Systemic Treatment
Systemic Treatment of Advanced cSCC
Unlike the melanoma and basal cell carcinoma therapeutic landscapes, treatment options for cSCC have not advanced significantly over the last 5-10 years. Current regimens with minimal data and marginal response include cisplatin, interferon alpha, cis-retinoic acid, cetuximab, and gefitinib. Over 15 years ago, Shin and colleagues published their phase II data from 39 patients with advanced cSCC, who received triplet therapy of interferon alpha, cisplatin, and cis-retinoic acid. Overall and complete response rates were 34% and 17%, respectively with one-, two-, and five-year survival rate estimates of 58%, 32%, and 21%, respectively. A small (n=36) phase II study in patients with unresectable cSCC evaluated weekly cetuximab for 7 weeks with a 48-week follow up. The primary study end point – disease control rate at 6 weeks – was 69%. Lastly, a small Phase II study of gefitinib (with individually escalated doses up to 750 mg) in patients with advanced cSCC of the head and neck reported a median progression free survival (PFS) of 1.9 months and median overall survival of 5.1 months. The investigators concluded that gefitinib has clinical activity as monotherapy in SCC of the head and neck. While dose escalation is feasible and may increase skin toxicity, the data do not support increased activity. No large, phase III studies have followed up on these preliminary findings leaving the clinician with very few effective and safe treatment options for advanced and metastatic cSCC. These findings are reflected in the current NCCN guidelines.
Treatment - Cutaneous SCC: Immune Activation as Therapy
Based upon the underlying pathophysiology of cSCC, the high mutational burden of this cancer, and early data, the FDA approved cemiplimab for the treatment of patients with metastatic cSCC or patients with locally advanced cSCC, who are not candidates for surgery.
Early data of cemiplimab showed a response rate of 50% (95% CI, 30-70) and the rate of durable disease control was 65% (95% CI, 44-83). The median observed time to response was 2.3 months and the duration of response exceeded 6 months in 54% of the patients. In metastatic disease, the response rate was 47% (95% CI, 34-61) and the rate of durable disease control was 61% (95% CI, 47-74). A partial response was observed in 24 patients and a complete response (CR) in 4 patients. The median time to response was 1.9 months and the median duration of response was not reached at the time of analysis. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.
Ongoing clinical trials are studying the efficacy and tolerability of cemiplimab in this highly underserved malignancy. For example, Rischin and colleagues presented up to three-year data in patients with advanced cSCC from the EMPOWER-CSCC-1 study. Cemiplimab achieved ORR of 46.1%. Overall, the complete response (CR) rate was reported as 16.1% and a median time to CR was 11.2 months with an ORR of 46.1%. A recent study also looked at neoadjuvant use of cemiplimab (treatment given as a the initial step to shrink a tumor before the main treatment, which is usually surgery). Neoadjuvant cemiplimab was associated with a high percentage of pathological complete response (51%) or major response (13%) in those with resectable cSCC.
Another checkpoint inhibitor approved for cSCC is pembrolizumab. The Keynote 629 study investigators examined the efficacy and safety of pembrolizumab in patients with recurrent or metastatic cSCC in an open-label, nonrandomized, global trial. Interim analysis of data after a median follow-up of 11.4 months found a mPFS of 6.9 months and ORR of 34.3%. Treatment-related AEs occurred in 66.7% of patients the most common being pruritus (14.3%), asthenia (13.3%), and fatigue (12.4%). Recent follow up of 14.9 months and 27.2 months, respectively, for both the locally advanced and recurrent/metastatic patients reported ORR of 50% and 35.2%.
Additionally, in the ongoing CARSKIN study, 39 patients with cSCC received first-line pembrolizumab. The primary endpoint was ORR at week 15. The primary cohort’s ORR was 41% (95% CI, 26% to 58%), including 13 partial responses and 3 complete responses. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were at least grade 3. One death was related to rapid cSCC progression; another resulted from a fatal second aggressive head and neck SCC diagnosed 15 weeks post inclusion.
The current NCCN cSCC guidelines reflect the efficacy and tolerability of checkpoint therapy in patients with locally advanced or metastatic disease (Table 2).
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