Predicting the Risk of Relapse in Early-Stage Melanoma

Most patients with newly diagnosed melanoma present with early-stage disease. Although surgical resection can lead to a cure for most of these patients, a high-risk subset faces the risk of relapse and death from melanoma. However, this subset may benefit from approved systemic adjuvant therapy. The question is, how do we identify these patients?

Inside Precision Medicine’s editor-in-chief, Damian Doherty, spoke with Merrick Ross, MD, a professor in the department of surgical oncology, division of surgery at the University of Texas MD Anderson Cancer Center, and Friedrich Ackermann and Daniel von Janowski, co-founders of NeraCare, about the importance of identifying these patients and the validation of a prognostic multiplex assay that can predict relapse in early-stage cutaneous melanoma.

Q: Dr. Ross, great to speak with you. Could you give us a short introduction to melanoma? What are the different stages of disease and how are they typically treated?

Ross: Let us start with the basics. Melanoma is a type of skin cancer that develops when melanocytes (the cells that give the skin its tan or brown color) start to grow out of control. While much less common than some other types of skin cancers, melanoma is more dangerous because of its higher propensity to spread (metastasize) to other parts of the body.

The American Joint Commission on Cancer (AJCC) staging system predicts survival outcomes (prognosis) according to disease substage, broadly defined as localized to the skin (stages I and II), metastatic to regional lymph nodes (stage III), and metastatic to distant sites (stage IV), helping clinicians in making treatment recommendations. Patients with localized disease make up the “early-stage” population. The prognoses of these patients are defined by critical histopathological features of the primary tumor, including tumor thickness and ulceration, and according to established national consensus guidelines, are further differentiated into clinically low-risk (stages IA, IB, and IIA) and clinically high-risk (stages IIB and IIC) patient subgroups.

Surgery is the primary treatment modality for most patients with stage I, II, and III disease and for some patients with stage IV disease, with the goal of resecting all sites of documented clinically apparent disease. Based on the stage at the time of the surgery and the predicted risk of relapse, patients are offered systemic adjuvant therapy with the goal of preventing future relapse by eradicating subclinical micro-metastatic disease.

Between 2017 and 2019, the U.S. FDA approved two types of adjuvant therapy for stage III and IV patients after surgical resection, including immune checkpoint inhibitors (anti-PD-1) and targeted tyrosine kinase inhibitors (BRAF/MEK). More recently, the approvals for two checkpoint inhibitors (anti-PD-1) were expanded to include patients with stage IIB/C disease and therefore represent a new standard of care option for these patients. These therapies reduce the rate of relapse by 50% compared to patients treated with surgery alone, regardless of the disease stage.

Q: That means that melanoma patients presumed to be at high-risk for recurrence have really benefitted from the recent treatment advances with both immune checkpoint inhibitor and small-molecule targeted adjuvant therapies. Would you see a need to expand the use of effective therapy to earlier stage patient cohorts, e.g. earlier than stage IIB disease? If so, why has this not happened yet?

Ross: It is clear these therapies are very effective and have greatly impacted the treatment landscape in a positive way. Yet, the process through which a decision is made to recommend adjuvant therapy is not a simple one. Multiple factors need to be considered, including the predicted risk for relapse, the efficacy of the therapy, predicted potential absolute percentage benefit, and the risk for serious long-term life altering side effects.

Fundamental to this process is the acknowledgement that not all “high-risk” patients will relapse, and therefore, a significant fraction of patients is cured with surgery alone. The patients who will experience a surgical cure, cannot derive treatment benefit from adjuvant therapy but are at risk of enduring the costs and toxicity of an unnecessary therapy. Ultimately, the goal would be to avoid treatment to the patients likely to be cured with surgery and only treat the patients most likely to relapse. Therefore, accurate assessments about which patients are likely to be cured or to relapse is central to this decision-making process.

The AJCC stage groupings provide valuable baseline prognostic information. But the seemingly disparate prognostic subgroupings defined by AJCC criteria, are, in reality, comprised of patients with significant prognostic heterogeneity and overlap. Attempts have been made to assign more individualized risk assessments with nomograms that incorporate a variety of known prognostic factors in addition to the stage-related factors and molecular based gene expression profiling (GEP). Despite these efforts, we still need more discriminating risk stratification data. Validation of new and more discriminating biomarkers will be necessary as we try to identify all patients at risk for relapse who may benefit from adjuvant therapy, while at the same time sparing the patients cured with surgery unnecessary treatment morbidity. This is particularly true for the subset of high-risk patients hidden within the very large group of earlier stage patients with an overall excellent prognosis.

One could certainly make the argument that identifying this subset is an important unmet need. While this high-risk subset represents a relatively small percentage of the very large stage IB and IIA population, it is the source of essentially all of the relapses observed from the stage IB/IIA group. Because the stage IB/IIA population is so large, the absolute number of patient events generated by a small subset is substantial and accounts for a significant share of advanced stage disease and overall melanoma-related mortality. The overall prognosis of the entire stage IB/IIA population is way too favorable to embark on a large phase III randomized trial to test the efficacy of available adjuvant therapy. This is why there are currently no phase III studies targeting this population.

However, a biomarker directed trial would be rational if we had a reliable way to distinguish the high-risk patients from the greater pool of low-risk patients. Such a trial would only randomize the high-risk patients to treatment versus placebo and simply observe the low-risk patients for outcomes. One biomarker in particular that was developed for selecting the appropriate early-stage melanoma patients (Stage IB/IIA) for an adjuvant therapy trial is NeraCare’s immunoprint assay.

Q: You say there is an unmet need in treating earlier stage patients, but a phase III trial would require additional stratification by biomarkers to select the patients at high risk of relapse for treatment, correct?

Ross: Yes, that is correct. One trial to be mentioned in this context is the NivoMela trial. In this phase III study, patients with stage II disease are all tested with a biomarker—in this case, an 11-gene expression profile (called MelaGenix, also developed by NeraCare)—and allocates to either a high-risk or low-risk group. Patients in the high-risk group are randomized to nivolumab vs. placebo. The trial has fully accrued with 374 patients and is expected to read out in 2025. This is the first biomarker-directed adjuvant trial to be completed in early-stage melanoma.

Q: So there is a great precedent in melanoma for this type of biomarker directed trial. Let’s switch over to Immunoprint to further address the biomarker topic. Fred and Daniel, could you give us a brief introduction to Immunoprint? Which biomarkers are included in the assay and what clinical results have you seen to date?

Ackermann: Immunoprint is an immunohistochemistry (IHC) assay that measures expression of five risk markers (Bax, Bcl-X, CD20, COX-2, PTEN) and two protective markers (MTAP, β-catenin) in cutaneous melanoma tissue sections. After conducting successful clinical validation studies that were published in 2023, we realized that Immunoprint may be particularly helpful in stratifying patients with early-stage (IB/IIA) cutaneous melanoma to guide adjuvant therapy decisions, as Dr. Ross explained previously.

For this reason, we initiated the MELARISK-001 study, which looked at this specific early-stage population. Results were recently presented at the 2024 American Society of Clinical Oncology meeting.

The study enrolled 382 patients with stage IB/IIA melanoma. Immunoprint classified 212 patients (55%) into the high-risk and 170 (45%) low-risk groups, accurately predicting 98% of relapses and 100% of melanoma-related deaths. High-risk patients had relapse rates comparable to later-stage melanoma patients for whom the adjuvant treatments are approved, suggesting that the early-stage iImmunoprint high-risk patients could be candidates for adjuvant therapy.

Q: Dr. Ross, could you please provide some context on the MELARISK-001 data and potential implications for melanoma?

Ross: I think melanoma physicians are looking forward to access to biomarkers that have been validated and demonstrated to have true clinical utility to aid in the decision-making process for adjuvant therapy. As mentioned, we do have effective adjuvant treatments available for patients in stage IIB or higher, reducing the rates of relapse by 50%. But we also need to be more precise in selecting the right patients, especially if we want to treat earlier stage patients. We are waiting with great anticipation for the results of the NivoMela trial to provide proof of concept of a biomarker directed strategy in melanoma. We are hoping that Immunoprint can lead to the same kind of selective approach to adjuvant therapy recommendations for IB and IIA patients, accounting for a similar percentage of patients as those in IIB-V disease combined. Of course, this approach will have to be validated within the context of an Immunoprint directed phase III randomized controlled trial.

In that context—having biomarkers like Immunoprint and Melagenix that have been appropriately validated to help us to reliably distinguish between low and high risk of relapse, is very valuable and if the results of the phase III study would be as anticipated—meaning that Immunoprint can identify early stage high-risk patients that then are shown to benefit from adjuvant treatment—this would be practice changing.

Q: OK, so what is the current status of the Immunoprint assay in its pathway to the clinic?

von Janowski: We are transitioning the assay from a conventional IHC format to the PhenoImager HT multiplex platform by Akoya Biosciences. This is an essential step in the clinical development pathway for several reasons: it enables the assay to be fully automated and ensures the necessary level of robustness required by regulatory authorities. It will also allow us to use a lot less tissue than is needed for the current IHC and still retain the same level of performance.

Going beyond the technical aspects, there are many additional requirements in which our partner Akoya has been giving foundational guidance. This includes expertise and experience in navigating regulatory pathways for the approval of multiplex assays for clinical use, as well as having a global network of partners to enable the go-to-market process and commercialization.

Q: When do you think Immunoprint would be ready to be included in a phase III trial?

von Janowski: Regarding the timeline, we are confident that we would have an investigational-use only assay ready for regulatory submission within the next twelve months.

Damian Doherty has been in media and publishing for nearly 30 years, beginning in the early nineties at News Corporation. Damian has managed, edited, and launched life science titles in drug discovery and precision medicine. He was features editor of Drug Discovery World for fourteen years and founded, established, and edited the Journal of Precision Medicine in 2014. In parallel, Damian founded and organized the Precision Medicine Leaders’ Summit, a global, immersive 3-day senior leadership conference that still runs today. He edited AIMed magazine in 2019 before launching Photo51Media, a platform for illuminating untold, compelling stories in precision healthcare. Damian joined Mary Ann Liebert in 2021 to help steer the new rebrand and relaunch of Clinical OMICS to Inside Precision Medicine.