Improving outcome of melanoma patients upon immunotherapy

Immunotherapy with immune checkpoint inhibitors (ICB) has greatly improved survival for advanced melanoma patients. This thesis examines strategies to further optimize these therapies. We found that neoadjuvant ICB in stage III melanoma offers advantages over adjuvant therapy, including enhanced immune activation and the ability to assess treatment response. The OpACIN study revealed that standard dosing of ipilimumab and nivolumab was too toxic, but the OpACIN-neo study demonstrated that a lower dose of ipilimumab reduced side effects while maintaining high response rates. Patients with a pathological response had excellent outcomes with the IFN-γ gene signature and tumor mutational burden identified as key biomarkers for response and survival. For BRAFV600-mutated melanoma, both targeted therapies (BRAF/MEK inhibitors) and ICB are effective. The IMPembra study found that short-term addition of dabrafenib and trametinib to pembrolizumab was feasible, and seems to improve progression-free survival. Anti-PD-1 monotherapy remains attractive for patients with favorable characteristics, but optimal treatment duration is unknown. In a cohort of patients who stopped treatment without progression or toxicity, median treatment duration was only 12 months, and the majority remained free of progression. Early increases in LDH or S100B can identify patients who may need additional therapy. The findings in this thesis contribute to the significant advances in the treatment of advanced melanoma and have the potential to reshape the standard of care for stage III melanoma.