The Future of TMB as a Predictor of Immunotherapy Response Depends on Harmonization

The arrival of the American Association of Cancer Research (AACR) annual meeting this week was accompanied by mixed feelings for me. AACR has always been the first big opportunity of the year for the oncology community to come together, share the latest research and debate the high-profile topics of the moment. The reality of a virtual meeting was a stark reminder of how the coronavirus pandemic was impacting the cancer community as a whole.

But, our participation in AACR also brought with it some reassurance that collective commitment to advancing care for cancer patients continues as does our determination to do everything possible to maintain the pace of progress and realize the full potential of precision medicine for patients with cancer.

TMB Harmonization Project

Even with a shift in format, AACR provided an important platform to present and discuss the results of the second phase of the Tumor Mutational Burden (TMB) Harmonization Project. This project, led by the Friends of Cancer Research (Friends), brought together a consortium of pharma, diagnostic, academic and government organizations to undertake one of the most pressing, complex challenges for immunotherapy guided biomarkers since the advent of next generation sequencing.

These results represent an important milestone for us, as Foundation Medicine has been at the forefront of TMB research for several years and played a significant role in this harmonization effort. To explain why the project and these emerging results are so pivotal, it would be helpful to examine a bit of history on TMB and why we see it playing such a critical role in immunotherapy treatment.

TMB: A Complex, Yet Important Genomic Signature

Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor’s genome. Higher TMB levels predispose the recognition of a tumor by our natural defense mechanism, the immune system. The immune system plays a critical role in nearly every cancer type, however for some cancers, the same mutational process that caused the cancer also acts as its Achilles heel.

In these hyper-mutated cancers, the immune response can be aggressive and robust. However, immune responses left unchecked can also cause unintended damage, and to this extent nature has evolved a checks and balances system to prevent a hyper-response that can lead to auto-immune disorders. The challenge is that cancer has evolved a way to hijack this system in order to veil itself from the immune response.

The brilliance of checkpoint inhibitor therapies is that they remove this veil, allowing the immune response to re-engage with the tumor and in some cases, eradicate it altogether. In this way, measuring the rate of somatic mutations within a tumor, or TMB, allows us to predict the likelihood that checkpoint inhibitor therapies will have an effective response.

Evidence has grown in recent years that supports TMB as a valid quantitative predictor of a patient’s response to immunotherapy across tumor types. The potential of TMB as a pan-cancer predictive signature is an incredibly exciting prospect, and bringing it into routine clinical practice so the right patient at the right time can benefit from immunotherapy has always been our mission and core to the dogma of precision medicine. This prospect is now closer than ever given the recent announcement from Merck that the FDA has granted priority review to the application of pembrolilzumab to treat solid tumors based on a TMB result.

Alongside growing evidence of utility, however, there also exists a strong need to ensure that labs take a harmonized approach to validating and reporting TMB so we are comparing apples to apples. This type of pre-competitive effort across the industry adopts a “patient first” mindset as our north star, and while harmonization is a simplistic idea, the execution is far from it.

Creating “Harmonization” with TMB Measurement

It is clear that TMB can only become an important tool for research and clinical decision making if there is a consistent and harmonized approach to TMB testing that standardizes results across labs and chosen testing panels. The alternative is bespoke labs with different testing methodologies and reporting strategies that can add confusion to trial designs, disrupt clinical practice and in the worst case lead to the wrong conclusion at the point of care for patients.

Harmonization is by no means a new concept. In chronic myeloid leukemia (CML), the development of the International Scale for BCR–ABL measurement brought harmonization to molecular monitoring in CML through a set of universal reference standards that harmonized results across labs, equipment and approaches to testing. Additionally, harmonization of PD-L1 immunohistochemistry (IHC) for immunotherapies was identified as a critical need to support the biomarker strategy, unfortunately the conclusions came too late to broadly ameliorate the caveats previously mentioned.

In the same vein, the TMB Harmonization Consortium began in late 2017 to address these challenges head on, anticipating the success of TMB as a predictive biomarker for IO across multiple tumor types. Phase 1 of the TMB Harmonization Project compared panel-based TMB estimates from participating laboratories to identify and characterize the theoretical variability that could occur in panel-based estimates. The results identified that variability between panels increased with higher TMB estimates and indicated that certain cancer types such as uterine, bladder and colon cancers exhibited greater variability compared to lung or head and neck cancer.

These results reinforced the notion that harmonization was required to maintain consistency in TMB across platforms, and more importantly could be achieved through consistent TMB definitions, validation studies, and the utilization of reference standards that could align panel-based values. Furthermore, enforcing this level of alignment now could help improve the consistency and reliability of TMB testing in future clinical practice.

Phase 2 of the project was focused on identifying the most appropriate methods for calibrating TMB values to align results across testing panels in order to develop an appropriate set of reference standards. The results indicated that calibration methods using samples derived from The Cancer Genome Atlas (TCGA) may be a viable approach to aligning TMB scores. This approach needs further testing in additional tumor samples, particularly in TMB-high tumors, but it has the potential to deliver much needed reference standards.

The Road Ahead for TMB

TMB has incredible potential to be the key that unlocks the precision medicine door for immunotherapies. It can often feel like the story is mostly complete, only to learn that more work and research is still required before the final pages are written. However, the results presented by Friends at AACR indicate that we are making progress towards that goal. And importantly, the platform AACR provided has brought this debate to focus.

In addition, the project has also shown that a collaboration of this breadth and nature is not only possible, but can achieve real and meaningful results. The need for harmonization or collaboration does not begin and end with TMB, and I hope we can use the learnings from this effort as a model for future collaborations requiring complex, cross-industry support. It’s quite remarkable to observe what is possible when we come together as colleagues, not in the interest of our respective companies or organizations, but with a “patient first” mindset to tackle these important challenges.

My lasting impression of AACR 2020 will be that, despite the challenges we are currently facing as a global society, cutting-edge science and groundbreaking innovation continue to move forward, driving the advancement of personalized medicine. Cancer doesn’t care about social distancing, and in these times of personal isolation and reflection we must not leave behind those who are most vulnerable and continue to rely on our collective support.