MRD: The Future Foundation of Solid Tumor Trials

The terms minimal residual disease, measurable residual disease, and molecular residual disease, interchangeably referred to as MRD, denote what is left after cancer treatment with curative intent. Originally used to monitor patients with hematologic malignancies, MRD is becoming increasingly important in the field of solid tumor oncology because of its correlation with disease outcomes.

Testing for MRD
Whether it is monitoring patients, guiding clinical trials, or being integrated into drug development programs, screening for MRD is generally done in one of two ways: tumor-informed or plasma-only liquid biopsy assays.

Tumor-informed assays are designed using tissue from a patient’s own tumor, which is screened for tumor-specific mutations. These mutations are then used to develop polymerase chain reaction-based assays that subsequently screen the patient’s blood for circulating tumor (ct)DNA with the same mutations, indicating MRD.

This technique “is the true definition of precision oncology,” according to Adham Jurdi, Medical Director of Oncology at Natera.

“Since we are designing the assay from the patient’s own tumor, we are able to track up to 16 clonal variants specific to that tumor [and] by tracking only 16 variants, we are able to perform ultra-deep sequencing,” said Jurdi.

The ultra-deep sequencing gives tumor-informed assays a very high level of sensitivity and specificity. Assays which target a higher number of variants cannot be sequenced at such a deep level.

Natera are the molecular diagnostics company behind Signatera – the first tumor-specific assay for the detection of MRD. The assay is validated for use in patients with colorectal, bladder, lung, gastro-esophageal, and pancreatic cancers, and in all solid tumors being treated with immunotherapy. It also has Medicare coverage for stage II–IV colorectal cancer and for immunotherapy-treated solid tumors.

As well as its proprietary Signatera assay, Natera recently partnered with Foundation Medicine. Foundation’s strength in comprehensive genomic profiling (CGP) combined with Natera’s ctDNA analysis technology resulted in the development of the FoundationOne Tracker, which was granted breakthrough device designation from the U.S. Food and Drug Administration (FDA) for the detection of MRD in early-stage cancers after curative therapy, and detection of disease progression and resistance in late-stage cancers during treatment. It is expected to be available as a laboratory-developed test (LDT) for clinical use later this year.

Priti Hegde, Chief Scientific Officer at Foundation Medicine said that a prototype of the test was used in two studies presented at the 2022 ASCO GI and ASCO GU meetings. “At ASCO GI, we explored the feasibility of MRD in metastatic colorectal patients who have undergone curative intent surgical resection. At ASCO GU, we presented data on the genomics of resected early-stage bladder cancer to validate CGP-informed MRD detection in ctDNA,” she remarked.

The tumor-informed technology used by both Natera and Foundation has the advantage that it only tracks clonal, non-driver mutations. This means that the assays can detect cancer recurrence irrespective of previous systemic therapy because these mutations are not subject to treatment pressure.

“This is not the case with static panels used in plasma-only ctDNA assays,” Jurdi remarked.

However, a limitation when using tumor-informed assays is the turnaround time. The bespoke nature means that the initial test design turnaround time is 2 to 3 weeks. It is 7 days on average for subsequent tests.

“We are constantly working at improving our technology and decreasing turnaround times,” said Jurdi. He also pointed out that “since the test is designed to detect a patient’s specific tumor, it will not pick up new (second primary) cancers that the patient may develop. Therefore, patients should still undergo the recommended screening test as per guidelines.”

Guardant Health is another major player in the MRD testing market, but their focus is on plasma-only assays. These assays, which are also called tumor-uniformed or tumor-agnostic assays, are cancer-specific but not patient-specific.

Guardant’s assays look for genomic alterations, methylation signatures, and fragmentomic signals that identify early-stage cancer patients with MRD who may benefit most from adjuvant therapy. In advanced cancers, the company says their tests have helped to accelerate the adoption of precision medicine by matching patients to targeted therapies.

The first test, Guardant360, was introduced as an LDT in May 2014 and its successor Guardant360 CDx was approved by the FDA in August 2020 as the first blood test “for complete genomic testing across all solid cancers, providing doctors with guideline-complete genomic results in 7 days from a simple blood draw to inform treatment decisions,” explained Guardant’s Chief Medical Officer Craig Eagle.Guardant360 CDx covers all genes recommended by the National Comprehensive Cancer Network, including the 55 most relevant to clinical care and is also approved as a companion diagnostic to identify patients with non-small cell lung cancer who may benefit from treatment with osimertinib, amivantamab-vmjw, or sotorasib.

While Guardant360 CDx is aimed at monitoring patients with advanced cancers, Guardant Reveal, launched as an LDT in February 2021 focuses on early-stage cancer by searching for MRD shortly after surgery.

“We believe that Guardant Reveal is pushing the boundaries of what was considered possible for MRD,” said Eagle. The assay can be initiated as soon as 4 weeks after surgery, requires no tissue samples, and gives results within 2 weeks.

“We have found that many people are surprised to discover that a blood-only liquid biopsy could have such excellent specificity and sensitivity,” Eagle remarked, adding that the test is unbiased and can therefore detect recurrence when there are multiple primary tumors or when a tumor has evolved.

The test is currently validated in patients with colorectal cancer, but Eagle said that Guardant are now conducting clinical trials to test its ability to detect MRD in people with lung, breast, or pancreatic cancer.

MRD in clinical trials

All of these tests, along with many more that are currently available, are now shaping the way clinical trials are carried out.

“Some providers are looking for data from prospective, interventional trials that will help clarify whether modifying treatment based on ctDNA analysis for MRD will improve outcomes,” noted Eagle.

Pashtoon Kasi, Director of Colon Cancer Research and Liquid Biopsy Research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and the Englander Institute of Precision Medicine explained that MRD is adding treatment arms to trials, with different regimens given on the basis of MRD positivity or negativity.

“I think it’s changing the designs where rather than all patients getting the same therapy [versus placebo], there are scales of therapy that could be more intense or less intense based on if you are MRD positive or negative, respectively. That’s something that wasn’t there before,” he said.

Kasi gave the example of the phase II/III COBRA trial, which enrolled more than 1,400 patients with stage IIA colorectal cancer. The post-surgery standard-of-care for these patients is active surveillance, but the trial is investigating whether patients who are ctDNA positive on the Guardant Reveal assay after surgery benefit from chemotherapy.

Another study, CIRCULATE Japan, which was presented at ASCO GI 2022, showed that MRD, this time measured by Signatera, was predictive of response to chemotherapy in patients with stage III colorectal cancer. Interim results suggest individuals positive for ctDNA benefit from adjuvant chemotherapy whereas those without ctDNA do not. The trial is also looking at treatment escalation or de-escalation (doublet vs triplet chemotherapy) on the basis of MRD.

Away from colorectal cancer, which Kasi describes as the “poster child for MRD-based studies” due to its relatively high prevalence and its high level of ctDNA shedding, trials in other cancers are also underway. These include BESPOKE-IO, which is investigating immunotherapy decision making in patients with melanoma and NSCLC as well as colorectal cancer, and the DARE and LeadER trials among patients with breast cancer.

Furthermore, in 2021, Elicio Therapeutics announced that the first patient in its phase I/II AMPLIFY-201 trial was given its investigational lymph node-targeted vaccine ELI-002. What makes this trial unique is that it specifically enrolls patients with MRD postsurgery. ”The AMPLIFY-201 trial is a great example of the use of liquid biopsies to identify patients with MRD who test positive for ctDNA following surgery and chemotherapy,” said Elicio’s Chairman Julian Adams in a press release. “An estimated 25% of all cancer patients have RAS mutations present in their tumor. ELI-002 targets the seven most common KRAS mutations andhas the potential to become a multi-targeted mKRAS therapy that can prevent disease recurrence in patients with KRAS-driven tumors.”

The trial will include patients with KRAS-mutated solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (NSCLC) among others and expects to share initial findings in the first half of this year.

Using MRD as a surrogate endpoint
Aside from using MRD to guide treatment decision-making, researchers and pharmaceutical companies are now considering ctDNA clearance as a new primary endpoint in clinical trials.

“As these assays become more standardized, I would envisage MRD will become more commonplace in clinical studies and over the next few years, MRD could become validated as a surrogate endpoint in some situations,” said Anne-Marie Martin, Senior Vice President & Global Head, Experimental Medicine Unit, Oncology R&D, at GlaxoSmithKline.

In addition, Martin explained that ctDNA and MRD are being used to enrich patient population for trials and enable earlier decision making to optimize drug development trials.

She also noted that GlaxoSmithKline are currently working in collaboration with a number of other organizations, including the International Independent Team for Endpoint Approval of Multiple Myeloma, the Foundation for the National Institutes

of Health Biomarkers Consortium, and the Blood Profiling Atlas in Cancer Consortium, to “validate the research and use of surrogate endpoints such as MRD in clinical trials [and] accelerate the development, validation and clinical use of liquid biopsy assays through the development of standards and best practices across the field.”

Having the final word, Kasi said that “ctDNA MRD is here to stay.”

Laura Cowen is a freelance medical journalist who has been covering healthcare news
for over 10 years. Her main specialties are oncology and diabetes, but she has written
about subjects ranging from cardiology to ophthalmology and is particularly interested
in infectious diseases and public health.