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Early Detection, MRD Test Data Get Optimistic Reception From GI Oncologists at ASCO Meeting

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NEW YORK – Oncologists considered a variety of emerging data on noninvasive genomic tests last week that made them optimistic these will be able to help them detect gastrointestinal tumors at earlier, removable stages, and more precisely identify patients who will not be cured by surgery and should receive adjuvant treatments. 

Gastrointestinal tumors, such as colorectal and pancreatic cancers, tend to be aggressive, diagnosed at late stages, and notoriously refractory to available targeted and immunotherapy treatments. These tumors have become a critical proving ground for companies developing liquid biopsy and other noninvasive genomic tests to screen for early signs of cancer, detect minimal residual disease, or MRD, and monitor for cancer relapse. 

At the American Society of Clinical Oncology's GI cancer symposium last week, leading MRD testing companies like Natera and Guardant Health shared new data on their competing tests, while early detection firms like Exact Sciences presented evidence for a new generation of screening tools. During a session at the meeting, oncologists discussed the available evidence currently supporting the use of these genomic tests and highlighted data gaps that need to be filled for broader use. 

Naureen Starling, an oncologist at the Royal Marsden NHS Foundation Trust, highlighted the poor prospects faced by patients with advanced GI cancers and forecast that emerging early detection and early diagnosis technologies will be crucial if the field hopes to drive any reduction in mortality. 

"The difference in survival between patients presenting with localized and advanced disease is stark, even more so for GI cancers … and particularly so for HPV cancers, the majority of which are associated with late presentation," she said. "Whether it's early detection or early diagnosis, simple noninvasive diagnostics, which are effective and which correlate with disease, are urgently required." 

Starling noted that the UK has an ambitious goal to diagnose 75 percent of all cancers at stage I or II by 2028. Currently, only around 50 percent of cancers in the UK are diagnosed that early, she said, and easy, noninvasive tests for screening an asymptomatic population will be required to move the needle over the next six years. 

Cautious optimism for early detection tests 

The field is particularly interested in new stool- or blood-based colorectal cancer screening assays that promise to improve test uptake and guideline-recommended screening rates, which hover around 60 percent in the UK. 

At the ASCO GI meeting, Exact Sciences shared new data on the performance of its second-generation multi-target stool DNA test, Cologuard, from a study of 777 samples collected in the US and Canada. Investigators reported overall sensitivity of 95 percent and specificity of 92 percent for the new version of the assay. Subgroup analyses also showed 83 percent sensitivity for high-grade dysplasia, the most dangerous precancerous colorectal lesions, and 57 percent sensitivity for all advanced precancerous lesions.

A multi-center pivotal trial of the enhanced stool test, as well as a blood-based assay that could drive even more uptake, is currently ongoing with results expected late 2022 or early 2023.

Bluestar Genomics also shared results at the meeting, from a performance evaluation of its epigenomic pancreatic cancer test, showing 55 percent sensitivity and 98 percent specificity in a cohort of 1,433 patients with new-onset diabetes. 

Since these blood- and stool-based colorectal and pancreatic cancer assays don't address the larger population of GI cancers, the field is also closely tracking the development of multi-cancer screening assays by Grail, Exact Sciences, and others. Although detection rates for these tests have varied across tumor types, they have been relatively high for some of the more lethal tumor types, like HPV-driven cancers. 

The field is cautious about broadly adopting these new tools, Starling said, but eager to see readouts from prospective studies like Grail's UK trial of its Galleri multi-cancer detection test, which is recruiting over 140,000 asymptomatic patients. 

According to Starling, oncologists should remain attentive to unanswered questions as early detection tests enter the clinic. "We need to understand how many more cancer patients with cancer [these assays] bring into the system; what was the cost of additional invasive tests that those patients underwent; [and] what were the potential harms to the patients … particularly when a cancer diagnosis isn't forthcoming [although] a DNA test is positive," she said. She added that she expects noninvasive early detection tests "will be a reality" in the future, but "there's a whole lot more work to be done." 

Navigating the MRD landscape 

MRD-based detection and monitoring is also a particularly crowded sector of the broader liquid biopsy market, where the existence of established competitors like Guardant Health and Natera hasn't deterred other players from entering the space with novel technologies.

Scott Kopetz, a physician-scientist at the MD Anderson Cancer Center, urged attendees to recognize the extent to which this new suite of technologies stands to improve clinical care and patient outcomes. 

"We certainly recognize the improvements that CT scans brought over chest X-rays … and we think that we're seeing a very similar jump with circulating tumor DNA in that we can detect much smaller numbers of cancer cells in the body that are well below the limits that a CT scan can detect" he said.

Although competition is heating up among commercial testing firms, especially around demonstrating the potential advantages of tumor-informed versus tumor-agnostic approaches, Kopetz observed that in the absence of published head-to-head comparisons, it may be counterproductive for oncologists to be overly concerned with the merits of one MRD assay over another.

"This way lies insanity," he said during a question-and-answer session at the meeting. "We just don't have the data to really compare."

Among commercially available MRD tests for GI tumors, Natera's Signatera and Guardant's Reveal tests are the most prominently marketed, but at the ASCO GI conference next year, Kopetz predicted there will be new options for his colleagues to consider in the space. In such a competitive commercial testing environment, "we have to be good stewards of understanding what these assays can do and their strengths and limitations," he said. "But it will be hard in the short term to compare them."

Regardless of technology, one thing that has become clear is that these MRD tests have nearly a 100 percent positive predictive value in their primary indication — identifying residual disease in early-stage colorectal cancer after surgical resection, Kopetz said. 

That said, based on emerging data, sensitivity is clearly lower, he added. "You can see that there are [MRD negative] patients that will recur, so it's not a perfect assay in that regard," Kopetz said. "But you recognize that a patient with a negative ctDNA post-operatively or post-adjuvant has a very good outcome." 

The improvement in lead time in detecting disease relapse by blood-based MRD tests compared to imaging is also clear, he said. "We can detect these patients who are positive [immediately after surgery], but we may not see the disease [return clinically] for a year or more." 

In the US, early evidence demonstrating these advantages of MRD testing has already led to Medicare coverage in colorectal cancer, though Kopetz predicted that new studies will rapidly push that bar and help expand coverage to other tumor types.

At the ASCO GI meeting, Gregory Botta, an oncologist at the University of California, San Diego, discussed one such study using Natera's personalized tumor-informed Signatera test in 115 patients with pancreatic adenocarcinoma. Investigators collected plasma samples at 450 time points from these patients and tracked their MRD and outcomes.

"Most of the stage I and stage II patients … had ctDNA that was negative post-operatively, which we felt very much correlated with the hope of most of our patients with early-stage disease," Botta said. In contrast, patients with stage III disease were more frequently MRD-positive.

Across disease stages, ctDNA dynamics tracked with patients' treatment regimens and ultimately reflected whether their cancer recurred or they remained cancer-free and MRD negative. Overall, the investigators determined that ctDNA MRD was a very strong predictor of recurrence, Botta added. 

Refining treatment decisions 

Although Kopetz argued that MRD tests seem to have clear prognostic value, other aspects of clinical utility still need to be proven. For example, it's still not clear how blood-based MRD tests should be used to support specific treatment decisions, such as treatment escalation, or de-escalation in the adjuvant setting. 

The COBRA trial is one ongoing study in stage IIA colorectal cancer that could provide some insights in this regard. In that study, researchers are randomizing patients who they think can forgo adjuvant treatment to either receive Guardant Health's MRD testing or receive standard of care observation. 

In another trial, called CIRCULATE US, researchers are recruiting stage III colorectal cancer patients, testing them with Natera's Signatera tumor-informed assay, and randomizing MRD-negative patients to either receive adjuvant therapy or be monitored with longitudinal testing and receive treatment only if they become ctDNA-positive. 

In an oral presentation at the ASCO GI meeting, researchers from the parallel CIRCULATE Japan effort shared data from the observational GALAXY arm of the trial, in which they are assessing the association of ctDNA dynamics with short-term clinical outcomes and adjuvant chemotherapy efficacy. 

Based on an analysis involving 1,365 stage II/III colorectal cancer patients, the researchers reported a 68 percent post-surgical sensitivity for Signatera performed at a single time point. While MRD-negative patients didn't appear to benefit significantly from chemotherapy, those with a positive test at four weeks post-surgery did show a benefit from adjuvant treatment across all disease stages. 

On-treatment ctDNA dynamics also appeared to predict therapy benefit, with 68 percent of adjuvant-treated patients showing no ctDNA by week 24. These patients also had significantly better outcomes relative to those who remained ctDNA-positive.

In a statement, Natera's VP of oncology medical affairs, Alexey Aleshin, said the firm is optimistic that the results could change current colorectal cancer treatment guidelines, which recommend combination chemotherapy for all stage III patients, despite data suggesting that about 40 percent are cured by surgery alone.

At the ASCO GI meeting, Guardant also presented an interim analysis of its MRD test in the first 100 patients enrolled in the prospective and observational COSMOS-CRC-01 study. Investigators reported that the data adds to existing evidence that Guardant's tumor-agnostic Reveal test can detect MRD prior to disease recurrence with an average lead time of greater than six months when performed after curative-intent surgery for stage II-III colorectal cancer patients. 

Taking MRD in new directions 

According to Kopetz, unanswered questions for MRD testing in GI cancers include whether new therapies can be identified, tested, and proven in MRD-positive patient cohorts, ultimately improving the cure rate of the overall population. 

"Right now, we get to the point where the disease has progressed to the point that it's detectable by imaging, and we then consider them incurable," he said. "So the question is, can we take advantage of earlier opportunities to try to accelerate and have more intense adjuvant therapies?" 

Among efforts in this vein, Kopetz cited a study with vaccine firm BioNTech taking high-risk stage II or stage III colorectal cancer patients and randomizing MRD-positive individuals to either watchful waiting or treatment with a personalized mRNA vaccine after standard adjuvant chemotherapy. 

"Unlike prior adjuvant therapies that took 1,000 patients to get a signal, we now have the ability to do Phase II proof of concepts that enable a rapid path to registration … because these are patients who have very high event rates in the absence of any interventions," he said. 

Clinicians are also exploring whether MRD positivity can serve as a biomarker of response, even a primary endpoint in its own right, to further accelerate adjuvant drug trials. 

"My hope is … that over the next several years, ctDNA will dramatically change our approach in this setting," Kopetz said. "But I would encourage us to really develop the data. We need to make sure that we don't jump ahead … [and], in the absence of good data, prematurely adopt any interventions." 

William Hall, an oncologist at the Medical College of Wisconsin, agreed that the field should await the results of larger ongoing trials before using ctDNA testing routinely in patient care. "We're hearing it brought up more and more frequently in our multidisciplinary tumor boards, often followed by some long pauses, as I think many of us are unsure exactly how to use it," Hall said.

Hall further pointed out that while there are many trials exploring ctDNA MRD tests for guiding chemotherapy use, there are fewer efforts studying how such tests can inform the use of localized therapy.

"Many of these trials are in patients with non-metastatic disease, so the presumption is that the ctDNA is shed from a … residual tumor," he said. "It could be very interesting to see more trials on how ctDNA may guide locoregional therapies, whether that's radiation therapy or extensive surgical resection." 

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