Dr. David Fisher discusses advancements in melanoma treatments that offer stage 4 patients hope for cure as well as prevention of recurrence and progression in earlier melanoma stages.
David E. Fisher, MD, PhD, Professor and Chair of Dermatology at Massachusetts General Hospital and Director of the Melanoma Program at MGH Cancer Center
“The treatment outlook for those with advanced melanoma is continuing to improve to a point where stage 4 metastatic melanoma now is probably curable in about 50% of patients. Ten years ago, that number was in the low single digits. This is likely one of the most striking advances in the history of oncology,” said David E. Fisher, MD, PhD, who presented “Medical Advances in the Treatment of Melanoma,” at the Masterclasses in Dermatology in Sarasota, Florida.
Some of the new and FDA-approved therapeutic strategies for melanoma have been introduced into the clinic within the last year, said Dr. Fisher.
“It’s also very striking that these advances by and large are extremely data-driven, hypothesis-driven, and mechanistically based. They are utilizing therapeutic therapies which… are focused on known molecular targets.”
Immune Checkpoints
At the core of the greatest advances in melanoma is immunotherapy’s success in blocking immune checkpoints, said Dr. Fisher.
“These are important molecular receptor ligand pairs which control the T cells’ ability to produce autoimmune disease. The checkpoints are critical to our health on a daily basis. However, it was discovered a number of years ago that if we block those tolerance checkpoints, in fact, allowing some autoimmunity to occur, that there can be a benefit that spills over in the context of melanoma.”
Two major targets are programmed cell death protein 1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), said Dr. Fisher.
“There are a number of different antibodies that serve as drugs to block these two pathways. The PD-1 target alone probably cures 30% to 35% of melanoma patients in the stage 4 setting. CTLA-4 alone probably is in the 20% range, and the combination is upwards of perhaps 50%.”
However, there also is toxicity to be concerned about, he said.
“There is significant toxicity, including life-threatening toxicity, primarily with CTLA-4. There is some with PD-1 that can also be life-threatening but quite rarely. The combination of the two is much more toxic and therefore much riskier to give. So, it is typically given to a much more select population of patients, even though the combination has the greatest efficacy of any current therapy in advanced melanoma.”
During the last year, investigators have confirmed another checkpoint and a targeted antibody that blocks the lymphocyte activation gene-3 (LAG-3) checkpoint, according to Dr. Fisher.
“Relatlimab is a drug that has been FDA approved in combination with anti-PD-1. The combination has greater efficacy than anti-PD-1 alone and, unlike the combination of anti-PD-1 with anti-CTLA-4, it does not introduce a massive amount of toxicity risk. This is likely to be moved to pretty close to frontline therapy for advanced melanoma.”1
Brain Metastasis
Investigators have recognized in recent years that simultaneous targeting of anti-PD-1 and anti-CTLA-4 can result in major regression of brain metastases of melanoma, said Dr. Fisher.
“[The brain] is one of the most debilitating and rapidly progressing refractory clinical manifestations of advanced melanoma. There are now patients with brain metastases of melanoma whose brain disease is eradicated by the combination of anti-PD-1 and anti-CTLA-4.”
Studies have also shown that brain metastases that are asymptomatic have even better outcomes than those causing symptoms, he said.
“There is work now looking at trying to make brain metastases asymptomatic using radiation therapy or, in some cases, even surgery then adding this combination of therapy. So, nibbling away at trying to get even greater outcomes.”
Variations on This Theme
An advance in melanoma that is particularly important for dermatologists to recognize has been to expose patients to these drugs not only during the most advanced stages of disease, but also in earlier phases. This includes stage 3 melanoma and possibly stage 2 disease, said Dr. Fisher. The thinking is that there are fewer cells in the body, and it’s a lower bar for the agents to be able to eradicate the smaller tumor volume.
“This was tested originally for stage 3 disease using anti-CTLA-4 first, and that was FDA approved. But like in stage 4 disease the therapy was highly toxic,” he said.
“The problem with treating stage 3 or even more so for stage 2 disease is that you don’t know which patients are the ones who will be the unfortunate ones for whom relapse may occur.”
As a result, this approach to adjuvant treatment exposes all patients to the risk of toxicity in the hopes that the proportion of patients who relapse will be diminished, said Dr. Fisher.
“This has now been looked at very carefully and there is great news. In fact, anti-CTLA-4 helps [to reduce risk of relapse]. Anti-PD-1 helps even more with less toxicity, and in fact BRAF-targeted therapy also has a very significant benefit in stage 3 melanoma at decreasing the odds of relapse. Just over the past year, we’ve seen anti-PD-1 diminish the risk of relapse in stage 2 melanoma, which is amazing.”
Investigators have recently presented and had a study published in the New England Journal of Medicine looking at using these drugs in the neoadjuvant setting, according to Dr. Fisher.
“The question was asked, if the patient has a lymph node involved, a regional lymph node for stage 3 disease, should you remove the lymph node (knowing this patient has a significant relapse risk) or should you consider giving several cycles of anti-PD-1 before you remove the lymph node, then remove the lymph node and continue the anti-PD-1 for the same total duration? The idea is that the immune system may be educated more effectively if the tumor is still present and if the lymphocytes are still present within that tumor during the neoadjuvant period of time.”
The study clearly showed additional benefit with giving the therapy prior to surgery,2 said Dr. Fisher.
“In addition, when you do neoadjuvant therapy, after those first couple of cycles when the tumor is removed, there is an opportunity for pathologic assessment of the tumor. The vast majority of patients whose tumors were responding … had a fantastic prognosis. If the patients were not responding, you could quickly say these people need to be on another therapy.”
Skeptics would say that for the patients who were not responding, you just delayed the surgical removal of that resistant tumor giving the tumor time to metastasize, said Dr. Fisher.
“This is a question we still need to answer. Neoadjuvant therapy is very exciting, very provocative and this will be an area of much greater analysis in the future.”
The Future
The only thing better than curing advanced disease is to prevent disease from progressing and relapsing in the advanced stages. We’re getting closer, but we’re not there yet, said Dr. Fisher.
“What we need very much in the field is biomarkers. We need to be able to predict on the basis of certain features of the tumor or the patient or the clinical scenario which patients are likely to benefit….”
Moderna announced that it has made an investigational personalized RNA vaccine directed against mutated neoantigens in melanomas and combined that with an anti-PD-1 checkpoint inhibitor drug. The concept is to avoid relapse with an adjuvant approach, using a personalized vaccination against a person’s own MHC-class 2 presentable mutations, identified by sequencing their tumors. This helps to determine the likeliest immunogenic mutations in their tumors, said Dr. Fisher.
“This vaccine in combination with immune checkpoint inhibition showed a 44% improved decrease in relapse versus anti-PD-1 alone.”3
“So, the neoadjuvant vaccine strategy is going to be coming along very shortly, reflecting the fact that we’re not only going to be better at managing advanced disease, but I think we’re doing much better in very exciting ways in preventing the formation of advanced disease altogether with these novel approaches.”
References:
- Tawbi HA, Schadendorf D, Lipson EJ, et al; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. doi: 10.1056/NEJMoa2109970. PMID: 34986285; PMCID: PMC9844513.
- Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437. PMID: 36856617.
- Moderna. Moderna and Merck Announce mRNA-4157/V940, an Investigational Personalized mRNA Cancer Vaccine, in Combination with KEYTRUDA(R) (pembrolizumab), Met Primary Efficacy Endpoint in Phase 2b KEYNOTE-942 Trial (modernatx.com). Press release. December 13, 2022. Accessed March 20, 2023.
Disclosures: Dr. Fisher is cofounder of Soltego and is a consultant for or on the scientific advisory board of Tasca, Pierre Fabre, Escient, and Ventus.