NEW YORK (GenomeWeb) – After reviewing data presented to them on a range of genetic tests already in clinical use for personalizing cancer treatments, an advisory group for the Centers for Medicare & Medicaid Services voted this week that two well-established breast cancer recurrence risk tests and microsatellite instability (MSI) testing in colorectal cancer have sufficient prognostic validity and utility.
At a meeting of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC), a group that reviews available evidence on medical interventions and advises CMS, a few panelists and at least one presenter pointed out that many of the markers the committee was tasked with evaluating have evidence backing their use as predictive, but not prognostic, markers. Predictive markers provide information that healthcare providers can use to guide treatment decisions for patients, while prognostic markers provide information on disease outcomes, such as the likelihood that a cancer will recur.
Still, CMS maintained the committee's focus in looking at the evidence behind these markers' prognostic application. "Considering the treatment perspective is sort of a moot point," James Rollins, director of CMS' Division of Items and Devices, said at the meeting in response to participants who highlighted how testing for mutations in EGFR and KRAS were informing cancer care. "Since we're still focusing on the prognostic value of the tests, we're still looking at the recurrence as opposed to treatment."
After averaging committee members' votes, only Genomic Health's Oncotype DX breast cancer recurrence test met MEDCAC's threshold for analytical/clinical validity for impacting positive or negative health outcomes, and for having a positive benefit in terms of clinical utility. The panelists were satisfied that Agendia's breast cancer recurrence test MammaPrint and MSI testing had analytical/clinical validity and impacted health outcomes in terms of benefits and harms, but didn't quite meet the mark for impacting a positive clinical utility benefit.
Testing for BRAF and KRAS mutations, according to the committee votes, had analytical and clinical validity, but not clinical utility. Meanwhile, the committee found that Oncotype DX for gauging colon cancer recurrence risk, as well as ALK, EGFR, and KRAS mutation testing for non-small cell lung cancer prognosis, satisfied evidence requirements for only analytical validity. The lack of evidence presented on MLHI promoter methylation testing resulted in the committee voting that the test lacked even analytical validity.
The impact of MEDCAC's backing, or lack thereof, is unclear. Oncotype DX for breast cancer and MammaPrint both have had Medicare coverage for a number of years now. Moreover, there are now analyte-specific CPT codes for many of the markers the committee considered, such as KRAS, BRAF, and EGFR — and Medicare contractors have been using these codes to pay for predictive testing.
Genomic Health announced in 2011 that Medicare contractor Palmetto GBA began covering its Oncotype DX colon cancer test. However, the negative MEDCAC review for the test raised concerns among at least one investment firm. "Medicare is a significant portion of Oncotype DX Colon reimbursement," William Quirk, Piper Jaffray senior research analyst, wrote in a note to investors following the meeting. "Given MEDCAC's assessment, we believe a reversal of Medicare's coverage decision represents a potential risk."
Prognostic or predictive?
From the start of the meeting, there was much confusion among panelists and meeting participants as to why CMS wanted MEDCAC to consider the evidence on many of these genetic markers — such as BRAF and KRAS mutation testing for colorectal cancer, and EGFR, ALK, and KRAS mutation testing in NSCLC — in a prognostic context and not a predictive one. One of the MEDCAC panelists questioned whether it was "even fair" to look at the prognostic value of some of these markers when the tests were developed to be predictive of treatment benefit.
From a prognostic standpoint, "whether they have good or bad outcome is irrelevant," Jeffrey Ross, chair of the department of pathology and laboratory medicine at the Albany Medical College, said at the meeting. In his presentation, he emphasized repeatedly that for many of these tests it was their predictive capabilities that ultimately would positively impact outcomes by guiding patients to the drugs they would benefit from or by helping them to avoid toxicities and costs of drugs to which they wouldn't respond.
Even when MEDCAC panelists were asked to consider and vote on the impact of test results on guiding anti-cancer treatment, they were asked to consider the tests from a prognostic standpoint. The clinical utility question read, "How confident are you that there is sufficient evidence to conclude that using the molecular pathology test to estimate prognosis has clinical utility (meaning, that it improves health outcomes either due to increased benefits and/or reduced harms) for Medicare beneficiaries with cancer whose anti-cancer treatment strategy is guided by the test's result?"
This is like assessing penicillin while excluding data on its use as an antibiotic.
Well before the MEDCAC meeting was held, Medicare policy expert Bruce Quinn warned the committee that its approach toward some of the biomarkers under consideration was misguided. In a Feb. 22 letter to MEDCAC, Quinn wrote that "while public concerns and evidentiary needs may be important for actual prognostic tests in cancer, there is no public demand or rich scientific debate about whether KRAS, ALK, or EGFR have pressing issues regarding their 'prognostic' value." These markers have little prognostic value, as the technological assessment revealed, but this was well known before the survey was performed, he added.
"Medicare paid for a technology assessment of tests like ALK and EGFR while excluding their benefits for choosing correct chemotherapy," Quinn, a senior health policy advisor at the law firm Foley Hoag, told GenomeWeb. "This is like assessing penicillin while excluding data on its use as an antibiotic. Oncologists and experts in precision medicine recognize the mistake."
The tech assessment was done based on literature published upto the end of 2013. The MEDCAC meeting was originally slated to be held last year, but was delayed. The evidence review data were not updated.
Current clinical practice guidelines clearly recommend testing for several of these markers for guiding treatment decisions, such as KRAS mutations in colorectal cancer and EGFR and ALK mutations in NSCLC. The FDA has updated labeling for the drugs Vectibix (panitumumab) and Erbitux (cetuximab) to note that only patients without certain KRAS mutations are likely to benefit from treatment. Meanwhile, the labels for NSCLC drugs Tarceva (erlotinib) and Gilotrif (afatinib) state the drugs should be given to those as a front-line therapy when they have EGFR-mutated tumors, and the labels for Xalkori (crizotinib) and Zykadia (ceritinib) indicate those drugs for patients with ALK-positive tumors.
Making a more general observation, some MEDCAC members commented that stakeholders in the life sciences community needed to figure out ways to collaborate and gather clinical utility evidence, which undoubtedly necessitates large, expensive, and long-term studies.
"As we worked our way through the decision making, it became clear that the data regarding patient outcomes and what was influencing patient/physician decision making and the downstream effects of these tests, it all got very thin very quickly," Beverly Guadagnolo from the University of Texas MD Anderson Cancer Center said at the meeting. "We're going to have to focus more attention on actually gathering the data about the patient experience and the actual patient-centered outcomes that go with that."
CMS' Rollins noted that Medicare would increasingly ask to see clinical utility evidence going forward from test developers. "We've approached various lab vendors and they are able to show us plenty of information in terms of analytic validity, as well as clinical validity, and some of them feel that demonstrating clinical utility is something that they don't need to provide commercial insurers," Rollins said at the meeting. "I don’t know why they feel that way but … as time goes on [CMS] will be using more and more clinical utility."
Does FDA approval matter?
Finally, CMS also asked MEDCAC to discuss whether the tests' regulatory status or the type of lab performing testing might impact the generalizeability of the evidence behind the tests for the Medicare cancer population. These questions brought up ongoing contentions in the life sciences community about the US Food and Drug Administration's decision to oversee lab-developed tests (LDTs).
Jan Nowak, medical director of molecular diagnostics and cytogenetics at the NorthShore University HealthSystem, presented data from the College of American Pathologists' proficiency testing program to suggest that testing for markers such as BRAF, KRAS, and EGFR is "uniformly outstanding" among participating labs. CAP's proficiency testing determines how accurately a lab tests for specific analytes and compares the lab's performance against other labs testing for the same analytes.
"CAP hasn't perceived any difference in performance," in terms of analytical validity, "that distinguishes FDA-approved tests from lab-developed tests, not for any of these analytes," Nowak said. "These things don't start with someone bringing forward an FDA-approved test. These assays start because there is clinical need, labs develop the tests, and they take responsibility for doing it well." CAP also hasn't observed any differences in testing performance according to the types of labs (i.e. academic, commercial) performing testing, he added.
Noting that tests are often launched first as LDTs, Nowak highlighted that CAP's proficiency survey for MSI testing in colorectal cancer has been around for a decade and still there is no FDA-approved test. Similarly, before FDA approved a companion diagnostic for gauging KRAS mutations, oncologists were using LDTs to determine whether or not to give their colorectal cancer patients Erbitux or Vectibix.
Ross, who is also medical director at next-generation sequencing-focused cancer testing firm Foundation Medicine, noted that an FDA-approved test is not always the best test. He cited the example of a metastatic lung cancer patient whose disease had spread to the brain and who had tested negative for an ALK rearrangement by an FDA-approved ALK FISH test. But the patient was then tested for an EML4-ALK fusion by NGS and was found positive for the marker.
According to Ross, FISH testing picks up 70 percent of ALK-driven lung cancers but misses 30 percent of patients who could benefit from an ALK inhibitor, such as Xalkori. "This is one of the issues that always comes to play when a gold standard test in the label of a drug after approval turns out not to be the gold standard," he said, adding that the lung cancer patient has been doing well for four years now on Xalkori.
Since MEDCAC was discussing the evidence for markers already in clinical use, Ross further recommended the committee consider newer, emerging cancer markers, such as ROS1, RET, and the BRCAness signature in ovarian cancer.
Some panelists, such as Lakshman Ramamurthy, a director at the healthcare advisory company Avalere Health and former senior reviewer in FDA's device division, spoke out in favor of a more accountable regulatory system for diagnostics.
While he was sympathetic to the fact that FDA approval takes time and patients can't always wait for access to critical tests, the lack of FDA oversight of LDTs also brings risk, he suggested. "When the tests work and patients are saved, that's great," he said. "But when the tests don't work, there is no adverse events reporting system, is there?"