Immunotherapy followed by cetuximab in locally advanced/metastatic cutaneous squamous cell carcinomas: the I-TACKLE trial

Abstract

Background

Immunotherapy with pembrolizumab and cemiplimab achieves an overall response rate (ORR) of 34–51 % in locally advanced/metastatic (LA/M) cSCC, but primary and acquired resistance remains a challenge. This study evaluates whether adding cetuximab to pembrolizumab can overcome resistance by reducing immune escape.

Patients and methods

I-TACKLE is a phase II, open-label trial conducted at three Italian centers. Patients received intravenous pembrolizumab 200 mg every 3 weeks, and cetuximab was added in cases of stable disease or progression. The primary endpoint was cumulative ORR by a single agent or by combination strategy. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and response duration.

Results

From May 2019 to April 2021, 43 patients were enrolled and treated with pembrolizumab, and 23 received combination therapy. Median treatment durations were 3 months (pembrolizumab) and 4 months (combination). Cumulative ORR was 63 % [95 % CI 48–77], with 19/43 (44 %) responding to pembrolizumab and 8/21 (38 %) responding to the combination after resistance. Both patients experiencing an acquired resistance to pembrolizumab obtained partial response when cetuximab was introduced. Overall, 10/23 (44 %) responded to the combination. One-year PFS was 51 % with pembrolizumab and 42 % with combination therapy. Grade 3–4 treatment-related adverse events occurred in 7/43 (16 %) during pembrolizumab and 8/23 (35 %) during combination therapy, primarily dermatitis (30 %).

Conclusions

In LA/M cSCC, the addition of cetuximab to pembrolizumab reverts primary and acquired resistance with manageable toxicities. This sequential approach warrants further study.