Expert Highlights Role of TMB in Evolving Immuno-Oncology Landscape

Conor E. Steuer, MD

Over the last year or so, the role of tumor mutation burden (TMB) has been debated as a biomarker for immunotherapy in solid tumors, most recently in non—small cell lung cancer (NSCLC).

The one FDA-approved immunotherapy biomarker is PD-L1; however, it has been called an imperfect biomarker with limitations, said Conor E. Steuer, MD. For example, the PD-1 inhibitor pembrolizumab (Keytruda) in combination with carboplatin/pemetrexed has demonstrated activity in the frontline setting for patients with NSCLC, regardless of PD-L1 expression.

Recent data have suggested that TMB can be useful as a predictor for immunotherapy response versus chemotherapy. For example, patients with high levels of TMB have typically responded better to immunotherapy combinations compared with chemotherapy, said Steuer.

Next-generation sequencing (NGS) has emerged as an important tool for measuring TMB. In contrast with the standard single-gene testing, NGS allows clinicians to get a broad understanding of a patient’s genomic profile with just 1 test. It is also more cost-effective, Steuer explained.

OncLive: How would you characterize the role of TMB in the evolving immuno-oncology landscape?

In an interview with OncLive, Steuer, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, discussed the pros and cons of TMB as a biomarker and the utilization of NGS.Steuer: Tumor mutation burden is emerging as an important biomarker in the treatment of cancer, including NSCLC. PD-L1 expression is currently the only FDA-approved biomarker for NSCLC, with standard of care in the frontline setting for PD-L1—high NSCLC being the immune checkpoint inhibitor pembrolizumab [Keytruda]. However, this is rapidly changing, as recent data have shown success across the board for immunotherapy plus chemotherapy in a first-line setting.

Based on current data and trends, can you discuss next-generation sequencing (NGS) as a tool for measuring TMB from a clinical perspective?

As the availability of NGS increases, what are the practical implications of its broader utilization as a biomarker for various cancers?

Nonetheless, we know that PD-L1 is an imperfect biomarker. While many immunotherapy biomarkers are currently being explored, TMB’s ability to predict for immunotherapy response is demonstrating great promise. This is demonstrated most clearly by recent data showing that high TMB potentially serves as a biomarker for immunotherapy combinations and may help chose patients who benefit from immunotherapy versus chemotherapy. Numerous retrospective and prospective studies have also shown that this biomarker holds promise to aid in the selection of patients who will most benefit from immunotherapy.Genomic testing has become an important tool in the NSCLC landscape. For nonsquamous NSCLC that is metastatic, the current standard of care now is to do genomic testing for the driver mutations EGFR, ALK, BRAF, [and] ROS1 at minimum, with other genes such as MET, RET, and NTRK demonstrating promise as targeted therapy options in clinical trials. Next-generation sequencing allows for the testing of all of those genes as well as other genes that might prove to be important to the treatment of NSCLC. NGS can be both cost- and tissue-use effective versus single gene testing. Because of this, NGS has become an approved testing method for NSCLC and is a more clinically practical test than whole exome sequencing, which was previously used to define TMB.NGS testing can be more tissue- and cost-effective for determining the genes of interest in NSCLC than single gene testing. Using NGS tools to test for TMB would be a very clinically logical step and is already being done in some trials and institutions. Therefore, it would translate well to TMB given its established clinical familiarity. In addition, NGS, at least in NSCLC, is often covered by insurance carriers.

What insights can you share about the process of NGS testing, from the clinician obtaining the biopsy to the pathologists reading the results?

Can you specifically address the turnaround time from biopsy to results, as well as the overall significance of timing when it comes to this kind of testing?

One issue that remains with NGS is that there are many different platforms and companies that perform NGS. Because TMB can be defined differently by different tests, further work moving forward needs to be done to validate and standardize these tests. Given the number of vendors in the NGS space, it is important to ensure that wherever the sample is going to be tested, that it’s done in a certified and regulatory laboratory where you can trust the results received to make treatment decisions.If there is concern that a patient may have lung cancer, the next step would typically be for the patient to undergo a biopsy. Once the biopsy is taken, it is prepared and sent to pathology. Testing is done to determine the presence of cancer as well as the type. If it is determined that a patient has NSCLC, then the tissue will be stained for PD-L1 and if nonsquamous histology, will be sent for genomic testing. It is worth noting that many NGS tests are available. From a timing standpoint, the process from biopsy to results can vary, but tends to be along the lines of 2 to 4 weeks. After the results return, treatment recommendations are then made for the patient.The current standard is to wait for the results to recommend the most appropriate treatment, barring clinical emergencies necessitating sooner treatment. Although a 2 to 4 week turnaround from biopsy is remarkable compared [with] years ago, this timeframe needs to continue to improve. For certain mutations, targeted therapies are known to be a better treatment option than immunotherapy or chemotherapy. Therefore, the results are needed. Moreover, many patients are anxious to begin treatment, but you also want to make sure you have all of the data to start patients on the right treatment.

With more NGS platforms becoming available, can you offer perspective on the challenges associated with this relatively new technology?

Continuing to decrease that time would be of great value in the clinic. Close collaboration with pathologists and proceduralists may greatly enhance the timing of the testing process, allowing for orders to be placed and a seamless transition between providers. This helps decrease the time between diagnosis and getting the results needed to treat the patient.In addition to difficulties due to timing and turnaround, another potential challenge is tissue constraints. The field has been rapidly adapting, and as we learn more about the genomics of lung cancer, it is important when we do biopsies to gather enough tissue to run these important tests. Proceduralists, pathologists, and oncologists should be aware that the appropriate amount of tissue is taken at the time of diagnosis when feasible. This would help avoid the need for repeat biopsies.

Based on your current view regarding the integration of NGS tools in the immuno-oncology spectrum, what do you foresee over the next several years as the technology is increasingly integrated?

With continued utilization of NGS, how will advances in technology and best practices potentially optimize the use of NGS tools, and do you have any take-home points regarding the broader significance of TMB?

One recent development that may help to address the issue of tissue collection is the liquid biopsy. By analyzing circulating tumor DNA from the blood, liquid biopsies have gained traction in lung cancer and are currently used for genomic analysis when not enough tumor tissue is available, biopsy is not feasible, as well as in targeted therapy resistance settings. As it becomes more commonly used, liquid biopsy technology holds great promise to noninvasively get the information needed to most appropriately treat patients. Another challenge that will need to be addressed as adoption of NGS technology increases is the possibility of “too much” information. Given the variety of vendors and the number of genes that can be tested using NGS technology, clinicians need to be educated on how to interpret and apply the results appropriately, especially in a rapidly evolving landscape.Firstly, I see single gene testing in NSCLC becoming less utilized in favor of NGS. There are a multitude of platforms that run NGS, and these tests run different gene panels and may differ in terms of calculating TMB. If TMB becomes a standard of care, it is important to run a validated test to know that the results are consistent and accurate. Nonetheless, NGS is a very logical and practical way to obtain TMB. In the next few years, continued prospective studies will further elucidate TMB’s role as a predictor for outcomes from immunotherapy and immunotherapy combinations.Currently, NGS is the standard of care for nonsquamous NSCLC and select squamous cell patients. For people already familiar with the test, being able to use technology to measure TMB will be an important asset in the future if TMB should become a standard of care. Clinical trial results have shown that TMB does hold much promise to predicting response and outcomes to immunotherapy; however, it’s not quite standard of care yet as more data are acquired.

As we learn more about how TMB interacts with PD-L1 and various other immune biomarkers, it is important that all oncologists and physicians who treat lung cancer are aware of this data in real time to make the best treatment decisions for their patients. Hopefully, TMB will prove to be an important immune biomarker, allowing for better treatments for our patients. Finally, decreasing turnaround time and standardizing for NGS tests is an important step if NGS-determined TMB is to become standard.