Agnostic Biomarkers In Precision Medicine - Challenges And Future

By Dr. Song Ling Poon, Senior Precision Medicine Architect Lead of ACT Genomics

Recently, comprehensive genomic profiling of patient tumors has undergone revolutionary changes owing to the continuous evolution of knowledge, technology, and standard clinical practice. These changes have facilitated a shift from using a few small, predictive, disease‐specific, evidence‐based tests (i.e., EGFR, KRAS, ALK fusion, etc.) to broader panel testing that measures either the levels of or changes in a pool of “genes or gene products” 

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What Are Agnostic Biomarkers?

Traditionally, biomarkers are used to define therapeutic targets within a given histological cancer type, for example, trastuzumab in HER2-positive breast cancer. Currently, a new concept, tumor-agnostic treatment, where the intended therapy targets a specific genetic or molecular spectrum regardless of the anatomical location, is on the rise. In fact, a recent drug approval by the Food and Drug Administration (FDA) has marked another milestone in the treatment of cancer. This recent approval for an immune-checkpoint inhibitor is the fourth time that the FDA has approved a drug to be used in a tissue-agnostic manner, which, in this case, is based on the results of a complex biomarker status – high tumor mutational burden (TMB-H).

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Challenges Facing Agnostic Biomarker-Directed Therapies

For any tumor-agnostic indication, it is the biomarker that defines the "optimal" patient population. Therefore, before such an assay can be used for patient selection in a clinical trial, it must undergo an extensive analytical validation and be able to demonstrate both accuracy and precision. During the drug development process and the subsequent clinical use of the drug, false positive and false negative test results may have serious consequences for the individual patient and must be reduced to an absolute minimum.

Indeed, various local laboratory-developed assays/methodologies are used during the clinical development, in relation to the approval of immune-checkpoint inhibitor for MSI-H/dMMR tumors as well as TRK inhibitors in NTRK fusion positive cancers. This undoubtedly increases the test-to-test variability and likely results in a more heterogenous patient population across the clinical test sites. Accordingly, in an article in the New England Journal of Medicine, the US FDA stated that it was a shortcoming that an FDA approved test was lacking1. In the same article, they stated: "Although sponsors have conventionally focused on the development of a drug, the strategy of pursuing site-agnostic indications must focus on both drug and biomarker development.’ It was further emphasized that if a biomarker, in essence, defines the "disease" indication, the development of an appropriate molecular assay should be a more collaborative approach than conventional drug development, and will require the involvement of multiple different stakeholders. Currently, post approval, the sponsors of the respective thereapeutics have committed themselves or are in collaboration with diagnostic companies to develop the respective validated assay.

Although the latest TMB-H approval includes the co-development of a CDx assay, there is still the need to be transparent and establish recommendations for consistent TMB estimation and reporting across different diagnostic entities. Friends of Cancer Research (FoCR) and Qualitätssicherungs-Initiative Pathologie GmbH (QuIP) have both gathered multiple stakeholders, who include academic, regulatory, pharmaceutical and diagnostic entities, to address this issue, and we certainly look forward to the unblinded data that will be presented in the near future.

Road To The Future

If superior vs. existing approaches are supported by additional trials, a tumor molecular signature-based approach may eventually become part of the treatment in earlier lines. An example of the sponsor following this approach is the basket trial design for NTRK fusion positive patients, which is an ongoing assessment of response in both common and rare tumor types. In conjuction, the NCI-MATCH trial, led by the National Institutes of Health who are at the forefront of the effort in this direction, aims to treat patients with 11 different inhibitors based on the mutations they carry. Several of the drugs listed in Table 1, which represent a variety of targets, are currently under development and will likely be introduced in the clinic within the next five years. However, our experience from the past 20 years of oncology drug development has taught us that even if the same oncogenic driver can be identified across different tumor types, there is no guarantee for a positive treatment outcome.

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Finally, apart from the efficacy of the tumor-agnostic treatment, there are also tremendous challenges faced by the existing diagnostic, regulatory and HTA frameworks, and market entry pathways. Therefore, several aspects should be taken into consideration:

i. Obtain early scientific advice

Given the complextity of the trial design used for tumor-agnostic therapies, early scientific advice from regulatory agencies (e.g. FDA), HTAs and payers can facilitate early alignment and appropriate evidence generation to assist in gaining approval for relevant markets.

ii. Access to genetic testing

Patient screening may be a hurdle as universal testing for rare biomarkers may not be covered by insurance owing to the high costs. These drugs may also come with an expensive price tag. Therefore, diagnostic providers should initiate discussion with regulatory agencies to facilitate companion diagnostic test development in the respective developed market.

iii. Real-world evidence data (RWD)

RWD helps to validate and bulid up the precision medicine paradigm in the overall long-run that may faciliatate use into early lines of therapy.

iv. Post-launch life-cycle management (LCM)

Initiate post-launch LCM to test tumor-agnostic therapies in a broader set of tumor types to increase the size of the funnel, including potential combination use.

v. Provider awareness and time

Strong provider education/system awareness, which is tailored to patient education for the genetic test, is needed. Ultimately, a mind-shift to bring the physician into the fold is also important.

The tumor-agnostic treatment approach is likely to become more prevalent. These opportunities will arise sooner if all stakeholders continue to lay the groundwork of genetic testing, NGS in particular, for the establishment of robust clinical and RWD.

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About The Author

Dr. Song Ling POON  

Dr. Poon is senior precision medicine architect lead of ACT Genomics and she received her Ph.D. degree from the University of British Columbia in Canada and conducted her postdoctoral training in translational research at National Cancer Centre Singapore. Dr. Poon principal research interests circumscribe the topic of genetic instability in cancer cells. During the postdoctoral training, she utilized both experimental and computational techniques to understand the consequences of multiple mutational processes where her team discovered novel mutational signature in a wide range of tumor types including kidney, bladder and liver cancer. Also, Dr. Poon is specialized in using high throughput screening to elucidate the roles of aberrant signaling pathways in cancer cell biology for the development of cancer therapeutics where a synthetic lethality drug screening program was then established in the cancer institute.

Currently, Dr. Poon plays the role in working with the most influential stakeholders in precision medicine, identifying the unmet needs and challenges faced when using genomic profiling for clinical decision making, aiming in building precision medicine healthcare program together with the key opinion leaders in the region. 


1. LemeryS, KeeganP, PazdurR . First FDA approval agnostic of cancer site - when a biomarker defines the indication. N Engl J Med. 2017;377:1409–1412.


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