Recent breakthroughs are significantly altering the treatment paradigm for advanced skin cancers, offering new hope for patients with melanoma, cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). While melanoma has long been a focus of innovation, advancements in immunotherapies and targeted treatments are now extending improved outcomes to other, less common skin malignancies. This evolving landscape, however, introduces complexities in managing treatment side effects and necessitates a reorganization of care pathways to optimize patient benefit.
The landscape of cutaneous oncology has dramatically changed over the past decade. While melanoma remains at the forefront of therapeutic innovation, significant advancements have also been made in treating advanced cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). The integration of immunotherapies and targeted therapies has expanded options for sustained disease control, but also presents new challenges, including managing immune-mediated toxicities and the need for reorganized care pathways.
Historically, systemic treatment for advanced skin cancer was limited. Chemotherapies like cisplatin and taxanes offered only modest and temporary responses. The emergence of checkpoint inhibitors marked a turning point: patients previously considered to have a poor prognosis are now experiencing prolonged survival, with data showing potential for long-term disease control.
Advanced Melanoma: Prolonged Survival and New Approaches
The CheckMate 067 study remains a landmark achievement in melanoma treatment. Extended follow-up data demonstrates a median overall survival exceeding 70 months with the combination of nivolumab and ipilimumab, compared to 36.9 months with nivolumab alone. A significant proportion of patients continue to experience durable responses even after discontinuing treatment. These results position the combination as a strategy with greater curative potential, although it is associated with increased toxicity – approximately 55% of patients experience grade 3–4 events.
The introduction of relatlimab, a LAG-3 inhibitor, has further expanded therapeutic options. The combination of nivolumab and relatlimab showed improvement in progression-free survival with an intermediate toxicity profile between single-agent anti–PD-1 therapy and the classic PD-1/CTLA-4 combination. For patients with relative contraindications to the more aggressive combination, this represents a relevant alternative.
Alongside these advances, targeted therapy with dabrafenibe and trametinib continues to play a central role in tumors with BRAF V600 mutations, both in the metastatic and adjuvant settings. The choice between immunotherapy and targeted therapy as initial treatment remains individualized, considering tumor burden, rate of progression, symptoms, and molecular profile.
Advanced cSCC: Consolidation of Anti–PD-1 Therapy
Cutaneous squamous cell carcinoma, while often curable with surgery in early stages, can behave aggressively in patients with compromised immune systems, transplant recipients, or those with locally advanced disease. The pivotal study with cemiplimab demonstrated an objective response rate approaching 50%, with durable responses and acceptable tolerability, even in older and frail patients – a demographic that is common in advanced cSCC.
Subsequent data reinforces that the benefit extends to complex subgroups, such as patients with associated hematologic malignancies and individuals with extensive perineural invasion. Radiation therapy remains relevant, particularly as adjuvant treatment for high-risk tumors or as definitive treatment when surgery is not feasible.
With the rise of immunotherapies, a new population of long-term survivors is emerging, requiring a systematic approach to surveillance. Oncologists are now focused not only on remission but also on managing late-onset effects, irreversible toxicities, and preventing new skin cancers. These advances highlight the importance of comprehensive, long-term care for skin cancer patients.
Immune-related adverse events (irAEs) represent the primary limitation of immunotherapies. While some toxicities are reversible, others can leave permanent sequelae.
The most frequent toxicities include endocrinopathies (hypothyroidism, hypophysitis, adrenal insufficiency), immune-mediated colitis, pneumonitis, and immune-mediated hepatitis.
Optimal management requires clear institutional protocols, with regular monitoring during the first 12–16 weeks, the period of highest risk for events. In patients with a prior history of autoimmunity, the decision to initiate immunotherapy requires careful discussion, involving specialists.
December’s Skin Cancer Awareness Month reinforces the importance of prevention and early diagnosis, but oncology must extend beyond the annual campaign by structuring education, protocols, and interdisciplinary workflows.
