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Higher tumor mutation burden predicts better response to checkpoint inhibitors

A step forward towards the precision medicine in non-small-cell cancer management is made with a new clinical trial

A recent issue of the New England Medical Journal features a study which tested two new biological agents, nivolumab, and ipilimumab, against chemotherapy in a specific population of non-small-cell lung cancer patients - those with a high tumor mutation burden (TMB).

The study on the two new biological agents, nivolumab, and ipilimumab, showed a significantly higher response to them than to the conventional chemotherapy and proved that TMB may become a great marker for selecting the patients for specific treatment. Here, a brief overview of TMB concept and its implications for lung cancer is given.

Tumor mutation burden: less specificity for precision medicine

Tumor mutation burden is a number of mutations carried by a neoplastic cell per unit of genetic material (usually, per 1 million bases, or per 1 megabase). The more mutations the cancer cell has, the more aberrant proteins, or neoantigens, it expresses. This, in turn, makes it more susceptible to host immune response and immunotherapy. 
TMB is measured by comparing the genome from normal body cells with neoplastic ones using genome sequencing techniques and sophisticated computational algorithms; though, there is no standardized procedure for TMB measurement yet. 

It is not tied up with mutations in genes for any concrete proteins being rather a generalized measurement. Thus, the advantage of TMB as a biomarker is that it can potentially be applied to any type of cancer cells to predict its response to treatment.

A potent predictor of response to checkpoint inhibitors

The major experience with the TMB as a marker comes from the investigations of the checkpoint inhibitors which influence the molecular pathways essential for inducing self-tolerance. Key elements of these pathways are actively investigated as targets for inhibitory immunotherapy because evasion from the immune system is one of the hallmarks of cancer.

The significance and potential of TMB are particularly evident in studies of programmed death 1 (PD-1) receptor inhibitors for non-small-cell lung carcinomas (NSCLC). The CheckMate 026 trial investigated the efficacy of PD-1 inhibitor nivolumab against platinum doublet chemotherapy in advanced NSCLC with more than 5% of PD-1 expression. It did not find any significant advantage of the investigated agent over the conventional therapy; however, when the outcomes were split into three groups by the TMB level, it turned out that in case of a high TMB level the response rate was better in the nivolumab group than in the chemotherapy group (47% vs. 28%), and progression-free survival was longer (9.7 vs. 5.8 months). If the patient had both high TMB and PD-1 expression (more than 50%) the response rate was even higher (75%) but was not powered by a statistical analysis.

Further CheckMate 568 trial has shown that nivolumab is much more effective in combination with another checkpoint inhibitor, ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody.

These results led to another study published recently in the New England Medical Journal, a CheckMate 227 trial. In this trial, the advanced NSCLC patients with PD-1 expression of more than 1% and less than 1% were randomized to receive either nivolumab plus ipilimumab, chemotherapy, or nivolumab monotherapy (for PD-1 more than 1%) or nivolumab plus chemotherapy (for PD-1 less than 1%). A portion of patients’ outcomes from the nivolumab plus ipilimumab group and chemotherapy group were analyzed in regard to TMB.

The 1-year progression-free survival rate was 42.6% 13.2%, and the progression-free survival was 7.2 months versus 5.5 months in the immunotherapy group versus the chemotherapy group. After the adjustment for PD-L1 expression level (≥1% vs. <1%), sex, tumor histologic type, and ECOG performance-status score (0 vs. ≥1) the response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy.

Among patients with a high TMB, nivolumab plus ipilimumab was almost equally more efficacious than chemotherapy in patients with both PD-L1 expression levels of at least 1% and less than 1%.

The trials' impact

From the discussed trials, it can be clearly seen that TMB is a good criterion to select the NSCLC patients eligible for treatment with checkpoint inhibitors, even better than a rate of expression of target proteins. There is the possibility that the main effect is actually mediated via the immune system which attacks cancer cells which have higher TMB (and thus express more neoantigens) more aggressively once a reactivity is restored by the checkpoint inhibitors. Although there is much more research to be done to prove TMB usability, the available data suggest that this is only the matter of time.

Sources
1. Hellmann, M., Ciuleanu, T., Pluzanski, A., Lee, J., Otterson, G., Audigier-Valette, C., Minenza, E., Linardou, H., Burgers, S., Salman, P., Borghaei, H., Ramalingam, S., Brahmer, J., Reck, M., O’Byrne, K., Geese, W., Green, G., Chang, H., Szustakowski, J., Bhagavatheeswaran, P., Healey, D., Fu, Y., Nathan, F. and Paz-Ares, L. (2018). Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. New England Journal of Medicine. [online] Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1801946 [Accessed 26 Apr. 2018].
2. Carbone, D., Reck, M., Paz-Ares, L., Creelan, B., Horn, L., Steins, M., Felip, E., van den Heuvel, M., Ciuleanu, T., Badin, F., Ready, N., Hiltermann, T., Nair, S., Juergens, R., Peters, S., Minenza, E., Wrangle, J., Rodriguez-Abreu, D., Borghaei, H., Blumenschein, G., Villaruz, L., Havel, L., Krejci, J., Corral Jaime, J., Chang, H., Geese, W., Bhagavatheeswaran, P., Chen, A. and Socinski, M. (2017). First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer. New England Journal of Medicine. [online] Available at: http://www.nejm.org/doi/10.1056/NEJMoa1613493 [Accessed 26 Apr. 2018].
3. Oncologypro.esmo.org. (2017). Tumour Mutational Load: ESMO Biomarker Factsheet | OncologyPRO. [online] Available at: http://oncologypro.esmo.org/Education-Library/Factsheets-on-Biomarkers/Tumour-Mutational-Load#eztoc2103759_0_0_2 [Accessed 26 Apr. 2018].
4. Medscape. (2017). Tumor Mutational Burden as an Immunotherapy Predictive Biomarker. [online] Available at: https://www.medscape.com/viewarticle/888968 [Accessed 26 Apr. 2018].