Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy.
Fondazione IRCCS Istituto Nazionale Dei Tumori, Department of Pathology, Unit of Experimental Molecular Pathology, Milan, Italy.
Eur J Cancer. 2018 Jul;97:7-15. doi: 10.1016/j.ejca.2018.04.004. Epub 2018 May 4.
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.
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.
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.
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.
在不适合放疗（RT）或手术的复发性或转移性（R/M）皮肤鳞状细胞癌（sSCC）中，化疗（CT）具有姑息性作用，临床反应有限。在一项临床试验中，研究了口服泛 HER 抑制剂达可替尼在这种情况下的作用。
对诊断为 R/M sSCC 的患者进行治疗。达可替尼的起始剂量为每天 30mg（QD），连用 15d，然后剂量增加至 45mg QD。主要终点为缓解率（RR）。通过使用针对与 sSCC 相关的 36 个基因的定制面板进行下一代测序来分析肿瘤样本。
42 名患者（33 名男性；中位年龄 77 岁）接受了治疗。大多数（86%）患者接受了以前的治疗，包括手术（86%）、放疗（50%）和化疗（14%）。RR 为 28%（2%完全缓解；26%部分缓解），疾病控制率为 86%。中位无进展生存期和总生存期分别为 6 个月和 11 个月。大多数患者（93%）至少经历了一次不良事件（AE）：腹泻、皮疹（各 71%）、疲劳（36%）和黏膜炎（31%）；36%的患者发生 3-4 级 AE。由于药物相关毒性，有 16%的患者停止治疗。TP53、NOTCH1/2、KMT2C/D、FAT1 和 HER4 是最常突变的基因。BRAF、NRAS 和 HRAS 突变在无反应者中更为常见，而 KMT2C 和 CASP8 突变仅存在于该亚组中。
在 sSCC 中，达可替尼的活性与抗表皮生长因子受体药物观察到的活性相似，并观察到持久的临床获益。安全性与以前在其他癌症中的经验相当。分子患者选择可能会提高治疗比率。
