What’s Next for Systemic Therapy in CSCC?

The future of systemic therapy for cutaneous squamous cell carcinoma (CSCC) is rapidly evolving, with research focused on expanding immunotherapy use, refining treatment strategies, and improving patient selection. According to Vishal Anil Patel, MD, of the George Washington Cancer Center, one of the most promising directions is the earlier integration of immunotherapy across the disease continuum.

Emerging approaches include intralesional immunotherapy, in which agents are injected directly into tumors. Ongoing phase 3 trials are evaluating whether this strategy can treat lower-risk lesions, reduce the need for surgery, and even generate broader immune responses that affect untreated tumors. This localized approach could be especially beneficial for patients with multiple lesions or those seeking non-surgical options.

For patients with more advanced or treatment-resistant disease, combination strategies are another key area of focus. Pairing immunotherapy with radiation or other systemic agents may improve response rates, particularly in patients who do not respond to single-agent checkpoint inhibitors or who experience recurrence after neoadjuvant or adjuvant therapy.

At the same time, researchers are exploring ways to de-escalate treatment, including shorter courses or fewer doses of immunotherapy. Early data suggest that even limited exposure may produce durable responses, potentially reducing both toxicity and cost. Minimizing immune-related adverse events remains a critical goal, as toxicity continues to be a major limiting factor in broader immunotherapy use.

Newer agents, such as cosibelimab, are also under investigation for their potential safety advantages, particularly in vulnerable populations like older adults, immunocompromised patients, and transplant recipients. These therapies may expand treatment eligibility if improved safety profiles are confirmed.

Finally, the development of predictive biomarkers is a major priority, with the goal of identifying which patients are most likely to benefit from specific therapies.

Overall, Patel emphasizes that systemic therapy will become increasingly integrated, personalized, and refined—reshaping CSCC care in the years ahead.