The Importance of Tumor Mutational Burden in Cancer Treatment Demonstrated Once Again

For many patients diagnosed with cancer, understanding the latest treatment options and clinical research is important. Today I will discuss a study examining the relationship between immune checkpoint inhibitors—that is, immunotherapy treatment and outcomes in patients with advanced cancer, focusing on tumor mutational burden (TMB) and its association with these outcomes.

TMB measures how many mutations are present in a tumor's DNA. Better survival with immunotherapy in patients with high tumor mutational burden (TMB-H) than in those with low tumor mutational burden (TMB-L) had previously been demonstrated.

In this sense, TMB is a tumor-agnostic (tissue-independent) biomarker. We describe drugs that target genetic alterations specific to cancer cells, regardless of the organ in which the cancer originated, as tumor-agnostic . The number of cancer drugs approved in this way is steadily increasing.

Tissue-Independent Biomarkers and Their FDA-Approved Settings

The first FDA approval for this purpose was granted in 2017 for tumors with MSI-H or dMMR , to the immunotherapy pembrolizumab (Keytruda). With this approval, MSI-H and dMMR status became the first tumor-agnostic biomarkers.

FDA approvals independent of a tumor's tissue of origin can be listed as follows:

1. 2017: Pembrolizumab (Keytruda) - for MSI-H or dMMR tumors.
2. 2018: Larotrectinib (Vitrakvi) - for NTRK gene fusions.
3. 2019: Entrectinib (Rozlytrek) - for NTRK genetic alterations.
4. 2020: Pembrolizumab (Keytruda) - for all patients with solid/organ tumors with high tumor mutational burden (TMB-H).
5. 2022: The combination of Trametinib (Mekinist) and Dabrafenib (Tafinlar) - for BRAF-mutated tumors.
6. 2022: Selpercatinib (Retevmo) - for RET fusion-positive tumors

Thus, in oncology we now have 5 tumor-agnostic  biomarkers  (MSI-H/dMMR, NTRKs, TMB-H, BRAF, and RET) and 5 different treatment regimens.

The Tempus Study

Published on May 2, 2023, in JAMA Network Open , this study used patient information from the database of the cancer genetics company Tempus, covering approximately 300 cancer centers. Patients included in the analysis had advanced solid tumors (arising in tissues and organs) and had undergone next-generation sequencing (Tempus xT) testing between 2018 and 2022. They had eight different cancer types and received FDA (US Food and Drug Administration)-approved immunotherapies in the first or second line of treatment. The primary outcome was the difference in overall survival between TMB-H (≥ 10 mut/mb) and TMB-L.

A total of 674 patients were included in the study. Their mean age was 69.4, 40.2% were women, and 64.5% were White. The most common cancer types were small cell lung cancer (KHDAK, 49%), bladder cancer (22%), and head and neck squamous cell cancer (14.8%).

• Overall, 30.6% of patients (206 patients) had TMB-H cancer.
• Median follow-up in the total evaluable patient group was 7.2 months.
• Overall survival was significantly better in the TMB-H group than in the TMB-L group: 17.4 months vs 12.7 months (hazard ratio [HR] = 0.72, upper 95% confidence bound [UCB] = 0.91, P = 0.01).
• In a subset of 403 patients who received immunotherapy after TMB testing, median follow-up was 9.4 months. Compared with patients with TMB-L cancer, those with TMB-H cancer (135 patients, 33.5%) had significantly better overall survival (median = 32.8 months vs 14.9 months), progression-free survival, and time to disease progression.
• In this subset, the overall survival benefit in patients with TMB-H cancer was observed regardless of the immunotherapy drug used. Most patients (339 people) had received pembrolizumab. This finding also held in an analysis that included adjustment for PD-L1 expression and microsatellite stability status.
• However, among 43 patients with head and neck squamous cell carcinoma, 1-year overall survival rates did not differ significantly between TMB-H and TMB-L patients. PD-L1 may be a better biomarker than TMB for predicting immunotherapy response in head and neck cancers.

In conclusion, this study confirms significantly better clinical outcomes in TMB-H cancers than in TMB-L cancers among patients with advanced solid tumors treated with immunotherapy, highlighting the importance of TMB as an immunotherapy biomarker. The study demonstrates the importance of tumor mutational burden and the role it may play in cancer treatment.