A phase II trial of dacomitinib in locally advanced unresectable or metastatic skin squamous cell carcinoma

Abstract

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. The role of pan-HER inhibitor dacomitinib in this setting was investigated within an Italian clinical trial. Methods: Patients (pts) with diagnosis of sSCC not amenable to curative treatments were treated. Oral dacomitinib was started at a dose of 30 mg qd for 15 days, followed by 45 mg qd. 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%). Overall RR was 28% (complete response CR 2%, partial response PR 26%), disease control rate 86%. Median duration of response (DoR) and clinical benefit (DoCB) were 10.3 months (range 0.2-20.5+) and 3.8 months (range 0.2- 20.5+), respectively. Median treatment duration was 4 months (range 1-26+). Reason for discontinuation were disease progression in 69%, adverse events (AEs) in 19%, disease- related death in 5%; 3 pts are still on treatment. Median PFS and OS were 6 months (95% CI: 5-9) and 12 months (95% CI 9-NR), respectively. Most pts (93%) had at least one AE, mainly consisting in diarrhea and skin rash (71% each), fatigue (36%) and mucositis (31%). AEs higher than G3 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 cancers. A durable clinical benefit was observed as well. Molecular pt selection could improve therapeutic ratio.