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Liquid Biopsy Firms Eye Melanoma for Minimal Residual Disease Testing, Though Questions Remain


NEW YORK – Multiple companies advancing circulating tumor DNA tests have recently increased their attention to melanoma as a clinical target for their minimal residual disease (MRD) assays.

The use of liquid biopsy to detect MRD in solid tumor patients has grown over the last several years, with the first applications in colorectal cancer and more recently in lung and breast tumors.

Among companies now advancing their technologies in the skin cancer setting are NeoGenomics, Natera, and recent entrant Personalis. A central aspect of the promise of MRD in melanoma is that these cancers have become one of the most ubiquitous targets of immunotherapies, with early investigations showing that detection of emerging or vanishing ctDNA can indicate whether or not patients are responding to treatment.

A specific challenge in immunotherapy that is not shared by targeted drugs or standard chemotherapy is a phenomenon called pseudoprogression, in which tumors appear to be growing, despite therapy, when, in actuality, this boost of tumor activity is a precursor to response.

Current professional guidelines recommend periodic imaging and clinical assessment to determine therapeutic efficacy for melanoma patients, but MRD companies have been working to prove that their molecular approaches could overcome limitations of imaging-based surveillance, picking up recurrence earlier and distinguishing true progression from pseudoprogression.

In addition, firms are now building evidence that upfront testing can predict which patients will derive better outcomes on immunotherapy and which may need escalated treatment.

Both Personalis and NeoGenomics featured new data in this vein last week at the American Society of Clinical Oncology's annual meeting.

For Personalis, the data stuck to the central rubric of immunotherapy response monitoring. But NeoGenomics' study branched out into adjuvant therapy, where investigators used the firm's Radar technology (also tumor-informed and patient-personalized) in patients receiving Moderna's experimental vaccine therapy mRNA-4157.

Amber Carter, NeoGenomics' VP of clinical programs, said in an email that prior research with the Radar assays had shown that although post-op ctDNA levels are lower in melanoma than in some other tumor types, patients who test positive "clearly have a higher risk of recurrence and worse overall survival."

"This has led to interest from some of our partners in escalation trials," she added.

In an exciting turn for advanced melanoma patients, the study with Moderna found that the vaccine-combination significantly prolonged metastasis-free survival compared to immunotherapy alone. Furthermore, the same pattern emerged of post-op patients rarely showing ctDNA positivity.

Among 125 trial subjects with evaluable ctDNA, 110 were ctDNA-negative at the start of treatment, and these patients had significantly longer recurrence-free survival than the 15 who were ctDNA-positive. Notably, this was true across the vaccine and immunotherapy-only arms, meaning Radar testing didn't, at least here, identify responders versus non-responders for the vaccine specifically.

Carter said that the study cohort unfortunately only had two ctDNA-positive patients randomized to immunotherapy alone, which leaves the question of whether MRD positivity might be able to predict vaccine-specific response.

"Since this trial was not designed to randomize with ctDNA status in mind, that response predictor element will need further study," she said.

In the meantime, the overall association between ctDNA-negativity and better outcomes adds to growing evidence for that application of NeoGenomics' MRD tests. And, going forward, Moderna and NeoGenomics are also planning to analyze and share data from their longitudinal testing of patients, which could also confirm the ability of MRD to detect treatment failures and recurrences in real time.

Personalis, meanwhile, described a study of 23 stage IV melanoma patients, with over 150 plasma samples collected during immunotherapy treatment and profiled with the company's recently launched NeXT Personal.

NeXT Personal is also a tumor-informed ctDNA assay, but one that leverages whole-genome sequencing, allowing bespoke panels that are orders of magnitude larger than those provided by Natera and NeoGenomics. The firm's tests also include a fixed set of 2,100 loci known to be clinically actionable or associated with treatment resistance.

Personalis' partners at the University Medical Center Hamburg-Eppendorf reported that they could detect ctDNA down to a limit of detection or 1.97 parts per million, with 37 percent of samples showing ctDNA levels below 100 PPM. About 94 percent of the cohort had positive MRD results at baseline. As others have found, changes in ctDNA levels during treatment were predictive of clinical outcome. And the company was able to correlate those variations with allele frequency changes in specific variants associated with response and resistance.

In an email, a company spokesperson said that the work with University Medical Center Hamburg-Eppendorf is ongoing. Due to confidentiality concerns, Personalis declined to comment on research that could advance new indications in a pre-treatment predictive setting for adjuvant drugs or vaccines, like the NeoGenomics/Moderna work.

Natera's Signatera assays — also tumor-informed ctDNA panels personalized for each patient — have been covered by Medicare for pan-cancer immunotherapy monitoring since 2021, but the company has only recently begun to build up data specific to cutaneous melanoma.

Minetta Liu, Natera's chief medical officer of oncology, said in an interview that the company sees a spectrum of use cases for MRD in melanoma, not just in treatment response monitoring but also risk stratification in the adjuvant setting and post-treatment surveillance.

In a study published this March in Cancer, investigators working with Natera reported on the analysis of 555 plasma samples from 69 patients with stages III-IV melanoma across three real-world cohorts — stage III patients receiving immunotherapy or observation in the adjuvant setting, unresectable stage III/IV patients receiving immunotherapy, and stage III/IV patients under surveillance after completing immunotherapy treatment.

In the first setting, researchers concluded that MRD positivity post-resection was associated with significantly shorter distant metastasis-free survival. Signatera also detected recurrences with an average lead time of three months over standard imaging.

In the second setting, investigators reported that rising ctDNA levels between three and 11 weeks after starting immune checkpoint inhibitor therapy was associated with significantly shorter progression-free survival. All four patients in the study with increasing ctDNA experienced disease progression, while the 15 patients with decreasing ctDNA achieved complete or partial response. In two patients, Signatera also correctly differentiated between true progression versus pseudoprogression.

In the final group, researchers reported on 10 patients being watched post-immunotherapy treatment. All seven who were ctDNA-negative during this surveillance remained progression-free until the study's last follow-up (a median of about 15 months). All three ctDNA-positive patients experienced disease progression.

Liu said the publication provides good clinical validation data regarding the correlation of MRD with outcomes. "There's some hints for where the test could be effective in impacting outcomes, which is where we're focused now," she added, citing ongoing trials where Signatera is being incorporated to help demonstrate utility. She did not name specific studies or partners.

According to Liu, although Signatera is not covered by payors outside of the treatment response monitoring indication, the company has seen providers order it for melanoma patients for applications like post-treatment surveillance.