Pearls from Your Peers: Immunotherapy and the Changing Therapeutic Landscape for Cutaneous Squamous Cell Carcinoma

Which patients are currently approved by the U.S. Food and Drug Administration (FDA) to receive immunotherapy for cutaneous squamous cell carcinoma (SCC), and what have been the improved outcomes over conventional therapy?
Immunotherapy is FDA-approved (Cemiplimab, Pembrolizumab) for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or radiation. Approvals were based on data showing objective response rates (ORR) of 36%-44% including imaging complete response (CR) in up to 21% of patients, meaning a clinically meaningful percentage of patients with previously incurable disease can now be cured. Immunotherapy is generally well tolerated. Taken together, this represents a dramatic improvement over conventional therapy both in terms of clinical efficacy and toxicity.

_{Migden, MR, Rischin, D, Schmults, CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018, 379 (4), 341-351. DOI: 10.1056/NEJMoa1805131.}

_{Migden, MR, Khushalani, NI, Chang, ALS, et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 2020, 21 (2), 294-305. DOI: 10.1016/S1470-2045(19)30728-4.}

_{Grob, JJ, Gonzalez, R, Basset-Seguin, N, et al. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol 2020, 38 (25), 2916-2925. DOI: 10.1200/jco.19.03054.}

There have been some important trials looking at neoadjuvant immunotherapy for squamous cell carcinoma (including yours). Which patients do you think would be best served by a referral for a neoadjuvant approach?
Neoadjuvant immunotherapy remains investigational for patients with resectable CSCC.  Fortunately, for these patients a registrational-intent, randomized phase 3 trial is in development to test the neoadjuvant approach against standard-of-care surgery and radiation for Stage III/IV CSCC and expected to activate in early 2024. The primary outcome will be event-free survival. However, given the exceptional pathologic responses (>50% pathologic complete response, pCR) observed in both a single-institution pilot trial (n=20) and a confirmatory, multicenter phase 2 trial (n=79), there already is a strong rationale to apply a neoadjuvant approach to patients at risk of significant functional loss with up-front surgery (e.g., requiring orbital exenteration).

_{Ferrarotto, R, Amit, M, Nagarajan, P, et al. Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2021, 27 (16), 4557-4565. DOI: 10.1158/1078-0432.}

_{Gross, ND, Miller, DM, Khushalani, N I,  et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med 2022, 387 (17), 1557-1568. DOI: 10.1056/NEJMoa2209813.}

What is the most exciting new developments on the horizon for patients with cutaneous SCC?
I predict that the application of neoadjuvant immunotherapy to patients with resectable CSCC will be transformative over the next decade. Many patients will likely enjoy improved quality-of-life after neoadjuvant immunotherapy, with response-adapted oncologic surgery and the avoidance of adjuvant radiation therapy in responders. In the meantime, there remains a great clinical need for improved local therapies for early-stage disease and/or immunosuppressed patients. This is particularly important given the expected increased incidence for a disease that is already one of the most common malignancies worldwide. Intratumor therapies, including the application of intratumor immunotherapy, have shown promise for patients who might otherwise require Mohs surgery or are not currently eligible for immunotherapy. 

_{Burns, C, Kubicki, S, Nguyen, Q B, et al. (2022). Advances in Cutaneous Squamous Cell Carcinoma Management. Cancers, 14(15), Article 3653. https://doi.org/10.3390/cancers14153653.}