Clinical value of tumor mutation load (TMB)
The clinical use of immune checkpoint inhibitors and numerous breakthroughs have revolutionized the treatment of advanced cancer, yet only 20 percent of patients benefit from immunotherapy.For many years, there has been an urgent search for biomarkers that can predict the efficacy of immunotherapy in order to identify the dominant population.Numerous studies suggest that PD-L1 immunohistochemistry, T cell infiltration level, T cell receptor clonicity, gene expression signal and peripheral blood markers are closely related to clinical therapeutic efficacy. Among them, tumor mutation load (TMB) has received high attention in both academic and industrial circles.The stability and reliability of TMB monitoring have been increasingly discussed due to the wide variation in TMB levels among tumor types and the diverse results obtained from numerous clinical data.As early as 2014, the possibility of TMB as a predictor of tumor immunotherapy effect has attracted industry attention.When we analyzed whole exon sequencing data from melanoma patients treated with ctLA-4 antibody, we found that the higher the mutation load of tumor tissue, the higher the probability of immunotherapy benefit.After this, the clinical research exploration around TMB was officially opened with the promotion of Checkmate-026 trial.In patients with non-small cell lung cancer (NSCLC) with ≥5% PD-L1 expression, nivolumab(Opdivo) missed both primary and secondary clinical trial endpoints, causing it to fail in a key competition with The Keyno-024 trial of pembrolizumab (Keytruda).However, the subsequent retrospective study found that TMB could show more obvious clinical benefits if selected as a biomarker for Opdivo treatment of NSCLC:The ORR of nivolumab in the high-TMB subgroup was significantly higher than chemotherapy (47% vs. 28%) and PFS was significantly longer (9.7 months vs. 5.8 months).BMS seems to see the light at the end of the ray of hope. Checkmate 227 and Checkmate 568 were rapidly activated, further proving that TMB is an important indicator of NSCLC immunotherapy efficacy.Based on these findings, NCCN has also updated TMB into the 2019 NSCLC treatment Guidelines.Subsequently, the predictive effect of TMB has been preliminatively verified in many tumor domains.In keynote-158, pembrolizumab monotherapy was used to treat adults and children with unresectable or metastatic tumor tissue samples with a high mutation load (TBB-H) of ≥10 mutations per Mb in solid tumors.Nine different cancers, including anal, bile duct, cervical, endometrial, salivary, thyroid, vulvar, mesothelioma and neuroendocrine tumors, were evaluated and positive results were obtained.The study was also approved by the US FDA and the indication was quickly approved.As for whether TMB index has clinical significance as a sensitive indicator, there has always been a constant controversy, and clinical studies and evidence-based evidence have also presented a dissimilar outcome.For example, in order to provide high-level evidence-based medical evidence for TMB to prove its clinical effects, BMS significantly increased the sample size in the middle of the trial. Although CheckMate-227 based on TMB analysis obtained positive results for PFS, OS was negative.The NEPTUNE study, carried out by Astrazeneca, also had disappointing results.This is a randomized, open-label, multicenter, global study of all intentionally-treated populations, including non-squamous NSCLC, squamous NSCLC, EGFR/ALK mutation negative, and pD-L1 expression levels.The primary analysis population was patients with high TMB, and the primary endpoint was OS of patients with TMB mutation per Megabyte ≥20 (MUT /Mb), which was ultimately failed to reach the primary endpoint.Recently, some foreign studies have questioned the relationship between TMB and the effect of immunotherapy, especially for different cancers, TMB varies greatly, and the actual value of TMB detection is still worth discussing.At least for now, pD-L1 expression level remains the most widely used and relatively objective marker.In fact, TMB as a single biomarker is challenging to predict.The NCCN guidelines also make it clear: “TMB is an evolving biomarker that may help select patients who are suitable for immunotherapy.There is no consensus on how to measure TMB.”Annals of Oncology and Nature Communications have published articles recently, stating their views from different perspectives, that TMB detection cannot benefit all tumor patients and cannot achieve the expected clinical effects.Scientists at the University of Texas M.D. Anderson Cancer Center and other institutions have found that higher mutation rates in tumors, known as TMB, may be useful only in predicting clinical responses to immune checkpoint inhibitors in some cancer patients.These studies also showed that in some tumors, such as breast cancer and prostate cancer, high neoantigen levels did not lead to high CTL invasion.If the neoantigen levels were positively correlated with CTL infiltration, they were called type I cancers, and those with no CTL infiltration were called type II cancers. Of the new cancers diagnosed each year, type I cancers accounted for about 27% and type II cancers accounted for about 52%.The results showed that the correlation between TMB and immunotherapy was mainly for class I tumors, such as melanoma.Studies have also shown that TMB can predict the effect of immunotherapy to a certain extent in endometrial cancer, cervical cancer, colon cancer, melanoma, lung adenocarcinoma, bladder cancer and other type I cancers.On the other side of the coin, TMB has a limited predictive role in class ii cancers such as triple negative breast cancer, prostate cancer and glioma.While TMB status successfully predicted response to checkpoint blocker therapy in patients with certain cancer types, such as melanoma, lung, and bladder cancer, it did not appear to be associated with improved outcome in patients with other cancers, including breast, prostate, and brain cancers, according to the point-of-view analysis.In addition, TMB is a potential biomarker that can predict the therapeutic efficacy of immune checkpoint inhibitors. From the perspective of clinical detection, there is no standardized method for TMB detection, leading to the lack of standardized test results, which is still a challenge in practice. Currently, large panel detection method is recommended.However, there are still many factors affecting TMB detection results.There is a general consensus in the industry that more data are needed on TMB as an immunotherapy-related biomarker.