Immunotherapy Pan cancer-TMB
Our immune system is a complex process that our body uses to fight illness. This process involves various cells, organs, and proteins within our body. Cancer can commonly get around many of these immune system’s natural defenses, and thrive in our body.
Immunotherapy is a type of cancer treatment that boosts the body’s natural defenses to fight cancer. It uses substances made by the body or in a laboratory to help our immune system work to find and destroy cancer cells. Different types of immunotherapy work in different ways.
In the last few decades immunotherapy has become an important part of treating some types of cancer, monoclonal antibodies and tumor-agnostic treatments, such as checkpoint inhibitors have stood out pre-eminently. It represents a major breakthrough for a number of cancers, but not all patients derive benefit, leaving many with an unmet need. Thus, identification and investigation of potential biomarkers that may predict sensitivity to immunotherapy is also being explored. Tumor factors associated with enhanced response to immunotherapy include microsatellite instability, tumor mutational burden (TMB), and inflammatory gene expression.
Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays.
A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. KEYNOTE-158 trial has confirmed clinical activity of Pembrolizumab in tumors harboring a TMB ≥10 (TMB-High) across a variety of previously treated solid tumors including anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small cell lung, thyroid, and vulvar cancers. A response rate of 29% (versus 6% in patients with a TMB <10) in this biomarker-defined population is quite impressive.
The FDA has approved Pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden–high (TMB-H; ≥10 mutations/megabase), as determined by an FDA-approved test, who have progressed following prior treatment and have no satisfactory alternative treatment options.
Analysis of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies. TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across various cancer types. Next-generation sequencing-based techniques such as PositiveSelect Plus allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally.
Sources:
https://www.targetedonc.com/view/fda-approves-pembrolizumab-for-tmb-high-solid-tumors
https://pubmed.ncbi.nlm.nih.gov/30395155/
https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0799-2
-By Fatima
