NEW YORK – Invitae earlier this month launched a multi-center trial to gain insights into the real-world application of its Personalized Cancer Monitoring (PCM) minimal residual disease test, which it is offering as a tool for detecting cancer relapse early and guiding treatment.
In the prospective, observational study, dubbed MRD Assay Evaluates Recurrence and Response Via a Tumor Informed Assessment, or MARIA, Invitae hopes to enroll more than 1,000 patients at some 40 US sites and monitor their survival outcomes over five years.
PCM, which Invitae brought into its test portfolio when it acquired ArcherDx in 2020, is a tumor-informed assay that homes in on circulating tumor DNA, or ctDNA, as a marker for cancer, explained Amber Carter, Invitae's clinical program manager coordinating the MARIA study. According to Invitae, the test is currently available for most solid tumor cancers such as non-small cell lung cancer, colorectal, breast, and bladder cancers.
Within MARIA, patients with any type of solid tumor, who are receiving curative intent treatment or have completed treatment and are undergoing standard-of-care surveillance, can enroll and receive PCM monitoring as part of the study. Enrolled patients can maintain their local oncologist and provide tissue and blood samples, which Invitae uses to create a patient-specific assay designed to detect mutations unique to patients' cancers.
First, in its central lab in Iselin, New Jersey, Invitae performs whole-exome sequencing on the tumor tissue sample to identify variants. Then, using the accompanying tube of blood, it performs another round of whole-exome sequencing — this time looking for germline variants — to weed out any variants that aren't specific to the patient's tumor. After subtracting out the germline variants, Invitae uses a proprietary algorithm to identify up to 50 variants that can be reliably detected in plasma. This panel of variants make up the patient-specific assay for future MRD detection.
The process of generating this patient-specific assay with baseline samples can take up to 41 days from the time Invitae receives the initial sample, although according to Carter, "it's usually faster." Following this baseline component of the PCM test, Invitae sends a full report back to the patient's oncologist that includes both the somatic and germline variant findings.
As patients continue to receive treatment or be surveilled, they'll have their blood drawn several times a year for analysis using their personalized MRD assay to check for residual cancer or recurrence. The frequency of the blood draws may vary from patient to patient, and turnaround time for these subsequent blood tests can be around 10 days.
Invitae designed the MARIA study to be as flexible as possible, Carter said, meaning that the firm hasn't set a specific frequency at which patients must be sent for follow-up blood draws.
"We wrote the protocol … to allow flexibility and align with the patients' routine clinical care so that it's not putting undue burden on them," Carter said. Invitae has tried to design MARIA so enrolled patients don't have to schedule more visits than they would with standard surveillance or disease monitoring.
Importantly, because the study is observational, it's up to the physicians to alter their patients' treatment according to the baseline testing or based on subsequent blood tests. If physicians do use tests to guide treatment decisions in the study, it may help Invitae better understand the efficacy of curative intent treatment.
Data generation, regulatory ambitions
While the MARIA study is observational and exploratory in nature and not meant to guide regulatory submissions, Invitae hopes the data generated will inform the test's use down the line.
MARIA "is going to generate real-world data to help put forward the use cases that the PCM is very valuable for," said Ed Esplin, a medical director at Invitae and MARIA's principal investigator. "It will provide some insight into the indications that are going to be first applied for, even though the data wouldn't necessarily be directly submitted as part of a particular regulatory plan."
Currently, the PCM is available to academic and pharmaceutical researchers, and Invitae last June made it commercially available as a laboratory-developed test as part of an early-access program. In a call to discuss third quarter financial outcomes in the fall, Vishal Sikri, Invitae's president of oncology, shared that the company also had aspirations to apply for regulatory approval for a kitted version of the test.
"In 2022, we plan to launch our clinical offerings for PCM," Sikri said in early November. "Based on feedback from the FDA, we believe that we have a good road map for FDA approval for IVD products, including a path forward as an IVD for our PCM tests."
According to Sikri, Invitae will generate a "wealth of data" to support PCM, drawing on MARIA and other ongoing studies with academic partners. Data from MARIA could begin to readout by the end of the year, according to Carter. Data from the TRACERx study also validated PCM's performance in NSCLC, as do retrospective studies being done in partnership with Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center, among others. Sikri said Invitae next year plans to conduct prospective studies using MRD to guide patient care.
MARIA's "maximally inclusive" nature, according to Carter, has Invitae enthusiastic about the supportive data it could generate for PCM. Invitae has explored PCM's MRD detection capabilities retrospectively using samples from previously conducted studies but had to rely on whatever samples were available or left over. The studies Invitae is conducting with academic partners may also be stricter in terms of patient eligibility and protocols.
"That's where MARIA has more flexibility," Carter said. "We wrote it to be more forgiving than a lot of trials." Given Invitae's plans to conduct the study across more than 40 centers and enroll thousands of patients, the firm wants to generate data within MARIA about how MRD testing is used and accessed outside of stringent academic research settings, including, for instance, in the community oncology setting.
"How do you make a newer test like this work in the community oncology setting, or in a very rural setting?" Carter asked hypothetically. "We think that MARIA is poised to help us answer those questions to help with future availability for more patients."
Specifically, Invitae wants to observe the types of cases in which these oncologists would use PCM to monitor patients and treat them if testing picked up ctDNA indicating recurrence, and what the experience is like from both the patients' and oncologists' perspective.
Like Invitae, there are many other companies developing and marketing MRD tests that are interested in the same questions, such as Natera, with its Signatera test, and Inivata, with its RaDaR test. Personalis is developing a test dubbed NeXT Personal, though it is currently for research use only.
In Invitae's view, the fact that PCM has the sensitivity to include up to 50 variants could give it a leg up over other personalized MRD tests. Natera's Signatera can include up to 15 targets, and Inivata's RaDaR includes up to 48, for instance.
"[PCM] is unique in that it utilizes the maximum amount of information that can be acquired from a patient," said Esplin.
The personalized MRD test Personalis is developing, of note, is meant to identify some 1,800 somatic variants.
Although patients will receive PCM at no charge within MARIA, outside of the research setting, payor coverage is critical to patient access. According to Invitae's website, the PCM baseline report has a list price of $8,500 and the subsequent MRD monitoring tests have a list price of $3,500 apiece.
For its other commercialized tests, Invitae offers low out-of-pocket pricing for patients and separate in-network pricing for insurers and cancer centers. Invitae would not share whether this will be the case for the PCM as well. "Invitae's mission is to make high-quality genetic testing accessible through providing a comprehensive and flexible billing policy for patients," the company said in response to questions about its pricing strategy.
Recent indications regarding government payors' willingness to pay for these tests are encouraging also. For example, in November, Medicare Administrative Contractor Palmetto GBA released a final local coverage decision laying out the conditions under which it would cover noninvasive MRD monitoring in patients with a personal history of cancer and in tumor types where guidelines support the use of the test to guide treatment.
While Invitae's Medicare Administrative Contractor is Novitas, not Palmetto, Invitae is hoping that Palmetto's decision will help "support the value of MRD for clinical use" with its contractor.
"The local coverage decision is agnostic to specific [test] providers, so it is more based on the technology itself, and we are in discussions with [the Centers for Medicare and Medicaid Services] to leverage that support," said Sugganth Daniel, Invitae's director of oncology medical affairs.
Of course, commercial payors are known to lag behind CMS when it comes to coverage on new diagnostic tests, and Invitae knows that generating more data on PCM will be an important component of securing broader coverage. "We do feel there is a path toward reimbursement that would allow this [test] to be accessible, and we hope the data we generate will help to facilitate that process," Esplin said.