Tumor mutational burden (TMB) as a predictive biomarker for immunotherapy – to assess if a patient will benefit from the treatment with immune checkpoint inhibitors (ICI) – has garnered substantial attention from the researchers and major companies. Merck, one of such companies, received expanded approval for its drug, pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors that have progressed following prior treatment.
However, the approval was not restricted to pembrolizumab only. The FDA has also approved FoundationOne CDx as a companion diagnostic test for pembrolizumab (Keytruda) to identify patients with TMB. Trials have shown that TMB-high was associated with a higher objective response rate in patients with selected advanced solid tumors treated with pembrolizumab monotherapy, which suggests its predictive nature in terms of the efficacy; in spite of that, some experts are still not in support of this approval.
First, it is also important to understand the criteria for high/low TMB; the cut-off values are <20 mutations/Mb, <20 mutations/Mb ≥10 mutations/Mb, and <10 mutations/Mb for TMB-High, TMB-Medium, and TMB-Low, respectively.
Now, the question arises, whether these novel mutation biomarkers can help the researchers to understand better or predict the response of immunotherapies on cancer patients?
Although TMB has been of particular interest in skin cancers, including squamous cell carcinoma and melanoma, and cancers of the lung, bladder, and cervix, it has been recently explored in kidney cancer and breast cancer too. TMB and its strong association with immune checkpoint inhibitors (ICI) have always been the topic of interest and extensive research, which has facilitated the discussion on few implications related to an improved response rate in patients with high TMB and PD-L1 expression.
Interestingly, even though, renal cell carcinoma (RCC) has a modest mutation burden, recent analysis suggests that total mutation burden has shown a substantial impact on response or survival to PD-1 blockade in case of kidney cancer patients. This conclusion is contradictory to what has been observed in other cancer types and has given rise to a common belief that a high total mutation burden is a positive factor for PD-1 blockade, as there are more targets for the immune system and more neo-antigens that could be recognized. Similarly, in the case of breast cancer, certain studies suggest that 5% of breast cancers have high TMB, with enrichment in metastatic tumors. Additionally, high TMB and PD-L1 positivity do not significantly co-occur, and a majority of breast cancer cases with high TMB may be PD-L1 negative as well. Therefore, it is essential to understand that the establishment of TMB as a predictive biomarker is not a one-stop solution for every oncology indication as the cut-off for high TMB varies with indication.
Further, the question remains, whether the TMB is going to help the physicians make better treatment decisions or not?
Indeed, it is expected that TMB will improve the understanding to choose the apt therapies and aid in gaining better insights as to what kind of therapy should be given to an individual patient. Furthermore, TMB will shed light on what should be avoided, whether the therapy can have a significant risk of life-threatening toxicity despite response, and indicate the varying degree of chances of a response, to a particular therapy.
But is it a personalized approach?
We can give the nod on that, as the treatment will be guided based on TMB’s robust assessment, as it has been found to enhance the response rate of certain combinations in specific individuals. It can be better explained with an example: immunotherapy as mono or combination, resulting in a lower response or no response on a particular patient segment might give a higher response rate on a separate patient segment.
Industry Experts on the correlation of TMB with NSCLC:
“…TMB testing may be clinically relevant in selecting patients for IO [immuno-oncology] plus chemo or IO plus IO. Responses were more durable, and the 1-year PFS rates were higher with nivolumab plus ipilimumab versus nivolumab and chemotherapy in patients with high TMB and less than 1% PD-L1 expression, and there were fewer grade 3/4 treatment-related adverse events...”
This flexible and personalized approach is expected to create an immense market opportunity for the already existing therapies in the pipeline.
Initially, implications from the trials being conducted by Merck, such as KEYNOTE-021 and KEYNOTE-189, suggested that single-agent pembrolizumab may be useful particularly for older patients, with a low metastatic mutational burden, and significant comorbidities. However, in younger patients, with a high metastatic mutational burden and aggressive tumors, pembrolizumab presented with better results when used in combination. As per Merck, immense research work is being currently ongoing to improve the effect of immunotherapy in patients with lung cancer, where TMB has played a significant role as a potential predictive marker. The results have been somewhat mixed. Also, Correlation of TMB with PFS has already been established; even though, they are still unsure about its relation to the Overall Survival (OS).
“…We thought that we’d take advantage of the fact that we had 2 trials of single-agent pembrolizumab versus chemotherapy, one KEYNOTE-010 in a second or more line setting, the other KEYNOTE-042 in a first-line setting. We looked at those samples and did whole-exome tissue TMB testing, meaning that we looked at the whole-exome sequencing on tissue samples from these randomized studies against control, and that’s what I presented at the ESMO meeting...”
Additionally, another interesting analysis has been done with durvalumab as AstraZeneca recently drew attention towards the analysis of TMB in blood among patients receiving durvalumab in combination with tremelimumab and correlated it with an overall optimal survival benefit among patients with TMB ≥ 20 mutations/Mb.
Apart from Merck and AstraZeneca, Bristol Myers Squibb is also excited about its exploratory biomarker analysis, which suggested that a higher tumor mutational burden may potentially derive greater benefit from its combination regimen of Opdivo and Yervoy than those with lower TMB levels in patients with metastatic, castration-resistant prostate cancer (mCRPC) patients.
What remains to be the unmet need?
TMB assessment has not been standardized across research and clinical studies as a biomarker that affects treatment decisions so far. In addition, the definition of high TMB is still not optimized across cancer subtypes. Furthermore, implementation of TMB measurement assays requires consideration of factors such as biopsy sample type, sample quality and quantity, genome coverage, sequencing platform, bioinformatics pipeline, and the definitions of the final threshold that determines high TMB.
Overall, the beginning of a commercial journey of TMB as a predictive biomarker has already laid the foundation for a uniform diagnostic methodology in varying oncology Indications, where Merck takes the sole credit. Moreover, there are a lot of efforts ongoing to collaborate Friends of Cancer Research with not just several pharmaceutical companies but the FDA, the National Cancer Institute, and academic centers too, in an effort to homogenize the data. We remain optimistic that these groups will provide a set of universal best practices for defining and aligning TMB in the coming years, which will enhance the utility of TMB as a biomarker across variable oncology platforms