PARIS, June 21, 2024
New Immunotherapies Offer Hope for Melanoma Patients
Survival rates are climbing.
- Immunotherapy is now a primary treatment for skin melanomas.
- Neoadjuvant immunotherapies are gaining prominence over adjuvant treatments.
- Targeted therapies show progress, with molecule combinations improving effectiveness and reducing side effects.
With nearly 15,500 new cases diagnosed annually in France, **immunotherapy offers a promising approach** in the therapeutic landscape for treating skin melanomas, especially those with locoregional metastases.
Immunotherapy Takes the Lead
Immunotherapy, specifically checkpoint inhibitors, are solidifying their role in melanoma treatment. These treatments have shown particular promise when used in a neoadjuvant strategy, meaning they are administered before surgery.
Élisa Funck-Brentano, head of the general and oncological dermatology service of the Ambroise-Paré Hospital (Hauts-de-Seine), explains, “Administering immunotherapy before the operation greatly decreases the risk of recurrence. When there is a tumor, due to the presence of tumor neoantigens, the immune system is more stimulated by immunotherapy.”
Nadina Study Highlights Neoadjuvant Benefits
The Nadina study, presented at the American Society of Clinical ONCOLOGY (ASCO) 2024 congress, reinforces the benefits of neoadjuvant immunotherapy. The study found that treatment with ipilimab (anti-clt4 checkpoint inhibitor) and Nivolumab (anti-PD1) before surgery significantly reduced the risk of recurrence compared to nivolumab alone after surgery.
According to the study, 60% of patients didn’t need additional treatment after surgery, which Funck-Brentano calls “Quite revolutionary.” Neoadjuvant therapy also requires only two treatments, compared to 12 months for adjuvant therapy. “In practice, these neoadjuvant immunotherapies are already used in many centers, although there is yet no marketing authorization (AMM),” she adds.
Another immunotherapy option for melanomas with locoregional metastases is Daromun, an immunocytokine administered as neoadjuvant via intraleional injection. Funck-Brentano explains that it “induces an immunostimulator effect on tumor microenvironment.” This treatment is currently accessible through compassionate access, primarily for patients who have not responded to other therapies.
Improved Outcomes for Metastatic Melanoma
Significant strides have been made in treating metastatic skin melanomas.
Brigitte Dréno, oncodermatologist at the Nantes University Hospital Center (Loire-Atlantique), notes, “Faced with metastatic skin melanomas, inhibitors of checkpoint now offer a 36-month survival median for anti-PD1s alone and 71 months when combined with anti-CTL4s.” These statistics are particularly encouraging, considering that before these treatments, the global median survival was less than a year.
Anti-LAG3 Inhibitors: A New Weapon
A new class of checkpoint inhibitors, anti-LAG3, has recently emerged as another therapeutic option for metastatic melanomas. Funck-Brentano states, “It has been shown that a combination of Rectlimab (Anti-Lag3) and Nivolumab (anti-PD1) presented better results that nivolumab alone, without major increase in toxicity.”
Notably, the Relatlimab/Nivolumab combination exhibits significantly lower toxicity to healthy tissues compared to the previously used ipilimumab (anti-CTL4)/nivolumab regimen.
The Role of Pharmacies in Treatment
While immunotherapy treatments are administered in hospitals, targeted therapies are dispensed in local pharmacies. These therapies combine BRAF inhibitors, found in about 50% of skin melanomas, with MEK inhibitors. Combinations like dabrafénib and trametinib, as well as corafenib and binimetinib, are available for metastatic patients with unusable tumors. The dabrafenib/trametinib duo can also be used in adjuvant settings for patients with locoregional metastases.
“The association of two molecules increases the effectiveness of treatment, while reducing the risk of resistance and the occurrence of toxicities. The responsiveness of pharmacists is essential to deliver these drugs, which must be available within 48 hours,” says Elisa Funck-Brentano.
Brigitte Dréno adds that “these targeted therapies are proposed in first intention, according to recent European recommendations, only to the BRAF positive patients in the event of contraindication to immunotherapy.” She emphasizes that a key challenge in managing melanomas is better characterizing tumor mutation profiles to identify new potential targets, such as Nras, C-Kit, or FGFR2 mutations, for developing new drugs.
The Future: Personalized Vaccines?
A personalized mRNA vaccine (V940), developed by Moderna and Merck MSD, is generating considerable interest, although it is not yet available for therapeutic use. Funck-Brentano notes, “In association with the Pembrolizumab [Keytruda, immunothérapie anti-PD1, NLDR] he showed a greater efficiency than that of pembrolizumab alone during a 2B phase study.”
**How does the personalized mRNA vaccine work?** The process involves taking a biopsy of the tumor to identify 34 tumor neoantigens. Then, in vitro, mRNA is coded for these specific neoantigens, creating a personalized vaccine that is injected back into the patient. Recruitment for a phase 3 study, focusing on melanomas from stages II to IV, has been completed.
Future strategies for melanoma management prioritize extending survival without recurrence and minimizing the adverse effects of treatments. Dréno mentions tumor-infiltrating lymphocytes (TILs) as a promising therapeutic avenue: “From a skin or lying biopsy, tumor infiltration T lymphocytes, called tils, are multiplied in the laboratory and then reinjected to the patient. This treatment is intended for people who have become resistant to anti-PD1.”
The dermato-oncologist also highlights the importance of identifying new target proteins for immunotherapy and developing drugs that prevent tumor cells from altering their environment when exposed to immunotherapy or targeted therapies, thereby avoiding therapeutic resistance.
References
- Institute National du Cancer, 2023.
- « Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma », C. U. Blank, M. W. Lucas, R. A. Scolyer et coll., The New England Journal of Medicine, 2 juin 2024.
- « Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (Keynote-942): a randomised, phase 2b study » ; J. S. Weber et coll., The Lancet, volume 403,17 février 2024.
