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As Cancer Immunotherapy Evolves, Challenges Compound for Diagnostic Development

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NEW YORK (GenomeWeb) – At various sessions during Cambridge Healthtech Institute's Molecular Medicine Tri-Conference earlier this month, representatives from the diagnostics arena, pharmaceutical companies, and the medical oncology field discussed the main challenges and unknowns they believe will impact the future of cancer immunotherapy and associated diagnostic testing.

The immuno-oncology community is facing a number of important questions that will shape how these exciting new drugs are used, and how clinicians can best identify the patients that will respond to them. As earlier questions are starting to be put aside — for example whether existing biomarker tests identify all patients that they should, or how they compare to one another — newer, more complex ones are emerging.

Among the topics discussed at the TriCon meeting was the question of how diagnostics will evolve to serve the needs of treatment strategies that combine different immunotherapeutic drugs, or couple immunotherapy with things like chemotherapy or radiation.

Groups also debated whether genomic and other analyses of cancers that don't currently respond well to immunotherapy may reveal new strategies to spark a response — turning a tumor that is "cold" to the immune system into one that is "hot."

Participants grappled with the challenges of drug and diagnostic development as broad genomic strategies evolve that challenge current regulatory structures. And with growing recognition that there are multiple predictors of immunotherapy response — many of which appear to be independent of one another — researchers and clinicians pondered how best practices may evolve for combining different tests or assays considering that there is little precedent for this in the "one drug-one diagnostic" paradigm that has dominated much of precision medicine practice so far.

One informal breakout session at the meeting involved representatives of two different pharma companies leading the field of immunotherapy development — Merck and Bristol-Myers Squibb — as well as individuals from firms developing molecular diagnostics platforms like Nanostring and Cofactor Genomics. During this session participants discussed the barriers test makers face in establishing new biomarkers, or new test strategies that may be superior to those that are currently approved by the US Food and Drug Administration for use alongside immunotherapies.

Nanostring, for example, began working with Merck in 2015 to validate an 18-gene immune-related expression signature, which the company calls a Tumor Inflammation Signature or TIS. Merck said that it has seen exciting results with the signature, with evidence in some tumor types that it outperforms the PD-L1 tests that are currently approved to guide immunotherapy use. Despite this, the company said last year that it was scrapping plans to bring the TIS through regulatory approval as a companion or complementary diagnostic for its Keytruda (pembrolizumab).

During the conversation, Terri McClanahan, executive director of profiling and expression in translational medicine at Merck Research Labs, said that as far as she understands, this was a "strategic decision" on Merck's part — not necessarily a response to a scientific failing of the Nanostring approach.

Because of the benefits both to pharmaceutical companies' bottom lines, and arguably to patients, drugmakers tend to seek the fastest path to regulatory approval.

In the cast of immunotherapies, garnering accelerated approval has so-far meant approval for more limited populations or settings — either in second-line applications, or with the use of imperfect biomarkers like PD-L1 immunohistochemistry, which only identifies some of the patients likely to respond to these drugs, meeting attendees said.

Such things are rarely discussed openly, but attendees contributing to the session also acknowledged  that pursuing the best precision medicine strategy doesn't always match up with pursuing commercial success.

The result of accelerated approval for drugs with narrower biomarkers is that as superior tests become available, such as the Nanostring signature or tests that analyze tumor mutational burden, they have to overcome the inertia inherent in usurping an already-approved test.

This is a challenge that is not unique to immunotherapy. For example, in the rapidly accelerating liquid biopsy arena, clinical researchers and oncologists are faced with a similar dilemma in which there is a single FDA-approved technology for detecting EGFR mutations in blood samples, but data suggests that other approaches being offered as laboratory-developed tests may be superior.

"I can't tell you what Merck is going to do, but the better-validated biomarkers we have, the better for patients," McClanahan said during the TriCon breakout session.

Aside from Nanostring's panel — which appears so far to be targeting much of the same biology, and therefore the same patient subset, as PD-L1 tests — the object of some of the most intense attention at the meeting was the analysis of tumor mutational burden.

More specifically, stakeholders seem to be grappling with how tumor mutational burden tests will best be utilized, and how the competitive landscape for these technologies may evolve, either outside of FDA regulation, or in specific companion diagnostic approvals.

Numerous companies are now positioning themselves to offer TMB testing if it becomes a widely adopted strategy in clinical practice. Foundation Medicine has led the charge, offering TMB analysis using its 300-gene FoundationOne sequencing assay since 2016.

More recently, the company has said that it is that it is advancing a blood-based version as a companion diagnostic to Roche/Genentech’s Tecentriq (atezolizumab) in first-line treatment of non-small cell lung cancer patients.

Bristol-Myers Squibb has also reported data from a study of its immunotherapies Opdivo (nivolumab) and Yervoy (ipilimumab), which could support regulatory approval for the regimen in lung cancer patients identified as having high TMB using Foundation's next-generation sequencing companion diagnostic, which the FDA approved last year.

Meanwhile other firms like Personal Genome Diagnostics and Guardant Health have also said they are developing assays that measure how mutated a tumor is to predict immunotherapy response.

When PD-L1 assays first emerged as companions to immunotherapy, clinicians bemoaned siloed development and a lack of concordance, which has meant that results from one test cannot be translated from one drug to another.

With multiple different tests from different companies advancing alongside different drugs, the same could potentially happen with TMB. However, attendees at the Tri-Con meeting suggested that harmonization efforts are already beginning. During the Tri-Con breakout session, for example, an employee of Bristol-Myers Squibb mentioned an effort being spearheaded by Friends of Cancer Research to harmonize existing TMB assays.

Meanwhile, another challenge for the next few years will be negotiating the existence of multiple different classes of test, which appear to select different, independent subgroups of patients for treatment.

According to Merck's McClanahan, work with the Nanostring platform, for example, has suggested that the 18-gene TIS panel seems to overlap with PD-L1 tests. But TMB seems to access a separate group of responders, suggesting the two are independent and could have added value if combined.

Although the FDA has not been challenged with these types of scenarios yet, she said that the data suggest the future could hold something like a "decision tree" in which clinicians test for multiple markers, and "if you are high for any one then you get the drug."

Other groups are also now looking at things like immune cell invasion, overall immune system function, and other factors that could play a role, not only in response to individual immunotherapies, but importantly, in response to different combination treatment strategies.

Increasingly, preclinical research and clinical trials are shifting to combination treatment, Merck's McClanahan said. And at a separate presentation at the meeting, her colleague Sarah Javaid, a Merck senior scientist, discussed a variety of preclinical studies in which the drugmaker is exploring combination treatments that target different biological mechanisms of resistance to single immunotherapy agents.

This could be combinations of two immunotherapeutic drugs, pairing an immunotherapy with a targeted drug, or a cytotoxic treatment that breaks down some biological barrier that is hindering the immune system from responding.

A radiation oncologist at the meeting breakout session brought up the concept of radiation-immunotherapy combinations, for example. This is something researchers have begun investigating after case studies (some accidental) have shown that radiation treatment might be able to makes tumors sensitive to immunotherapy by inducing DNA damage in tumors that makes them more recognizable to the immune system.

In other cases, a drug treatment could precipitate the same opening of the immune floodgates, depending on the precise molecular or biological features that are driving the cancer.

Presumably, if these strategies move forward into the clinic, it will be necessary not only to assay response markers like escape gene-expression and TMB to pick out responders to single agents, but also to subtype patients that have non-responsive or "cold" tumors so as to pick the best combination approach to heat them up, meeting participants said.

The concept presents a difficult picture for test regulation and the development of best practices, session participants agreed.

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