S Cavalieri1, F Perrone2, R Miceli3, P A Ascierto4, L D Locati1, C Bergamini1, R Granata1, S Alfieri1, C Resteghini1, D Galbiati1, A Busico2, N Paielli2, R Patuzzo5, A Maurichi5, G Gallino5, R Ruggeri5, L Mariani3, M Palla4, L Licitra6, P Bossi7. 1. Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy. 2. Fondazione IRCCS Istituto Nazionale Dei Tumori, Department of Pathology, Unit of Experimental Molecular Pathology, Milan, Italy. 3. Fondazione IRCCS Istituto Nazionale Dei Tumori, Clinical Epidemiology and Trial Organization, Milan, Italy. 4. Istituto Nazionale Tumori Fondazione "G. Pascale", Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Naples, Italy. 5. Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Surgery Unit, Milan, Italy. 6. Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy; Università Degli Studi di Milano, Medical Oncology Department, Milan, Italy. 7. Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy. Electronic address: paolo.bossi@istitutotumori.mi.it.
Abstract
BACKGROUND: In recurrent or metastatic (R/M) 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 oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
BACKGROUND: In recurrent or metastatic (R/M) 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 oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS:Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
Authors: Michael R Migden; Nikhil I Khushalani; Anne Lynn S Chang; Karl D Lewis; Chrysalyne D Schmults; Leonel Hernandez-Aya; Friedegund Meier; Dirk Schadendorf; Alexander Guminski; Axel Hauschild; Deborah J Wong; Gregory A Daniels; Carola Berking; Vladimir Jankovic; Elizabeth Stankevich; Jocelyn Booth; Siyu Li; David M Weinreich; George D Yancopoulos; Israel Lowy; Matthew G Fury; Danny Rischin Journal: Lancet Oncol Date: 2020-01-14 Impact factor: 41.316