Growing Pains

As the world of molecular testing for cancer has evolved, so have the methods for analyzing solid tumors to identify the relevant biomarkers that are hallmarks of the disease. Collectively, these can suggest any number of new targeted therapies that have been developed over the past 15 years. But while tests looking for alterations in single genes evolved into panels with a few dozen relevant genes to help inform clinical care, basic research into cancer biomarkers accelerated, to where today assay developers have rolled out panels that can test for 500 or more genes and include other emerging biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI).

“Each type of cancer, where we categorize it by the origin from which it was derived, has its own catalogue of targetable variants and its own catalogue of approved therapies that if a patient with that cancer has that variant, they can benefit from a specific drug,” says Phil Febbo, M.D., chief medical officer of Illumina. “What we’re also seeing is the emergence of pan cancer markers that, regardless of the type of tumor you have, if you have that variant, there are studies to show that you may benefit from specific therapy.”

Proponents of using CGP say it has several benefits in fostering precision medicine. First, by running only one test against such a wide range of biomarkers, CGP preserves tissue samples by virtually eliminating the need for the iterative testing that is necessary if a smaller panel returns a negative test. Second, as drug companies increasingly turn their efforts to developing drugs that address rarer targets, testing across a broad swath of markers can be more efficient at identifying patients who may benefit from a life-saving clinical trial.

“Physicians are very focused on the therapies and getting the best therapies for their patients,” Febbo added. “They don’t want to think about how many different tests they have to run, they want a single test to make sure that they give their patient the best opportunity.”

Making the case
As with all things in healthcare, two major forces will drive greater adoption of CGP in the clinic: improved outcomes and overall reductions in the cost of care. For non-small cell lung cancer (NSCLC), the evidence shows that comprehensive tumor profiling for patients with advanced disease or metastatic disease can benefit from this broad testing approach. As a result, the practice is now included in recent National Comprehensive Cancer Network (NCCN) guidelines.

“For the 2020 update, the panel recommends that molecular testing be performed via a broad, panel-based approach, most typically performed by next-generation sequencing (NGS), so that testing is done for all of the actionable biomarkers at the same time, including the established and emerging biomarkers,” notes the NCCN “This testing technique helps ensure that there is sufficient tissue to test for all of the actionable biomarkers.”

The list of actionable biomarkers for NSCLC is long and continues to grow. The NCCN guidelines for biomarkers to aid decision making for the using of targeted or immune therapies now includes the genes, ALK, EGFR, BRAF, METex14, NTRK1/2/3, RET, and ROS1.

A notable absence for decision making in the application of immunotherapies for NSCLC, however, is TMB, which is relatively easy to measure using a broad panel, NGS-based approach. But despite the FDA’s approval in 2020 of pembrolizumab for unresectable or metastatic TMB-high in solid tumors, the NCCN is keeping it powder dry on including TMB as an actionable biomarker in NSCLC to suggest immunotherapies for the disease. Last year, citing new data from the CheckMate 227 (Phase III) and KEYNOTE-158 (Phase II) clinical trials, the NCCN stated “TMB, which is an immune biomarker, was deleted from the NCCN Guidelines based on clinical trial data, concerns about variable TMB measurements, and other issues. TMB was previously listed as an emerging biomarker.” Of particular concern to the NCCN was the fact that some patients who show low TMB also respond to immunotherapies, with further hesitancy expressed due to inconsistent cutoffs and testing variability.

While guidelines are important for driving CGP as a part of routine clinical practice, so too are reimbursement policies. In the U.S., the first National Coverage Determination for a CGP was granted by the Centers for Medicare & Medicaid Services (CMS) in early 2018 for Foundation Medicine’s FoundationOne CDx for all stage 4 or recurrent solid tumors. By early 2020, under the CMS MolDx program, 28 states covered CGP, and beginning in April, another 10 states will be added to the list via Medicare Contractor National Government Services’ coverage determination. As of April 1, that still leaves 12 states without a reimbursement policy in place for public payers.

According to Robert Dumanois, director of reimbursement strategy at Thermo Fisher Scientific, the landscape for private payer reimbursement of CGP is no less varied. “I would say Blue Cross Blue Shield of Massachusetts and Nebraska Blue are two that have been quite bullish as it pertains to CGP coverage,” Dumanois says. “Aetna and Anthem tend to be fairly mixed—they’ve got a bias towards IVD. And a number of national plans, including United Healthcare and Humana, really don’t recognize any comprehensive genomic profiling assays yet. There may be some one-off exceptions, but they’ve not accepted it.”

Charles Mathews, managing director at ClearView Healthcare Partners, says some of the payer reticence toward CGP reimbursement stems from how they view these broad panels— as research assays, as opposed to clinical diagnostics.

“There is always going to be a tension with payers it appears, who are going to look at them and say, ‘I don’t want to pay for that research piece. But I will pay for what’s (clinically) valid.’ I’m now coming to the conclusion that [CGP] will never have the uniform payer coverage we would like it to have, because it always incorporates this research element,” Mathews notes. “But I will also say, I think that might be okay. Payers recognize the progress in areas like non-small cell lung cancer. Things that have explicit continued diagnostic purpose, payers are more aligned to those, and they’ve been able to work out approaches that allow them to get the core value of the sequencing compensated.”

Reporting findings
Spotty reimbursement aside, another challenge to the broader adoption of CGP, especially in the community setting where oncologists don’t specialize in a particular cancer—as they do at larger urban health systems, academic medical centers, or large cancer centers—is providing actionable reporting once the test is completed.

With panels that are looking at hundreds of known cancer markers, fusions, deletions, and biomarkers pertinent to matching patients not only to targeted therapies, but potentially to immunotherapies, by its very nature a CGP will generate a broad swath of information about each patient’s tumor. But what are the pertinent genetic alterations that can point a physician toward the most effective targeted therapy and which ones can essentially be ignored? While an oncologist who specializes in lung cancer at a major academic medical center may be able to effectively wade through the data generated by a CGP to develop a treatment plan, a community oncologist, who is treating patients with many different forms of cancer, typically needs more guidance.

According to Anthony Magliocco, founder and president of Protean BioDiagnostics, the key to clinical utility of CGP is to provide a concise, focused report that provides direct guidance to oncologists on the actionable alterations, while also providing a support system that might include a virtual tumor board the doctor can consult, as needed, to aid in therapy selection.

“This is of the highest importance,” Magliocco noted. “Oncologsits feel threatened by these very complex reports, because they feel that they need to do something with it. We want to condense that report down into what do you do next: Here’s this recommendation based on current guidelines, or these things are possible based on your own judgment.”

Lee Schwartzberg, senior advisor for OneOncology and chief of medical oncology at Renown Institute for Cancer agrees that the community oncologist will need a helping hand to make the best use of CGP results. “I do think there are some lingering questions about utility. And I think the biggest question is distilling that vast amount of information that a CGP test gives you to prioritize treatments,” he says.

That means taking a report that could run upwards of 50 pages and condensing the pertinent information into a single page, or concise paragraphs, on a handful of the actionable markers to make it easy for the treatment team to select an appropriate therapy. At OneOncology, that means having a staffed tumor board that can triage test results to prioritize potential treatments as well as staff medical geneticists who can provide further expertise on a per-patient basis to further hone treatment recommendations. While Schwatrzberg admits this level of service would be difficult to scale, he notes that CGP test developers recognize the importance of not just uncovering actionable information, but refining how this information is presented.

“I’ve worked personally with probably the four largest CGP providers out there and I think all of them are very focused on improving their reports on a continual basis,” Schwartzberg says. “They’re improving the reports to make them more focused on clinical utility. There are enhancements coming all the time.”

As Magliocco sees it, continuous improvement in reporting is vital to helping break down resistance to using CGP as a part of oncologists’ regular practice routines. “If we don’t do that, they’re not going to use it because they don’t understand it, and it looks like alphabet soup. The report needs to help them know where to start,” he says.

Clinical trial matching
Good cancer care is also about getting patients enrolled in an appropriate clinical trial. With clinical trial participation already low, finding more patients to qualify who can be enrolled both helps to get new targeted therapies approved, while also being of clinical benefit to these patients. CGP is uniquely positioned to achieve these goals.

“It’s a very effective tool,” Magliocco says. “There are so many trials today and if you’re not testing, you’re not going to find the eligible people. By running CPG, you’re actually considering the patient for hundreds of potential trials, so the odds that they’re going to get onto one would actually be quite high.”

This makes the argument that in the clinical setting, virtually all patients with advanced cancers should be tested with CGP. This would effectively turn the old model of recruiting patients to trials on its head, where typically a patient would be tested for a specific marker to see if they would qualify. Instead, using CGP, the test queries hundreds of biomarkers for a patient’s cancer and the results can then be compared to the biomarkers needed to qualify a patient across all active trials to see if there is a match. With the growth in basket trials, the potential is even greater as these biomarker driven studies seek to discover a number of different cancers that may be treated with the same drug.

It’s not surprising then, that companies like Found Medicine and Tempus, which are performing CGP have also begun clinical trial matching programs for patients who take these tests. And increasing the use of CGP in the community oncology setting helps to provide broader access to a population of patients that haven’t typically been involved in these studies.

Yet despite this broader reach, Maggliocco still believes pharma companies will continue to have difficulty filling their trials, largely because they will be recruiting for cancers that affect ever-smaller cohorts of patients.

“Going to the future, they’re never going to be able to complete these trials,” Magliocco contends, “because there aren’t going to be enough people in the world. You’re going to have to do a personalized approach with matching to the therapies and then a monitoring approach using imaging or liquid biopsy to ask ‘Is this patient showing signs of responding? Or is the tumor evolving, and we’re going to have to switch therapies?’ I think it is going to be more about managing chronic disease and seeing how the tumor is changing, or if it is going back to a previous form. The treatments may bring the cancer back to a previous state and it might be sensitive again to an original treatment, several lines ago.”

Chris Anderson, a Maine native has been a B2B editor for more than 25 years. He was the founding editor for Security Systems News and Drug Discovery News, and led the print launch and expanded coverage as Editor in Chief of Clinical OMICs, now named Inside Precision Medicine. He is an avid supporter of the Boston Red Sox, the Boston Bruins, Aston Villa FC, and wishes U.S. professional sports would adopt the practice of relegation. In his spare time, he can found with headphones on playing Beatles and Bob Marley songs on his Fender Jazz bass while dwelling on the hundred degrees of separation between his abilities and those of Pino Paladino. He also mixes the best Manhattan in the world—prove him wrong.