9520 Background: In LA/M cSCC patients (pts), immunotherapy with pembrolizumab (P) and cemiplimab showed an overall response rate (ORR) of 34-49%, with durable antitumor activity. However, primary and acquired resistance represents a therapeutic challenge. In cSCC, monotherapy with cetuximab (C) showed promising signs of activity (ORR 28%), but with limited duration of response. This study aims at reverting P resistance by adding C, leveraging on its mechanism of action in reducing immune escape process. Methods: I-TACKLE is an open-label, nonrandomized, phase II trial in pts with LA/M cSCC conducted in 3 Italian centers. Eligible pts had LA/M cSCC not manageable with surgery or radiation and with ECOG PS= 0 or 1. They received intravenous P 200 mg every 3 weeks. In case of partial (PR) or complete response (CR), pts continued to receive P alone. In case of stable disease (SD) or progression (PD), pts received C (400 mg/sm loading dose, then weekly 250 mg/sm) in addition to P until progression. The primary endpoint was cumulative ORR by single agent or by combination strategy; safety, PFS (since start of P and P+C), OS and duration of response (DOR) were secondary endpoints. Results: Between May 2019 and April 2021, 43 pts were enrolled and treated with P. Table 1 depicts population baseline features. The median follow up was 24 (range 7-30) months. Twenty-three pts underwent the combination treatment (17/23 due to PD and 6/23 due to SD); 21 of them due to primary resistance and 2 because of acquired resistance. Median treatment exposure was 3 and 4 months to P and combination therapy, respectively. Cumulative ORR was 63% [95% confidence interval 48-77], including 19/43 (44%) pts with response to P and 8/21 (38%) with response to combination strategy after primary resistance to P. Both pts experiencing an acquired resistance to P obtained PR when C was introduced. Overall, 10/23 pts (44%) obtained a response to combination therapy. Median DOR and OS were not reached both with P alone and with P+ C. One-year PFS was 51% with P alone and 42% with P+C. Overall, grade 3-4 treatment-related adverse events occurred in 7/43 (16%) pts during treatment with P and 8/23 (35%) pts during P+C, mostly dermatitis 7/23 (30%). Three out of 43 (7%) pts discontinued treatment because of toxicity, one pancreatitis, one impaired renal function and one for worsening of clinical condition, all during treatment with P. Four patients died during treatment, due to PD. Conclusions: In LA/M cSCC, the addition of C to P reverts primary and acquired resistance, with manageable toxicities. The sequential approach deserves to be studied in future clinical trials. Clinical trial information: NCT03666325. [Table: see text]