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NCI-MATCH Sees Lots of Enthusiasm in Initial Months; Not Many Matches

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NEW YORK (GenomeWeb) – Enthusiasm for participating in the National Cancer Institute's MATCH trial has been higher than investigators expected, but, according to researchers knowledgeable of the project, the study hasn't yet "matched" many patients to treatments based on the genomic markers driving their disease.

The NCI-MATCH phase II study launched in August and is part of President Barack Obama's $215 million Precision Medicine Initiative. The study is testing the hypothesis that personalizing cancer treatments based on the genomic markers driving patients' tumors is an effective strategy. The trial opened with 10 arms into which researchers can enroll patients with a particular tumor marker after they have stopped responding to standard of care and treat them with drugs that are approved with a companion test or have some data suggesting they might work against the targets of interest.

"There's been an enormous amount of enthusiasm and hundreds of patients registered into the trial," Keith Flaherty, a medical oncologist at Massachusetts General Hospital and one of the study chairs, told GenomeWeb. Participants have been so eager, in fact, that the study reached its pre-planned interim analysis point, triggered in late October when 500 patient had been gauged for mutation screening, "shockingly quickly," Flaherty said.

He acknowledged, though, that there haven't been many matches yet. According to one update from November, only one out of more than 700 screened patients had matched to a molecularly defined treatment arm, although a number of patients were awaiting assessment at the time. NCI-MATCH is currently in pause mode, and researchers are not accepting new patients as they conduct the planned interim analysis into various aspects of the study — the range of tumor types, the kinds of patients that have matched, how many patients might match to other arms, and the quality of biopsy samples.

Experts GenomeWeb spoke to cited a number of factors for the lack of matches so far. The rapid pace of screening and enrollments may have overwhelmed the available arms open for entry, and around 15 percent of the samples were inadequate for analysis in terms of sample amount and quality.

In launching NCI-MATCH last summer, NCI Acting Director Doug Lowy called it a ground-breaking endeavor that "incorporates all of the tenets of precision medicine." As the public desire for precision medicine has increased, so has the pressure on the research community and regulators to consider trial designs that allow new ways of studying such drugs.

Basket trials offer a tantalizing alternative to traditional study designs in an era when cancer is seen as a complex, genetic disease, and not just as a malignant mass growing on body parts. Compared to traditional head-to-head randomized-controlled investigations, basket studies enable the simultaneous study of multiple drugs, markers, and histologies.

But amid all the excitement for precision medicine, it is easy to forget that this is difficult science, and basket trials are fairly new to the research scene and fraught with their own challenges. One 647-patient basket trial in advanced thoracic malignancies, called CUSTOM, was deemed "not feasible" due to the rarity of the mutations being studied and the lack of an adaptive design that would have allowed more flexibility.

Moreover, with the publication of the first basket study last year in the New England Journal of Medicine, Memorial Sloan Kettering Cancer Center researchers showed that tumor histology is still important in molecular medicine. Looking specifically at patients with a range of cancers with BRAF V600 mutations, researchers led by MSK's Jose Baselga and David Hyman found that certain tumor types but not all appear to respond to the BRAF inhibitor Zelboraf (vemurafenib).

"The idea behind any precision medicine study is that it's testing a hypothesis that using precision medicine will be better than not," said Michael Thompson, medical director for the early phase cancer research program at the Aurora Research Institute in Milwaukee, Wisconsin. "One thing that's often not brought up when one presents the hypothesis is ... that you have to formally test it, and that's what's being tested in this study." Thompson plans to activate a site for NCI-MATCH when it reopens.

The people that are excluded are the people we know [will respond] like people with EGFR in lung cancer.

Looking beyond standard of care

An important factor affecting the "match" rate is that molecularly defined cancer indications that are already standard of care aren't part of NCI-MATCH. For example, guidelines now recommend testing advanced non-small cell lung cancer patients for ALK rearrangements, which show up in 5 percent of cases. But in NCI-MATCH, researchers will enroll cancer patients with ALK-positive tumors in histologies other than NSCLC, where the prevalence of such markers may be even rarer or unknown.

The aim of NCI-MATCH is to move beyond what's already known and accepted, and test precision medicine theories in patients with new or uncommon cancer markers. And so, despite the enthusiasm for so-called basket trials as a way to study biomarker-driven treatment hypothesis, investigators are expecting a relatively low hit rate in some cases.

"When they opened [the study], they didn't think so many people would be sending stuff in. So, their first wave of 10 subprotocols are molecular markers we're familiar with, [such as] EGFR, ALK, and ROS1," Thompson said. "The people that are excluded are the people we know [will respond] like people with EGFR in lung cancer."

According to an update published by Thompson in the ASCO Connection, as of Nov. 7, NCI-MATCH researchers had molecularly screened 720 patients out of the planned 3,000 patients. Only one patient was on a study drug as of that time, although other patients still need to be assessed, wrote Thompson. A few hundred patients had "potential molecular matches," based on the 10 currently open arms or future arms slated to open, he wrote.

Ultimately, the plan is to enroll 1,000 participants and gauge responses to more than 20 drugs. Each treatment arm will enroll approximately 35 patients. However, in order to perform the interim analysis after testing 500 patients, on Nov. 11 the study stopped enrolling patients, which was planned.

According to Flaherty, in the few weeks before the deadline to stop enrolling patients, 300 new patients were registered in the trial."With 10 [arms], we knew that wasn't our highest rate of actionability," Flaherty said, but he expects matches to increase as more arms open. 

Other NCI-MATCH subprotocols slated to open this year are focusing on more common tumor markers, such as RAS and PIK3CA. If all the arms had been up and running last year, more patients could have matched, Thompson believes. "They had so many screened and didn't have all the subprotocols open," Thompson said. "So, the screened greatly overwhelmed the number of matched."

For example, MD Anderson Cancer Center — one of the four labs where participant samples are tested for mutations — processed 20 tumor tissue samples per day even though researchers had planned to process 20 samples per week."They weren't really prepared for that," said Thompson.

Sometimes researchers had to send back for more tissue and this happened 15 percent of the time, he said. Sequencing is being performed on fresh biopsies on an Ion Torrent PGM custom panel.

Within NCI-MATCH, MD Anderson Cancer Center, Massachusetts General Hospital, Yale University, and NCI Frederick Laboratory are sequencing patients' tumor samples for 4,000 variants in 143 genes. At a conference in September last year, James Doroshow, NCI deputy director for clinical and translational research, highlighted that researchers had validated and standardized gene sequencing at these four sites with greater than 98 percent concordance for "locked down" analysis of mutations in these genes.

'Something's got to change'

While enrollment is frozen, investigators will perform interim analysis on the treatment assignment rate, on how sites are performing with the biopsy process, and on the performance of the genetic testing platforms. This will serve as an early check in the trial to consider if any adjustments are needed, Flaherty said.

He couldn't provide a definitive timeline for when the interim analysis would wrap up. On the study website, NCI has projected patient testing will resume sometime in April or May this year.

As the investigators conduct the interim evaluations in NCI-MATCH, one matter that may come up is whether to increase the total number of enrolled and screened patients, particularly given the rarity of some of the molecular markers researchers want to study. "I think it's clear that if they are one-quarter of the way through for screening numbers that they can't continue what they are doing with just a thousand, right? So, something's got to change," Thompson said.

NCI put out the 3,000-patient screening number as an initial target, and achieving this may come down to budget. NCI put forth this number with the "idea that we were going to do all of this with 3,000 patients and that was as far as any commitment was being made in terms of NCI's budgeting for this," Flaherty said, noting that there hasn't been any public discussion about what would trigger an expansion in the number screened.

At the end of screening 3,000 patients, I'm sure we'll find differences of opinion about how worthwhile a study like this is in terms of actionability.

Even if the match rate increases, and more patients are able to get on a drug based on molecular markers, they may not ultimately benefit from treatment. "It's not likely that the people who go on the study will have a huge survival benefit, because of the way it's designed," Thompson said. "They're getting a single agent." However, combination treatments are allowed in the study design and may be a future option, he added.

For currently approved precision oncology drugs, patients respond dramatically at first, but most eventually develop resistance as cancer cells find alternative pathways to proliferate. Exploring new treatment combinations or different doses of drugs against molecular drivers in these patients might be a way to overcome resistance and improve responses, Thompson said. 

Within NCI-MATCH, patients that match to a treatment arm, respond initially, then experience progression could get on another arm if their tumors harbor another molecular target. This would require an additional biopsy and will depend on whether a slot is available in that arm.

If screened patients don't initially match to any of the arms, but a treatment becomes available that they could have matched to, they can still get on the study. However, their doctor will have to confer with the principal investigator and patients will need another biopsy if they've received treatment since being first screened.

Testing a hypothesis

"This is a large very public study and sometimes people may forget that this is hypothesis testing and we're looking for signals," Thompson said.

Flaherty expects that there will be a range of opinions among stakeholders as to how successful NCI-MATCH was in terms of being able to place patients on treatments that benefitted them. "At the end of screening 3,000 patients, I'm sure we'll find differences of opinion about how worthwhile a study like this is in terms of actionability," he said.

At Mass General, where doctors routinely perform next-generation sequencing on metastatic cancer patients and have access to an extensive portfolio of studies that they could potentially place patients in, more than 40 percent of patients receive actionable results. "You can't get higher numbers than that," Flaherty said. "Some people would say even that isn't good enough to make it a worthwhile enterprise for doctors and patients to go through."

"If that's the best we can ever do, then some people would say, 'We're not ready for this,'" Flaherty said. "Again, it's interesting to see how remarkably enthusiastic much of the investigator community was in terms of their early adoption of the trial."

Some researchers in the field have suggested that perhaps expanding the focus to different types of markers would improve actionability. In a Nature Reviews Clinical Oncology article last year about the challenges of implementing precision medicine in metastatic breast cancer, researchers led by Fabrice Andre from the French Institute of Health and Medical Research wrote that nucleic acid detection isn't enough and suggested conducting comprehensive tumor profiles, including protein expression patterns.

In NCI-MATCH, although genomic tumor features are the main focus, researchers could consider other types of tests, to detect RNA expression, for example. "We're a bit agnostic as to the analyte, it's much more based on [whether] you actually have some evidence that could point a patient to an effective therapy," Flaherty said.

He said he's aware that some in the field think that the actionability in precision medicine could be increased if other markers are factored in. "They'd have to have evidence showing this [strategy] can assign patients to treatments where they see response," he said. "All such opportunities are open for discussion."


This article has been updated from an earlier version which incorrectly referenced a basket trial called COMET. The trial is called CUSTOM.

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