Every year, over 16,000 Australians are diagnosed with melanoma. Most of these cases are detected early and can be successfully treated with surgery. However, for individuals with advanced or metastatic melanoma, which has spread beyond the skin to other organs, the prognosis was poor until the introduction of targeted therapies and immunotherapies. These treatments, developed over the past decade, have significantly increased the five-year survival rate for advanced melanoma patients, from less than 10% in 2011 to about 50% in 2021. Despite this progress, there are still many melanoma patients who cannot be effectively treated with current therapies.
Researchers have developed two promising new therapies that are currently being tested in clinical trials for patients with advanced melanoma. Both therapies use immunotherapy at different stages and in various ways. Initial results from these trials are being released, providing insights into future melanoma treatments. Immunotherapy enhances a patient’s immune system to destroy cancer cells. One form of immunotherapy involves “immune checkpoint inhibitors”. Immune cells have “immune checkpoint” proteins that regulate their activity, and cancer cells can manipulate these checkpoints to deactivate immune cells and evade the immune system. Immune checkpoint inhibitors prevent this interaction, keeping the immune system engaged in fighting cancer.
Results from an ongoing phase 3 trial using immune checkpoint inhibitors were published in the New England Journal of Medicine. This trial involved two types of immune checkpoint inhibitors: nivolumab, which blocks the PD-1 checkpoint, and ipilimumab, which blocks CTLA-4. 423 patients, including many from Australia, participated in the trial, and they were randomly split into two groups. The first group had surgery to remove melanoma followed by immunotherapy (nivolumab) to eliminate any remaining cancer cells, a standard post-surgery treatment. The second group received immunotherapy first (nivolumab plus ipilimumab) and then underwent surgery. This novel approach was based on observations suggesting that administering immunotherapy while the tumor is still present might better activate the patient’s immune response compared to after tumor removal. After 12 months, 83.7% of patients who received pre-surgery immunotherapy remained cancer-free, compared to 57.2% in the group that received post-surgery immunotherapy.
Georgina Long, Australian of the Year, who co-led this trial with Christian Blank from the Netherlands Cancer Institute, proposes that pre-surgery immunotherapy should become a new standard treatment for higher-risk stage 3 melanoma and suggests evaluating this strategy for other cancers. The results of this trial indicate that this combination treatment could be implemented in Australian hospitals soon.
Another emerging therapy for melanoma is a post-surgery combination of a different checkpoint inhibitor (pembrolizumab, which also blocks PD-1) with a messenger RNA vaccine (mRNA-4157). While checkpoint inhibitors like pembrolizumab have been used for over a decade, mRNA vaccines like mRNA-4157 are newer. You might know mRNA vaccines from the COVID vaccines by Pfizer-BioNTech and Moderna. mRNA-4157 works similarly: the mRNA is injected into the patient, producing antigens—small proteins that train the immune system to recognize and attack a disease, be it cancer or the COVID virus. mRNA-4157 is a form of personalized medicine, where the mRNA is specifically tailored to match a patient’s cancer. The patient’s tumor is genetically sequenced to identify the best antigens to trigger the immune system against the cancer, and then a patient-specific version of mRNA-4157 is developed.
Recent results from a three-year phase 2 trial combining pembrolizumab with mRNA-4157 were announced last week. After 2.5 years, 74.8% of patients treated with this combination remained cancer-free, compared to 55.6% of those who received only immunotherapy. These included patients with high-risk, late-stage melanoma, who usually have worse outcomes. These results haven’t yet been published in peer-reviewed journals but are available through company announcements and presentations at cancer conferences in the USA. The combination of pembrolizumab and this vaccine has moved to a phase 3 trial in 2023, and the first patients have been enrolled in Australia, with the final results expected in 2029. It is hoped these mRNA-based anti-cancer vaccines will open the door to vaccines targeting various cancers, working especially well with checkpoint inhibitors to boost the immune system.
Despite these advances, the best way to fight melanoma is prevention, which primarily means reducing UV exposure as much as possible.