Transforming early science into reality is the very essence of R&D, and research—particularly groundbreaking research—takes time. But time is something cancer patients do not have. In order to deliver on Foundation Medicine’s mission to bring precision medicine to patients at the highest quality, and as quickly as possible, we need to push the boundaries of R&D.
Alongside the targeted therapy collaborations with our biopharma partners that primarily focus on bringing innovation and new technologies to patients in the short-term, we dedicate a significant amount of our efforts and expertise into research programs that have a much longer-term outlook.
In a series of articles that explore our work in some of the most exciting areas of cancer treatment, I plan to share a few examples of where our innovative approach to research is laying the foundation for future progress. I’d like to begin with a topic that I have been personally immersed in for more than a decade. It’s a space where new insights and technologies are already changing the way we see, and treat, cancer: immunotherapy.
Mechanisms of immune surveillance
Tumor cells arise from multiple genetic mutations, some of which give rise to unusual cell surface proteins. Several of these proteins differ so significantly from those on healthy cells that the patrolling immune T cells recognize them as foreign, triggering the immune cascade that leads to cell death. This process is the first line of defense against tumor development.
But some tumors have the ability to evade the immune system by hijacking the inhibitory pathways – or checkpoints - that the body uses to regulate the immune response and prevent it from attacking healthy cells. Understanding these mechanisms led to the development of immune checkpoint inhibitors (ICPIs), which block these inhibitory pathways and reactivate the immune response. ICPIs have revolutionized the way we approach cancer, paving the way for the first pan-tumor, site agnostic therapy indications and demonstrating sustained efficacy in a small but significant proportion of patients.
However, disease still progresses in the majority of these patients due to primary or acquired resistance, or the emergence of serious side effects. The growing need to better predict which patients will benefit from specific treatment has stimulated another explosion of research, into predictive biomarkers.
From clinical utility of MSI to future possibility – our work in biomarker research
Foundation Medicine has been at the forefront of biomarker research for a decade, pioneering the use of CGP to deliver insights that will aid our understanding of this complex set of pathways and cells.
Our work with biopharma and academic partners continues to deliver evidence about the role of microsatellite instability (MSI) status and tumor mutational burden (TMB) as biomarkers, as well as helping to further optimize their potential. Earlier this week, the FDA approved FoundationOne®CDx* as the first and only pan-cancer companion diagnostic (CDx) for the identification of MSI-high status tumors that may be appropriate for immunotherapy treatment with Merck & Co’s KEYTRUDA® (pembrolizumab). This new CDx brings another validated tool to clinicians, alongside the previous approval of TMB as a predictive biomarker for immunotherapy response. Additionally, in the professional services section of our blood-based CGP test, FoundationOne®Liquid CDx*, we report on blood TMB (bTMB) and MSI status to help oncologists determine a patient’s eligibility for immunotherapy.
The three available predictive biomarkers for ICPIs, PD-L1 expression, MSI status and TMB value, all play an important role in guiding treatment selection, but they all have individual limitations ranging from low prevalence in some common tumor types to algorithmic complexity, high cost and lack of harmonization in how they are measured. This is why we are continuing to invest our resources into multiple research areas, building evidence for the utility of new potential biomarkers, as well as contributing to our growing understanding of the immune response against cancer and the influence of the tumor microenvironment on immune activation.
CD274 (PD-L1) alterations – an emerging predictive biomarker of ICPI response
Three recent studies demonstrate our approach in action, harnessing the power of our genomic and real-world databases to add to the current evidence supporting the potential of CD274 as an emerging biomarker of tumor cell intrinsic mechanism of immune evasion.
Across the three studies, we analyzed hundreds of thousands of tumor specimens over multiple tumor types, to characterize the real-world landscape and define the prevalence of CD274 short variants, copy number alterations and rearrangements, providing an invaluable reference for further clinical studies to confirm the potential of CD274 genomic alterations as resistance biomarkers for ICPI treatment. [1, 2, 3]
These studies also delivered insights into the relationship between CD274 alterations and the previously described ICPI predictive biomarkers of PD-L1 expression, TMB and MSI. [1, 2, 3]
Finally, we describe preliminary clinical utility evidence that patient selection based on CD274 alterations is correlated with improved survival outcomes, paving the way to inform prospective clinical trials. [3]Future directions in immuno-oncology
As we shift towards earlier treatment with ICPIs, the need to improve treatment selection and minimize adverse events associated with ICPI therapy becomes even greater. To maintain the speed of progress we have seen in recent years, we need to continue to refine, improve and expand on the current biomarker landscape. We’re already making progress; one example is ongoing research highlighting the potential of Somatic HLA class I loss as a biomarker that could help to refine the use of TMB and further improve patient identification. [4]
We are investing in the future of immunotherapy through multiple streams of research aimed at discovering more sophisticated and nuanced biomarkers and biomarker combinations. This is the key to unlocking the untapped potential of ICPIs and delivering further transformation in care for patients. This also helps identify future unmet need patients for whom there are many therapies currently being investigated in drug development.
I am immensely proud of our contribution to the advances we have seen in cancer immunotherapy, and I am energized about the future of this dynamic field of cancer. We will continue to conduct innovative research, find new ways to tap into the power of our data resources, and seek out new collaborations with stakeholders from across the cancer landscape in order to achieve our mission to transform cancer care.
*Rx only; IVD tests for solid tumor cancers. Intended to help identify those who may benefit from certain treatments. Use doesn’t guarantee match to treatment or that all alterations will be found. Full use & risk info: https://bit.ly/3xKGlcm or https://bit.ly/3ejou4R
References
1) Huang RS.P, Murugesan K, Montesion M, et al. Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression. Journal for ImmunoTherapy of Cancer 2021;9:e002680.doi:10.1136/jitc-2021-002680
2) Huang RS.P, Decker B, Murugesan K, et al. Pan-cancer analysis of CD274 (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression. Journal for ImmunoTherapy of Cancer 2021;9:e002558. doi:10.1136/jitc-2021-002558
3) Kelly AD, Murugesan K, Kuang Z, et al. “Pan-cancer landscape of CD274 (PD-L1) rearrangements in 283,050 patient samples, its correlation with PD-L1 protein expression, and immunotherapy response.” Journal for ImmunoTherapy of Cancer 2021;9:e003550. doi: 10.1136/jitc-2021-003550
4) Montesion M, Murugesan K, Jin DX, Sharaf R, Sanchez N, Guria A, Minker M, Li G, Fisher V, Sokol ES, Pavlick DC, Moore JA, Braly A, Singal G, Fabrizio D, Comment LA, Rizvi NA, Alexander BM, Frampton GM, Hegde PS, Albacker LA. Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response. Cancer Discov. 2021