Patients With Advanced Cancer With High TMB Show Favorable Outcomes on ICIs

A recent study found that patients with advanced solid cancers with high tumor mutational burden (TMB) saw improved outcomes on immune checkpoint inhibitors (ICIs) compared with patients who had low-TMB cancers.

Among patients with advanced solid tumors treated with immune checkpoint inhibitors (ICIs), those with high tumor mutational burden (TMB) cancers showed significantly improved outcomes compared with patients who had low-TMB cancers in a recent study. The findings were published in JAMA Network Open and suggest that patients with high TMB should be considered for treatment with ICIs.

TMB, which refers to the total number of somatic variations identified in the tumor genome, is a biomarker for ICI response across advanced cancer types, but it has shown mixed results in prospective and retrospective studies, the authors noted. This has limited its widespread use as a biomarker in routine clinical settings.

“The potential clinical benefit of this biomarker is founded upon the hypothesis that highly mutated tumors produce high-quality neoantigens that increase T-cell reactivity, which in turn leads to improved response to immune checkpoint blockade treatment,” the authors explained.

While retrospective studies have shown variation in the clinical benefit of TMB depending on the type of cancer and clinical end points being tested, these varied results may be attributable to differences in the type of biomarker testing panel used as well as the threshold for TMB from study to study. The current study aimed to determine the validity of a standard TMB biomarker across diverse advanced cancers in a large cohort.

A total of 674 patients whose tumors were sequenced between 2018 and 2022 were included in the study, which used the deidentified clinicogenomic Tempus database of patients. The retrospective, observational data included patients with 8 distinct advanced cancer diagnoses and more than 20 histologies from 199 community sites and 101 academic sites.

All patients had advanced solid tumors sequenced by Tempus xT, and all were treated with ICIs in the first- or second-line settings. ICIs included FDA-approved PD-1/PD-L1 inhibitors and/or in combination with a CTLA-4 inhibitor.

The most common cancers in the study population were non–small cell lung cancer (49.0% of patients), followed by bladder cancer (22.0%) and head and neck squamous cell carcinoma (14.8%).

The relationship between TMB and overall survival (OS) was the main end point, with high TMB defined as 10 or more genomic variations. Progression-free survival (PFS) and time to progression (TTP) were also assessed.

At a median (IQR) follow-up of 7.2 (3.2-14.1) months, patients with high TMB cancers (n = 206) showed significantly longer OS compared with patents who had low TMB cancers (HR, 0.72; upper confidence bound [UCB], 0.91; P = .01).

A prospective subset of patients (n = 403) was treated with ICIs after TMB testing. In this cohort, those who had high-TMB cancers (n = 135; 33.5%) had longer OS compared with patients with low-TMB cancers (HR, 0.61; UCB, 0.84; P = .005). PFS was also longer in patients whose cancer showed high TMB (HR, 0.62; UCB, 0.82; P = .003), and the same trend was seen in TTP (HR, 0.67; UCB, 0.92; P = .02).

Patients with high-TMB cancers saw an overall survival benefit regardless of ICI type, and the benefit was still seen after adjusting for PD-L1 and microsatellite stability status (HR, 0.67; UCB, 0.92; P = .02).

The study was limited in its retrospective nature and the limited available data for follow-up on patients who were treated with ICIs prior to testing, the authors noted. Further, the end points for efficacy could represent surrogacy relative to more established, prospective FDA-grade efficacy end points.

Still, TMB category was a consistent biomarker for ICI benefit in the study cohort, which included a range of advanced cancer types.

“More broadly, this study demonstrates the value of clinical genomic data sets for the assessment of evolving molecular biomarkers and clinical outcomes in diverse settings which are more representative of clinical practice patterns than clinical trials,” the authors concluded.


Aggarwal C, Ben-Shachar R, Gao Y, et al. Assessment of tumor mutational burden and outcomes in patients with diverse advanced cancers treated with immunotherapy. JAMA Netw Open. 2023;6(5):e2311181. doi:10.1001/jamanetworkopen.2023.11181

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