Promising Research Updates for Melanoma Patients Presented at ASCO

The recent American Society of Clinical Oncology (ASCO) Annual Meeting was held on May 31– June 4.  It is one of the largest and most prestigious cancer research conferences. The results of many melanoma clinical trials were presented- several of which may lead to practice changing advances. A few of these melanoma trials of potential interest are summarized below. 

Neoadjuvant vs. Adjuvant Therapy 

As part of the plenary session, the results of the NADINA trial were presented.  This multicenter phase III trial addressed the question of whether neoadjuvant, or pre-surgery, treatment is more effective than adjuvant, or post-surgery, treatment (which is the current standard of care) in preventing recurrence in resectable (removable by surgery), macroscopic (visible to the naked eye) Stage III melanoma patients.  Eligible patients were randomized to receive either neoadjuvant ipilimumab/ nivolumab (ipi/nivo) followed by surgery and additional adjuvant therapy if needed versus surgery followed by adjuvant nivolumab.  Results showed that neoadjuvant treatment followed by surgery and response-driven adjuvant treatment resulted in an increased event-free survival (EFS) benefit over standard of care surgery/adjuvant therapy alone in this patient population. As ASCO posted, NADINA: Neoadjuvant Ipilimumab Plus Nivolumab Poised to Become a New Standard of Care for Macroscopic Stage III Melanoma (ascopubs.org).  As noted in this article, this trial was a pioneering study as it “is the first phase 3 trial in stage III melanoma to evaluate neoadjuvant immunotherapy against adjuvant therapy, a current standard of care…it is the first trial on melanoma to adapt administration of adjuvant therapy based on response…and it is the first phase 3 trial in all of oncology to evaluate a neoadjuvant regimen consisting solely of immunotherapy alone without additional chemotherapy.” Results were published in the New England Journal of Medicine and the principal investigator talks about his work on The ASCO Post. 

Immunotherapy 

Immunotherapy is a type of systemic (whole body) therapy that attempts to treat the patient by activating their immune system so that it will destroy any melanoma cells within the body.  At the ASCO meeting, several presentations focused on various melanoma immunotherapy trials.  Some highlights included: 

Triplet Immunotherapy

As background, currently nivolumab is approved by the Food and Drug Administration (FDA) as both a single agent alone or in combination with relatlimab or ipilimumab for various melanoma indications.  In this phase 1/2 non-randomized trial (RELATIVITY-048), the investigators wanted to test the efficacy and safety of various triplet combinations, including nivolumab, relatlimab, and ipilimumab, in advanced melanoma patients. As ASCO posted, Triplet Immunotherapy Shows Promise in Early-Phase Trial of Untreated Advanced Melanoma (ascopubs.org). However, as this was such a small study, additional studies will need to confirm the results as well as identify the appropriate dosing schedule to ascertain if the long-term benefits outweigh the potential of increased toxicities. 

TILs+Pembrolizumab

Lifileucel was recently approved by the FDA for the treatment of adult patients with cutaneous melanoma that is inoperable or has metastasized. Lifileucel is made by using immune cells called tumor-infiltrating lymphocytes (TILs) from the patient’s tumor. In this small cohort from the IOV-COM-202 trial, investigators were assessing the use of TIL therapy plus pembrolizumab (pembro) in front-line advanced melanoma patients. As ASCO announced, TIL Therapy in Combination With Pembrolizumab Shows Promise in Patients With Immunotherapy-Naive, Advanced Melanoma (ascopubs.org).  This regimen is being further studied in the larger phase 3 TILVANCE-301 trial. 

To learn more about how TIL Cell Therapy treats melanoma, please view the MRF’s Animated patient video on TIL Cell Therapy here: Animation – TIL Cell Therapy for Melanoma (youandmelanoma.com) 

Novel Engineered Protein

For some context, this trial uses a novel type of engineered protein, immune-mobilizing monoclonal T-cell receptor against cancer (ImmTAC), altered to recognize the cancer antigen, PRAME (the immunotherapy is referred to as brenetafusp).  This specific treatment can only be used in patients whose tumors express HLA-A*02, or a human leukocyte antigen, which is a marker some cells in the body have that is determined through a blood test.  In this small phase 1/ 2 trial, Early Data Support the Safety and Efficacy of a Novel Engineered Protein for Advanced Cutaneous Melanoma (ascopubs.org).  In patients that were PRAME positive and received this agent, there was a doubling of progression free survival and overall survival. This work is being further studied in the larger phase 3 PRISM-MEL301 study, which compares brenetafusp plus nivo to nivo alone in HLA-A*02:01 positive patients with previously untreated advanced melanoma. 

Oncolytic Immunotherapy

This phase 1/ 2 trial (IGNYTE) tested the agent RP1, an oncolytic immunotherapy (or a cancer treatment that uses viruses to break open cancer cells in a process known as oncolysis), in combination with nivo in advanced or metastatic cutaneous melanoma patients who progressed on anti-PD1 therapy.  The data showed durable and clinically meaningful response rates. OncLive summarized the findings in a brief article, New Data with RP1 Plus Nivolumab in PD1 Refractory Melanoma Build on Positive Findings. 

Vaccines

Previous results have been presented/published for the phase 2b, KEYNOTE-942 trial showing that patients with completely resected high-risk stage IIIB-IV cutaneous melanoma receiving an adjuvant mRNA vaccine (mRNA-4157) plus pembro had prolonged recurrence-free and distant metastasis-free survival compared to those patients that received pembro alone. These results generated much excitement in the field, including articles such as this one by Medscape entitled Coming Soon: the First mRNA Vaccine for Melanoma? At ASCO this year, the investigative team reported data for these patients at ~3 years after treatment, showing continued durable long-term recurrence-free and distant metastasis-free survival benefit with the combination. A larger, confirmatory phase 3 trial (V940-001) is under way. 

Targeted Therapy 

Targeted therapy is a form of treatment in which drugs (or other substances) are developed with the goal of destroying cancer cells while leaving normal cells intact. These drugs are designed to interfere with the specific molecules that are driving the growth and spread of the tumor. Because they are “targeted” to the tumor, these therapies may be more effective and associated with fewer side effects compared to chemotherapy and radiation therapy. A targeted therapy approach allows the classification of melanoma into different “subtypes” based on the genetic profile of the tumor. 

Sequencing of Agents

The results of the DREAMseq trial (published in the Journal of Clinical Oncology) indicate that immunotherapy should be given prior to targeted therapy for treatment-naïve BRAF mutant metastatic melanoma patients. However, the EBIN trial presented this year at ASCO, suggested that patients with significantly elevated LDH or those with liver metastases may benefit from receiving induction treatment with targeted therapy (of encorafenib/ binimetinib) prior to immunotherapy (with ipilimumab/nivolumab). ASCO summarized the findings in: Encorafenib/Binimetinib Induction Improves PFS in Some Patients With Advanced BRAFV600E/K–Mutant Melanoma (ascopubs.org). 

Adjuvant Targeted Therapy

As background, dabrafenib plus trametinib are considered a standard of care adjuvant treatment option for BRAF-mutated stage III cutaneous melanoma. At ASCO this year, the final results of the COMBI-AD phase 3 trial at 10 years after treatment initiation were presented. In this study, patients receiving adjuvant dabrafenib and trametinib vs a placebo showed improved overall survival, and a more favorable recurrence-free and distant metastasis-free survival.   

Rare Melanomas 

Wrapping up our coverage of ASCO 2024, we wanted to highlight three trials focused on uveal melanoma that were presented during the rapid-fire melanoma oral presentations. The first was a phase 2 multi-center trial of adjuvant ipilimumab/nivolumab in high-risk uveal melanoma patients. The data showed promising improvement in 3-year distant metastasis-free survival warranting further investigation of this therapy. In the second phase 2 study, uveal melanoma patients were treated with neoadjuvant darovasertib prior to definitive management (enucleation, radiation therapy, etc.). This study concluded that neoadjuvant treatment is feasible and safe; further, the agent induced clinically meaningful tumor shrinkage in some patients. A larger trial is currently underway. The last trial used the agent RP2, an oncolytic immunotherapy agent, alone or in combination with nivolumab in previously treated, metastatic uveal melanoma patients. The results were promising in both arms and a larger trial is being planned.  

For questions related to melanoma clinical trials, please watch the MRF’s Animation – Clinical Trials in Melanoma (youandmelanoma.com)