Six years after the approval of the first checkpoint inhibitor, the explosion of research and development of cancer immunotherapies continues to accelerate at an unprecedented pace. As a class, cancer immunotherapies have amassed >$5.5B in sales through Q2, up 80% YoY, driven by Opdivo, Yervoy, Keytruda, and Tecentriq, which, combined, accounted for ~$4.8B through Q2 (see summary here). Additionally, new categories of immunotherapies, such as CAR-Ts, appear poised to drive growth in the near term (driven by the anticipated approval of Novartis’ CAR-T), while numerous other immunotherapy pathways, mechanisms, and combinations are visible on the horizon.Biomarkers and diagnostic strategies played a key role in shaping the current immuno-oncology (I/O) landscape, and we believe they will become increasingly important as the number of cancer therapy options and potential combinations, as well as the interests of payors to contain costs, will necessitate biomarker-based therapy selection to ensure that each patient gets the mechanism / drug / combo for which they are most likely to respond. Additionally, cancer immunotherapies appear to be creating an entirely new testing paradigm, immune-monitoring, which may provide a new way to manage patients on immunotherapies and new opportunities for diagnostic / test manufacturers.To keep track of the ever-evolving landscape of immuno-oncology biomarkers, we created our Immuno-Oncology BioMAP (Biomarker Analysis Platform), a database of >600 (and counting) open and active biomarker-containing immuno-oncology clinical trials. These include trials exploring the use of any kind of biomarker for any purpose alongside the use of any type of cancer-immunotherapy. From these trials, we captured detailed information and context about every biomarker mention (i.e., biomarker, testing purpose, analytical technology, sample type, trial sponsor, trial enrollment, phase, etc.) and built a data visualization tool to enable easy, dynamic, and granular analysis of the aggregated data.Here is a selection of some of the highlights and takeaways from the data captured to-date:Top Immuno-Oncology Biomarkers:

Immuno-Oncology Biomarkers mentioned in at least 5 different clinical trials.

The analysis to-date has captured >2,700 biomarker mentions from >600 different I/O clinical trials. Many of the top biomarkers identified in this analysis (i.e., PD-L1, HER2, ER, PR, EGFR, ALK, BRAF) will not surprise anyone, as testing for these markers has become standard of care for various therapies and indications. However, this analysis reveals many markers on the verge of becoming incorporated into clinical care. The top “novel” immuno-oncology biomarkers identified in this analysis are:

• Tumor-infiltrating immune cells (mentioned 70 times in 61 different trials)
• Immune cell populations / phenotypes (mentioned 60 times in 45 different trials)
• Cytokine profiles (mentioned 52 times in 43 different trials)
• Tumor mutation burden / genomic mutation profiling (mentioned 45 times in 35 different trials)
• Gene expression signatures (mentioned 33 times in 29 different trials)

Each of these biomarkers is represented in multiple mid-late stage (phase 2+) trials, indicating a significant degree of clinical energy being focused on these markers. Tumor-infiltrating immune cells (e.g., TILs) and tumor-mutation burden (TMB) are the I/O biomarkers mentioned in the most phase 3 I/O trials (4 each). Diagnostic manufacturers have clearly taken notice of these biomarkers as potentially clinically and commercially relevant biomarkers. For example, multiple Dx service providers are offering or developing TMB (e.g., Foundation Medicine, Caris Life Sciences, NeoGenomics Labs, PGDx, Guardant Health, and Personalis) and TIL (e.g., Halio Dx, NeoGenomics Labs, Perkin Elmer, Indivumed, Adaptive Biotechnologies, HTG Molecular) assays / services.In terms of growth, PD-1 and tumor mutation burden (TMB) have exhibited the highest CAGR in biomarker mentions since 2014, growing at ~159% and ~145% annually, respectively.

Growth of Cumulative Mentions of Top 30 Immuno-Oncology Biomarkers; 2014 – '17

Other high-growth biomarkers include T-cell receptor repertoires, CD8+ T-cells, and, despite being the most commonly researched biomarker, PD-L1, all of which have grown at >100% annually since 2014.Biomarkers by Testing Purpose:

Distribution and Growth of Cumulative Immuno-Oncology Biomarker Mentions by Test Purpose 2014 – 17

To date, ~27% and ~22% of biomarkers mentioned in the trials in our database are for inclusion / exclusion criteria, or for predicting / correlating to therapy response, respectively. For immunotherapy trials, there is also a relatively large share of biomarker testing being done for the sake of immune monitoring. This testing is done to assess whether, and to what extent, the therapy has elicited an immune response, and may present a new testing paradigm for cancer diagnostic. Whether immune monitoring testing ultimately becomes adopted as part of routine clinical care is a key question that diagnostic / test manufacturers must consider, as such testing, which could comprise multiple tests for each patient, could represent an attractive market opportunity. Currently, flow-cytometry and interferon-gamma-release assays (e.g., ELISPOT assays), are the most commonly used technologies for immune monitoring testing.Biomarkers by Trial Sponsors:

Top Sponsors of Late Stage (Phase 2/3 and 3) Immuno-Oncology Biomarker Clinical Trials

While Merck leads the pack of all industry sponsors in our database, with 77 different biomarker-oriented I/O trials (30 as primary sponsor, 47 as collaborating sponsor), Roche sponsors the most late-stage (phase 2/3 and phase 3) biomarker-oriented I/O trials in our data set. This is not surprising considering Roche’s unique position as both a pharmaceutical and diagnostic behemoth, and given their stated commitment to biomarkers:

“…Over the last few years, Roche has embarked on a systematic approach that interweaves our diagnostic and pharmaceutical expertise to pave the way for PHC. Our goal is to provide healthcare professionals with more powerful diagnostic tools and with targeted treatments based upon new insights about molecular markers that allow a more precise determination of the risk of certain diseases as well as drug efficacy and safety…”

- Roche Position on Personalized Healthcare Document, 2017

A deep dive on the biomarkers explored by some of the key players reveals interesting insights into the various biomarker strategies. For example, a look at trials sponsored by Novartis, which is on the verge of entering the I/O market with its CAR-T CTL019, reveals a focus on tumor-infiltrating immune cell markers (8 / 28 Novartis trials exploring various types of infiltrating immune cells), PD-L1 (6 / 28 trials) as well as gene expression profiles (5 / 28 trials).

Distribution of Immuno-Oncology Biomarker Mentions in Novartis-Sponsored Trials

Biomarkers by Therapy Type:Not surprisingly, checkpoint inhibitors dominate the clinical trial activity captured in our database. Pembrolizumab has the most biomarker-containing trials in our database (137), followed by Nivolumab (79), and Durvalumab (49).

Distribution of Immunotherapies in Biomarker-Containing Trials

While checkpoint inhibitors comprise the most common immunotherapy class in our trial set, cell and vaccine therapies represent the most diverse set of biomarkers, with no single biomarker accounting for more than 6% of all biomarker mentions for this class of drug.

Distribution of Immuno-Oncology Biomarkers for Cell Therapies / Vaccines

Cell therapies pose a attractive opportunity for test manufacturers due to the potential for ongoing monitoring of both the therapeutics cells as well as immune responses, however, the emphasis on personalized cell therapies may make the development of "off-the-shelf" assays / kits more challenging.Conclusions:Cancer immunotherapies have already fundamentally altered the cancer treatment paradigm, however, their impact on the cancer testing and diagnostics markets is still to come. We think cancer immunotherapies could re-write many of the rules for cancer diagnostics, with the potential to drive new technologies (e.g., multi-plex platforms, NGS, digital pathology), protocols (e.g., immune monitoring, biomarker-driven drug approvals), and even business models (e.g., universal companion diagnostics, value-based pricing, IVD single-site-labs) into routine cancer care.We are continuing to track the I/O biomarker landscape closely and will be adding to our database regularly. Feel free to reach out if you would like to hear some more of our thoughts about the I/O biomarker landscape and the implications of immuno-oncology biomarkers for research tools and diagnostics players. We are also happy to provide a demo of our Immuno-Oncology BioMAP; click here for more information and complete the form below if you are interested in a live demo of the tool:[gravityform id="2" title="true" description="true"]Disclaimer: Some of the companies listed above may be DeciBio Consulting clients or customers.—Author:Andrew Aijian, Sr. Project Leader at DeciBio Consulting, LLC, aijian@decibio.comConnect with Andrew on LinkedIn: https://www.linkedin.com/in/andrew-aijian