For years, melanoma has been at the forefront of immunotherapy breakthroughs, thanks to its high mutation burden and responsiveness to immune checkpoint inhibitors. However, recent advances have broadened the scope of immunotherapy for skin cancers beyond melanoma, offering new hope for patients with squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and Merkel cell carcinoma (MCC). These developments mark a paradigm shift in the treatment of advanced non-melanoma skin cancers, especially when surgery or radiation is no longer effective.
Understanding Non-Melanoma Skin Cancers
Non-melanoma skin cancers (NMSCs) are the most common malignancies globally. While most are curable with early detection and local treatments, a small subset becomes advanced or metastatic. These include:
- Cutaneous squamous cell carcinoma (cSCC): Often caused by UV exposure; may become aggressive in immunosuppressed patients.
- Basal cell carcinoma (BCC): The most common form of skin cancer, typically slow-growing but occasionally locally invasive.
- Merkel cell carcinoma (MCC): A rare but highly aggressive neuroendocrine tumor often associated with the Merkel cell polyomavirus and immunosuppression.
Until recently, these cancers had limited systemic treatment options beyond chemotherapy or experimental trials.
How Immunotherapy Works
Immunotherapy harnesses the body’s immune system to recognize and attack cancer cells. The most commonly used class in skin cancer is immune checkpoint inhibitors, which block the proteins that prevent T cells from attacking tumors. These include:
- PD-1 (Programmed death-1) inhibitors: nivolumab, pembrolizumab, cemiplimab
- PD-L1 (Programmed death ligand-1) inhibitors: avelumab
- CTLA-4 inhibitors: ipilimumab (less commonly used in non-melanoma skin cancers)
By releasing these “brakes” on the immune system, checkpoint inhibitors help stimulate a durable and sometimes curative anti-tumor response.
Immunotherapy for Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and has a relatively high mutation burden, making it a good candidate for immunotherapy.
Cemiplimab: A Milestone Approval
In 2018, the FDA approved cemiplimab, a PD-1 inhibitor, for advanced or metastatic cSCC. In clinical trials, cemiplimab demonstrated an objective response rate (ORR) of over 50%, with some patients achieving complete remission (Migden et al., 2018).
Key Advantages:
- Well-tolerated in most patients
- Potential for long-lasting remission
- Effective even in patients who are not surgical candidates
This was the first immunotherapy approved specifically for a non-melanoma skin cancer, opening the door for broader application.
Immunotherapy for Basal Cell Carcinoma
Basal cell carcinoma (BCC) is rarely life-threatening but can become problematic when it is recurrent, large, or located in high-risk areas like the face.
When Hedgehog Inhibitors Fail
Patients with advanced BCC are often treated with Hedgehog pathway inhibitors such as vismodegib. However, resistance or intolerance to these drugs is common.
In 2021, cemiplimab was also approved for patients with advanced BCC who had previously failed Hedgehog inhibitors. In a pivotal trial, cemiplimab showed an ORR of 31%, with manageable side effects (Stratigos et al., 2021).
This marks a significant advancement for a patient population that previously had few alternatives.
Immunotherapy for Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is aggressive and frequently metastatic at diagnosis. It is strongly linked to Merkel cell polyomavirus and immune dysfunction, which makes it a prime target for immune-based therapies.
Avelumab and Pembrolizumab: Game Changers
In 2017, the FDA approved avelumab, a PD-L1 inhibitor, for metastatic MCC. Clinical trials showed a response rate of 33%–40%, with some patients achieving durable responses lasting over two years (Kaufman et al., 2016).
Pembrolizumab has also shown efficacy in MCC, with a response rate exceeding 55% in treatment-naïve patients (Topalian et al., 2020).
These approvals provide a lifeline for patients with otherwise grim prognoses.
Challenges and Considerations
Despite the promise, immunotherapy is not a one-size-fits-all solution. Key challenges include:
- Immune-related adverse effects: Ranging from rash and colitis to endocrinopathies
- Delayed response times: Some patients may initially appear to worsen before improving (pseudo-progression)
- Access and cost: Immunotherapies can be expensive and require long-term monitoring
Moreover, predicting who will respond remains difficult, although biomarkers like PD-L1 expression and tumor mutational burden are under investigation.
Future Directions
Emerging research is exploring combination therapies (e.g., immunotherapy + radiation), neoadjuvant use of immunotherapy, and novel immune targets such as LAG-3 and TIM-3. Personalized approaches based on genomic profiling may also improve outcomes.
Clinical trials are ongoing for:
- Intralesional immunotherapy in skin cancers
- Vaccines targeting virus-positive MCC
- Combination checkpoint blockade in resistant tumors
The expansion of immunotherapy for skin cancers beyond melanoma marks a transformative moment in dermatologic oncology. With FDA approvals for cSCC, BCC, and MCC, patients who once had limited options are now seeing durable remissions and improved survival. While challenges remain, ongoing research continues to refine these therapies, offering hope for more effective and individualized treatment in the future.
References
- Kaufman, H. L., Russell, J., Hamid, O., Bhatia, S., Terheyden, P., D’Angelo, S. P., … & Nghiem, P. (2016). Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology, 17(10), 1374–1385. https://doi.org/10.1016/S1470-2045(16)30364-3
- Migden, M. R., Rischin, D., Schmults, C. D., Guminski, A., Hauschild, A., Lewis, K. D., … & Nghiem, P. (2018). PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. New England Journal of Medicine, 379(4), 341–351. https://doi.org/10.1056/NEJMoa1805131
- Stratigos, A. J., Sekulic, A., Peris, K., Bechter, O., Prey, S., Kaatz, M., … & Rischin, D. (2021). Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. The Lancet Oncology, 22(6), 848–857. https://doi.org/10.1016/S1470-2045(21)00126-1
- Topalian, S. L., Bhatia, S., Hollebecque, A., Awada, A., De Boer, J. P., Kudchadkar, R. R., … & Nghiem, P. (2020). Non-comparative, open-label, multiple cohort study to evaluate pembrolizumab in patients with Merkel cell carcinoma (KEYNOTE-017). Journal of Clinical Oncology, 38(22), 2616–2626. https://doi.org/10.1200/JCO.20.00283
