NEW YORK – When precision oncology experts help their colleagues in the community make treatment decisions based on next-generation sequencing reports, local doctors are finding they can treat their patients with more confidence, and insurers are more likely to cover off-label therapies.
The Centers for Medicare & Medicaid Services' decision in 2018 to grant national coverage for NGS tests to inform treatment strategies for advanced cancer patients eased reimbursement-related access barriers on the diagnostic front. However, with improving coverage for NGS panels that gauge alterations in hundreds of genes — many with scant evidence of therapeutic actionability — some oncologists and industry observers worried that these tests would increase off-label use of expensive drugs with little chance of improving outcomes for patients.
That influx in use of off-label treatments didn't happen, according to precision medicine experts like Howard McLeod, partly because insurers continued to limit off-label coverage, but more so because many oncologists still don't know how to apply NGS test results to guide patient care. "Interpreting NGS results is a major problem that both hampers appropriate ordering and makes it difficult to make the case to insurance companies for on-label, off-label, or no-label coverage," said McLeod, who in late 2019 started Clarified Precision Medicine, a virtual molecular tumor board, or MTB, service through which experts help community physicians review genomic test reports and apply the results to patient care.
In the fall of 2020, City of Hope also invested $40 million in an effort to address the expertise gap in cancer care, including in precision oncology. The subsidiary, called AccessHope, partners with employers who want to make experts from National Cancer Institute-designated comprehensive cancer centers available as a benefit to their employees through health plans, and in doing so improve the quality and reduce the cost of cancer care.
Given the pace of medical advances, most community oncologists welcome the help, according to Todd Sachs, chief medical officer of AccessHope. "It's hard to be a medical oncologist because the information is changing for the better so quickly," he said, estimating that information about treatment protocols, treatments, and genetic testing, and precision oncology changes every 73 days. "How do you as a medical oncologist keep up with that?"
The challenge is particularly acute in precision oncology, where more and more biomarker treatments are coming to market and forcing testing modalities to shift to larger NGS panels. In this rapidly evolving environment, doctors with limited genomics knowledge are scratching their heads as they sift through test reports and try to figure out how to treat patients. And when testing points to more experimental strategies, they're spending a lot of time battling with insurers for coverage.
Many in the field refer to this as the "last mile problem" in precision oncology. To help oncologists traverse this final hurdle, top-tier cancer centers and regional hospitals are increasingly making their experts available to community practitioners through programs like AccessHope and virtual MTBs.
When McLeod speaks to oncologists and mentions that genetic testing reports from even high-quality labs can be hard to interpret, they all shake their heads in agreement. "Part of it is expertise and part of it is just time," said McLeod. "They wish there was a body that could just help review [these NGS reports] in the same way that CT scans get reviewed or pathology get reviewed."
Making sense of the report
McLeod founded Clarified Precision Medicine with Lincoln Nadauld, chief of precision health and genomics at Intermountain Healthcare, because so many community oncologists were calling them up and asking for advice on how to treat their patients who'd had NGS profiling.
When patients have biomarkers that can be targeted with FDA-approved therapies, doctors know what to do. "That's some very easy math," McLeod said. "What they don't understand is what else is in the report." If there aren't any FDA-approved options for a patient, oncologists are nervous about missing an off-label or experimental treatment opportunity buried deep in the report, he reflected. And when patients have multiple options, oncologists often don't know in what order to try them.
Clarified Precision Medicine, which engages expert reviewers from multiple top-tier cancer institutions, is providing MTB support to a variety of clients — high-volume cancer centers with internal MTBs that are overextended, smaller community practices that lack the expertise and resources to start their own MTBs, and cancer centers serving Medicare Advantage patients who have more limited therapeutic coverage. When clients send patients' test reports to Clarified Precision Medicine, some algorithms are initially run to pull out actionable insights, but then a precision oncology expert, sometimes a panel of experts for complex cases, reviews the findings and makes recommendations.
"I like to call this the Uber Black for precision medicine. It's not somebody in a Toyota Corolla. It's an expert driver in a black Escalade," quipped McLeod, estimating that this distributed MTB service model can review hundreds of patients' reports a week, whereas at many institutions, internal MTBs can look at only a handful of cases a month. The MTB's recommendations, including references to published studies and other supporting evidence for off-label or investigational treatment options, are placed in a report with the names of the experts who reviewed the test results.
"The medical oncologist wants to know that the person saying yes [to a treatment] is not someone at a testing lab or someone who's just focusing on the computer science part of it but really someone who's thinking about how you manage their patient," he said. "Instead of taking a half hour to an hour to review that [NGS] report, the oncologist can now take less than 30 seconds to look at a ClarifiedSelect report, talk to the patient, [and] give the patient extra confidence that this has had a secondary review of an expert molecular tumor board."
Currently, the company's MTB services are funded through investor support, grants, or philanthropic donations from patient advocacy groups. Clarified Precision Medicine, which is established as a for-profit venture, is also working on enabling Medicare reimbursement for its MTB services. McLeod said there are CPT codes that expert reviewers could use to bill for their report interpretation work, which would not interfere with the professional and technical billing codes clinical laboratories use to get paid for molecular testing.
Bon Secours Cancer Institute in Midlothian, Virginia, which employs eight oncologists who treat approximately 3,500 cancer patients a year, are testing out Clarified Precision Medicine's MTB support services under a pilot program. William Irvin, medical director of oncology and director of clinical research at the cancer institute, said the aim of the MTB pilot program is twofold: to quickly determine the best treatment for patients, especially when the findings from NGS reports are unclear, and to educate oncologists at Bon Secours.
"A lot of times, may be even the majority of times, with the exception of lung cancer, the information you're getting back on an NGS report is not that obvious. There could be a list of five or six [detected] variants, where the knowledge of those variants may or may not be useful," Irvin said. "And that's where a lot of the value is in having a conversation with [MTB] experts, not just in terms of what to do but also what not to do. You don't want to offer patients something that's going to give toxicity without benefit."
At small community practices, and even within larger programs like Bon Secours, oncologists often lack the expertise to go beyond the information in the NGS report and figure out the best treatment course. Irvin hopes that the MTB pilot will provide educational opportunities for Bon Secours oncologists. "The next step after getting cases back from [the MTB] is to … discuss the differences between experts' opinions and what's actually written in the test report," he said.
Embracing NGS profiling
The University of Kentucky hired Jill Kolesar to set up an MTB at its Markey Cancer Center in 2016, recognizing early that with growing adoption of NGS testing oncologists would need help understanding what clinical actions to take based on the reports. "You order this test and get back a 20-page document that nobody can make heads or tails of," said Kolesar, who directs UK's Precision Medicine Center and co-chairs the MTB. "That's a reason why the tests don't get ordered because people don't know what to do with them when they get [the results] back."
The increasing availability of expert precision oncology services and virtual MTBs is intimately tied to growing use of large NGS panels and adoption of precision oncology as a discipline. But studies show that oncologists don't always test patients using NGS panels, even in settings like non-small cell lung cancer, where there are lots of biomarker-linked treatment options and guidelines support broader testing approaches. One study presented last year at the American Society of Clinical Oncology's annual meeting, showed that while NGS panel testing rates for lung cancer patients increased from 33 percent in 2018 to 45 percent in 2020, only 37 percent of the entire cohort received NGS panel testing.
Some of the undertesting captured in that study, McLeod suspects, may be due to oncologists not ordering NGS testing because they feel there's a low chance it will identify something actionable or they don't realize they should test stage III and IV patients. But they may also not be ordering tests because "it makes them feel dumb, or like there's liability sitting there, or like they're not serving patients well," he reflected. "We see a lot of oncologists not ordering tests because no one has their back."
Upon joining UK six years ago, Kolesar visited many community practices and academic cancer centers in the area and talked to them about the MTB. The volume of MTB-reviewed cases has grown steadily since those early days, from 152 in 2017 to 644 last year. Today, community oncologists from 16 practices send test reports to the MTB, comprising 40 percent of reviewed cases.
"As an NCI-designated cancer center, part of our job is to be a resource for the community," said Kolesar, who is also spearheading efforts to encourage greater use of NGS profiling among oncologists. The transition to NGS panels is particularly relevant in Kentucky's Appalachia region, which has some of the highest rates of lung cancer in the US.
UK recently hired a nurse navigator, who manages test ordering, MTB referrals, and communication of MTB recommendations back to the treating physician. Between the biopsy and molecular testing, a patient's sample travels through multiple departments and specialties. "There are surgeons who are getting the biopsies from patients, pathologists who are processing the tissues, and then there are doctors who treat patients," Kolesar said. "Coordinating among those people is the challenge."
Since engaging the nurse navigator, use of comprehensive NGS panels has grown at UK. Kolesar now wants to make the same resource available more widely throughout the state. She has applied for a grant to conduct a study and demonstrate the value of engaging a nurse navigator to standardize NGS testing and MTB referrals across 10 community practices in Kentucky that each see a least 50 lung cancer patients a year. "It's just really about having a person who is knowledgeable who can help follow up on this stuff," she said.
'Smoothing the way' with payors
In a study published in JCO Precision Oncology last September, Kolesar and her UK colleagues compared the outcomes of 77 NSCLC patients who had undergone MTB review at the cancer center between 2017 and 2019 against controls in Kentucky's Surveillance, Epidemiology, and End Results Program registry who did not have such a review. To adjust for bias, researchers included controls who had similar demographic and clinical features, were likely to harbor clinically actionable tumor alterations, and had lived as long as the patients with MTB review at study entry.
They found that controls without MTB review had more than eight times higher risk of dying than those who received treatment recommendations from UK's MTB. Even patients living in the Appalachia region had survival similar to patients living in other parts of Kentucky if they had MTB review. This suggested that MTB review can improve the standard of care and diminish outcome gaps for patients regardless of where they live or receive care.
Data like this, demonstrating that MTB review can improve patients' outcomes, may be attractive to payors, who experts say are more likely to approve experimental treatments based on NGS profiling if experts are backing the strategy.
When Kolesar looked at 679 cases that UK's MTB reviewed between 2017 and 2020, she found 93 patients got the MTB-recommended treatment, and the rest did not for a variety of reasons. Some patients' disease progressed, some died, others enrolled in a clinical trial. But insurers did not deny the MTB-recommended treatment for a single patient.
The point of this analysis, which Kolesar plans to publish, wasn't to compare the rate of coverage denials for patients with or without MTB review, but she expects that insurance denials may have been more of a problem for patients without this review. "If you don't have a letter from a molecular tumor board, it's up to the doctor to argue with the insurance company," Kolesar said.
Every month, Donald Goodin, one of two medical oncology/hematology doctors at Baptist Health Medical Group, in Elizabethtown, Kentucky, sends one or two patients' reports to UK's MTB for review. He recounted the experience of a male patient with metastatic squamous cell carcinoma of the skin, a type of cancer for which there aren't a lot of studies informing the best course of treatment. This patient previously responded to immunotherapy but had to stop due to side effects.
"But he did have a mutation on his NGS report, so we sent it to the MTB," Goodin said. Based on the MTB's recommendation, Goodin prescribed an off-label therapy targeting the mutation, which the patient is tolerating well. Without that MTB review, he doubts this patient's insurance company would have approved this treatment.
"It definitely helps if the patient has a mutation and there is an off-label medication [associated with it], and we send [the report] to the MTB," he said. "That often is the difference between having to fight [for coverage] or maybe not even getting it covered, versus having the patient on the drug."
Getting off-label treatments covered without MTB review requires a lot of back and forth between Goodin's office and the insurance company. He has to write letters explaining why a certain treatment is best for a patient and have "peer-to-peer" calls to convince the insurers' medical director to cover the therapy. "This ends up taking a lot of time out of our day that's already busy with trying to take care of other patients," he said. "A lot of times, if we have that [MTB] letter and there's a recommendation, it does smooth the way."
Toward rational care
Since October 2020, when City of Hope launched its AccessHope program, 76 employers covering 3.3 million member lives have signed up to offer expert oncology review and consulting services as an employee benefit. "Employers are looking for solutions," said AccessHope's Sachs. For employers, cancer treatments can cost more than $1 million per patient, and cancer diagnoses can usurp between 12 percent and 15 percent of the total medical spend, in addition to the costs associated with employees' lost time from work.
The employee benefit requested by more than 80 percent of clients is the Accountable Precision Oncology, or APO, service, within which AccessHope uses a proprietary algorithm of ICD10 CPT diagnostic and procedure codes and other treatment-related information in health plans' records to flag the 20 percent of cancers that are the most complex and costly to treat.
The idea with the APO service is to bring expert precision oncology support to community practitioners before their patients start treatment. "We're really targeting the places where we can have the most impact … on quality of life, outcomes, and decreasing side effects from chemotherapy treatments," Sachs said. "When you do that, you do see a cost savings."
According to AccessHope, every $1 invested by the employer to make the APO service available to its employees could yield more than a $3 return in value if a patient's local providers take up the treatment recommendations of experts.
After flagging the patients with complex cancers who are particularly challenging to treat, AccessHope's precision oncology experts from NCI-designated comprehensive cancer recommend drugs or trials they can receive currently and suggest future care options. AccessHope sends reports with these recommendations to patients' doctors, and they can even discuss these options with experts.
"Oncologists can opt out. We're just there to assist as needed," Sachs said. "But we've actually had some physicians call us eight, nine, 10 times."
While AccessHope was still being developed, researchers led by Sachs and City of Hope's Howard West found that for 110 lung cancer cases reviewed from 2019 to 2020, experts' recommended course of action aligned with local oncologists' management decisions 72 percent of the time and diverged for 28 percent of cases. Additional recommendations from experts were associated with improved outcomes for 69 percent of patients and could have potentially cured 13 percent of patients. The research, which was published in JCO Oncology Practice in December, also estimated that experts' advice reduced care costs for 14 cases, resulting in savings of $19,062 per patient for the entire cohort.
Recognizing the potential cost and outcomes impact of this program, Blue Shield of California is conducting a pilot program with AccessHope, through which community oncologists treating Blue Shield PPO members can consult with experts about their patients' treatments.
Clarified Precision Medicine is also discussing pilot projects with insurers to further demonstrate the value of its MTB strategy in guiding patients to evidence-based care, improving outcomes, and reducing wasteful spending. "The point I try to make with the insurance companies is they're going to pay for an expensive therapy one way or the other," McLeod said. "There's no such thing as a cheap therapy anymore. Why not pay for one for which there's a rational basis?"
The value of MTBs may lie not only in identifying the right molecularly informed treatments, but also in flagging the wrong ones. For example, it's not uncommon for some oncologists to see a BRCA1 variant in an NGS report and expect that the patient might respond well to a PARP inhibitor. "If the variant is not affecting homologous recombination, then a PARP inhibitor should not be recommended, even if you could fool the insurance company into paying for it," McLeod said. "We, as a field, need to make sure we're saying yes to precision medicine when it's a yes and saying no when it's no."