGFR (P < .01) alterations, whereas higher TMB was associated with TP53 (P < .01) alterations. Actionable genomic mutations that were not significantly associated with TMB included BRAF (P = .18), ROS1 (P = .24), and RET (P = .43).

Regarding patient outcomes, 67% and 68% of patients with TMB less than 10 and TMB greater than or equal to 10 were alive at the end of follow-up, respectively. In conducting a subgroup analysis of patients who received TMB testing by Foundation Medicine or Caris within 60 days of treatment initiation (n = 141), a significant association was found for those with high TMB vs low TMB with overall survival (HR, 0.43; 95% CI, 0.21-0.88; P = .02) and progression-free survival (HR, 0.43; 95% CI, 0.21-0.85; P = .02).

“Based on the results in this study and prior research, TMB along with other biomarkers, such as PD-L1, may help identify patients more likely to benefit from first-line immunotherapy,” they concluded. “Prospective research is warranted to validate the predictive utility of this biomarker specifically in patients with low PD-L1 expression.”

Reference

Willis C, Bauer H, Au TH, et al. Real-world survival analysis by tumor mutational burden in nonsmall cell lung cancer: a multisite U.S. study. Oncotarget. Published online January 31, 2022. doi:10.18632/oncotarget.28178