Immunotherapy has emerged as a significant development in the treatment of stage 4 melanoma, a serious form of skin cancer. For many facing this advanced diagnosis, it introduces new hope for long-term control of the disease. The question of whether it can offer a “cure” for some individuals is now a central topic in oncology, reflecting a shift in how this advanced cancer is approached.
Understanding Stage 4 Melanoma
Stage 4 melanoma is the most advanced stage of this aggressive skin cancer. Cancer cells have spread beyond the initial tumor site to distant parts of the body. This can include organs like the lungs, liver, brain, bones, or the gastrointestinal tract, as well as distant lymph nodes. Historically, a diagnosis of stage 4 melanoma carried a poor prognosis. The median overall survival was typically around six to eight months, with treatment focused on managing the disease and alleviating symptoms.
How Immunotherapy Functions
Immunotherapy harnesses the body’s immune system to recognize and attack cancer cells. This approach involves immune checkpoint inhibitors, which target specific proteins that regulate the immune system. Normally, these checkpoint proteins act as “brakes” on immune responses, preventing the immune system from mistakenly attacking healthy tissues. However, melanoma cells can exploit these checkpoints to avoid detection.
Immune checkpoint inhibitors block these regulatory proteins, releasing the brakes on immune cells, particularly T-cells. Two prominent types of inhibitors are PD-1 and CTLA-4 blockers. PD-1 inhibitors prevent the PD-1 protein on T-cells from binding to its partner protein, PD-L1, often found on cancer cells, activating the T-cells to fight the tumor. Also, CTLA-4 inhibitors block the CTLA-4 protein, which dampens T-cell activity, allowing these immune cells to remain active against the cancer. This dual action enhances the immune system’s ability to target and eliminate malignant cells.
Immunotherapy’s Effectiveness for Stage 4 Melanoma
Immunotherapy has profoundly changed the landscape for stage 4 melanoma, leading to durable responses and long-term remission for a notable subset of patients. While “cure” is used cautiously, sustained responses suggest some individuals can achieve effective cancer control for many years.
Historically, the five-year survival rate for stage 4 melanoma was about 22.5%. With immunotherapy, particularly combination regimens, 10-year overall survival rates have been reported to be over 43% to 52%. For patients with a complete response, five-year progression-free survival can be as high as 79%, and five-year overall survival can reach 83%. This durable response means patients can remain free from disease progression for extended periods, even after treatment concludes.
However, immunotherapy effectiveness varies among individuals. One factor influencing response is tumor mutational burden (TMB), where a higher number of mutations is often associated with a better response. This higher mutational load in cutaneous melanoma is frequently linked to ultraviolet (UV) light exposure.
The immune microenvironment also plays a significant role. The presence of tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, correlates with a more favorable response. Conversely, an immunosuppressive microenvironment, characterized by high levels of regulatory T cells or certain inhibitory cytokines, can contribute to treatment resistance.
Additionally, specific genetic markers, such as increased expression of genes like CD24, NFIL3, FN1, and KLRK1, may indicate resistance to immunotherapy. Research also suggests that inherited differences in mitochondrial DNA could influence how patients respond. Not all patients respond to immunotherapy; for instance, 40% to 60% may not respond to anti-PD-1 therapy alone, and some may develop acquired resistance over time.
Patient Suitability and Treatment Experience
Determining suitability for immunotherapy involves evaluating a patient’s overall health, performance status, and tumor characteristics. Biomarker testing, including analysis for BRAF mutations and tumor mutational burden, helps guide treatment decisions and provides insights into response likelihood. Immunotherapy drugs are typically administered intravenously, often every two to four weeks.
While effective, they can lead to immune-related adverse events (irAEs), side effects from the activated immune system attacking healthy tissues. These side effects range from mild (fatigue, skin rashes, diarrhea) to severe (inflammation of organs like lungs, liver, or intestines). Up to 90% of patients may experience some form of side effect, with varying intensity and onset times. Prompt reporting of new or worsening symptoms is important for effective management, which often involves the use of steroids or other immunosuppressants. A multidisciplinary care team, including oncologists, dermatologists, surgeons, pathologists, radiologists, and nurses, is essential for coordinating treatment, monitoring side effects, and providing comprehensive patient care.