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近些年，新型药物和标志物不断发展。2016 ESMO大会报道了泛FGFR（成纤维细胞生长因子受体）抑制剂BAY 1163877在难治性局部晚期或转移性实体瘤中的首次人体剂量递增研究。这种新型药物的特点之一是利用肿瘤信使RNA（mRNA）来识别可能有效的患者。
主要研究者，来自瑞士圣加仑肿瘤中心的Markus Joerger博士说：“大多数FGFR抑制剂相关研究着眼于肿瘤内FGFR异常，但鲜有成功案例。这项研究创新运用了FGFR的mRNA表达来作为预测生物标志物。”
这项多中心I期研究在六个国家进行，共计纳入80例患者进行治疗。在剂量爬坡研究后，以肿瘤FGFR mRNA高水平患者为扩展队列。其中剂量爬坡阶段的23例患者，扩展队列阶段有57例患者包括膀胱癌，头颈癌和肺癌。
剂量爬坡研究测试了50-800mg BID的5种剂量。结果显示，BAY 1163877的半衰期约为12h。由于无剂量限制性毒性出现，该研究并没有确定BAY的最大耐受剂量。根据临床前研究结果，以及其对血清磷酸盐水平影响的临床分析，推荐800 mg BID作为以后的研究的参考。
在毒性方面，对于所有的FGFR抑制剂，大多数患者会出现高磷血症。在BAY治疗同时给予磷酸盐结合剂，可以避免血液中磷酸盐水平的进一步升高。
在扩展队列中，BAY在膀胱癌中活性最高，3例（n=8）部分缓解。此外，肺鳞癌、头颈鳞癌和囊腺癌中也可见部分缓解，后者持续缓解时间可达1年以上。
Joerger博士说：“BAY 1163877耐受性良好，其新型生物标志物可以有效识别潜在的受益患者。未来应该开展进一步的研究，尤其是针对膀胱癌，其FGFR mRNA阳性患者占35%。”
意大利米兰欧洲肿瘤研究所早期药物开发部门主管Giuseppe Curigliano教授在评论该研究时表示：“FGFR抑制剂为罕见肿瘤提供了一个可能的治疗选择。在本研究人群中，部分囊腺癌患者疾病得到长期控制。对于FGFR mRNA表达的患者，分子筛查可为其提供治疗机会。”
BAY 1163877的毒性要弱于其他正在研发中的FGFR抑制剂。正如多数研究需要找到哪些患者能从FGFR抑制剂中获益一样，本研究中肿瘤FGFR的mRNA表达是最好的治疗预测指标，未来需要进一步在临床试验中验证上述结果。
信源：Phase I Study of Novel Anti-Cancer Drug Uses Tumour mRNA Expression to Identify Responders. ESMO 2016 Press Release.
摘要原文
Abstract：360O
Title：Phase I study of the pan-fibroblast growth factor receptor (FGFR) inhibitor BAY 1163877 with expansion cohorts for subjects based on tumor FGFR mRNA expression levels
Background: FGFRs are potential targets for anticancer therapy. Because FGFR expression can be de-regulated by genetic and epigenetic mechanisms, tumor FGFR mRNA levels may identify patients likely to benefit from FGFR-targeted approaches. BAY 1163877 (BAY) is an oral, potent small molecule inhibitor of FGFRs 1-3. We conducted a first-in-human dose-escalation (DE) study of BAY in subjects with advanced solid tumors, followed by expansion cohorts (ECs) in selected subjects with high tumor FGFR1-3 mRNA levels (NCT01976741).
Methods: Subjects with treatment-refractory advanced or metastatic solid tumors were enrolled in 6 dose cohorts ranging from 50-800 mg BID on a continuous 21-day cycle. Pharmacokinetics (PK) were evaluated on days 1 and 15 of cycle 1. Subjects were enrolled to 3 ECs (non-small cell lung cancer [NSCLC], bladder cancer and head and neck squamous cell carcinoma [HNSCC], and all-comers) based on high FGFR expression levels by RNAscope? and Nanostring? analysis of fresh or archival tumor specimens. Objective responses were assessed by RECIST 1.1 after cycle 2.
Results: Seventy six patients with advanced solid tumors were enrolled and treated, including 23 patients in the DE phase and 53 patients in the ECs. BAY was absorbed rapidly and exhibited an average plasma half-life of 12.7 hours. The most common adverse events were hyperphosphatemia, diarrhea and alopecia (grade 1 and 2). We observed a less than dose-proportional increase in exposure at doses > 200 mg BID, and based on effective target inhibition and a lack of dose-limiting toxicities 800 mg BID was declared as the recommended phase-2 dose. From 44 evaluable patients, 5 partial responses (PR) were seen from patients in the ECs, including HNSCC, sqNSCLC, adenoidcystic carcinoma of the tongue, and 2 with bladder cancer. An additional 18 EC patients had stable disease (SD) >12 weeks, of whom 8 had SD >24 weeks. The majority of patients, including 4 of 5 with PR, did not have FGFR genetic alterations.
Conclusions: BAY 1163877 at doses up to 800 mg BID was safe and well tolerated. The response profile supports selection of patients for treatment with a FGFR inhibitor based on tumor FGFR mRNA levels.
