9543 Background: In recurrent/metastatic skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. We investigated the role of pan-HER inhibitor dacomitinib within a phase II trial in this setting. Methods: Patients (pts) with diagnosis of sSCC not amenable to curative approaches were included. Oral dacomitinib was started at a dose of 30 mg daily for 15 days, followed by 45 mg daily. Primary endpoint was response rate (RR). Tumor samples were analyzed through Next Generation Sequencing methods (pgm, Ion torrent) using a custom panel targeting 36 genes associated with sSCC. Results: Forty-two pts (33 M, 9 F; median age 77 years, range 45-92) were treated. ECOG PS was 0 in 58%, 1 in 40% and 2 in 2%. One fifth of the pts had distant metastasis. Most pts (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). Among evaluable pts, overall RR was 28% (complete response CR 2%, partial response PR 26%), disease control rate 86%. Median duration of response was 11 months (range 1-26+). Median treatment duration was 4 months (range 1-26+). Reason for discontinuation were disease progression in 69%, adverse events (AEs) in 19%, non drug-related death in 5%; 3 pts are still on treatment. Median PFS and OS were 6 and 12 months, respectively. Most pts (93%) had at least one AE, mainly consisting in diarrhea and skin rash (71% each), fatigue (36%) and stomatitis (31%). G3/G4 AEs occurred in 36% of pts (diarrhea and skin rash 17% each). Tumor material was available from 7 responding (R: 6 PR, 1 CR) and 15 non-responding (NR: 13SD, 2PD) pts. Frequent TP53 (60%), NOTCH1/2 (60%) and FAT1 (40%) mutations were observed. NR pts showed a higher occurrence of HRAS/BRAF/NRAS mutations (40%) than R ones (28%). Moreover, HER3 (27%) CASP8 (27%), KMT2C (33%) and DCLK1 (27%) mutations were restricted to NR pts. Conclusions: In sSCC dacomitinib showed activity, similar to what observed with anti-EGFR monoclonal antibody cetuximab and panitumumab (RR 28% and 31%); safety profile was comparable to previous experiences in other diseases. Molecular pt selection could improve therapeutic ratio. Clinical trial information: NCT02268747.