Haslett K, Koh P, Hudson A, Ryder W D, Falk S, Mullan D, Taylor B, Califano R, Blackhall F, Faivre-Finn C
The Christie NHS Foundation Trust, United Kingdom.
University of Manchester, United Kingdom.
Clin Transl Radiat Oncol. 2021 Feb 25;28:24-31. doi: 10.1016/j.ctro.2021.02.008. eCollection 2021 May.
The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies.
Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy.
21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm (range 1-224 cm). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia.
We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.
RAS/RAF/MEK/ERK信号通路在癌症增殖和调节治疗反应中起关键作用。在临床前研究中，司美替尼可抑制MEK并增强放疗效果。
单臂、单中心、开放标签的I期试验。招募不适合同步放化疗的III期非小细胞肺癌患者或有明显胸部症状的IV期患者进入剂量探索阶段（斐波那契3 + 3设计；最大样本量 = 18），然后进入扩大队列（n = 15）。口服司美替尼，每日两次（起始剂量50 mg），在胸部放疗前7天开始给药，然后与放疗同时进行（6 - 6.5周；60 - 66 Gy/30 - 33次分割）。主要目的是确定司美替尼联合胸部放疗的推荐II期剂量（RP2D）。
共纳入21例患者（2010年6月 - 2015年2月）。中位年龄：62岁（范围50 - 73岁）。男女比例为12（57%）：9（43%）。东部肿瘤协作组（ECOG）体能状态0：1为7（33%）：14（67%）。III期16例（76%）；IV期5例（24%）。中位大体肿瘤体积（GTV）为64 cm³（范围1 - 224 cm³）。15例患者以起始剂量进入扩大队列。所有21例患者均按计划完成胸部放疗并接受诱导化疗。13例（62%）患者接受了全剂量的司美替尼。在起始队列中未观察到放疗相关毒性增强。2例患者出现剂量限制毒性（1例3级腹泻/疲劳，1例肺栓塞）。最常见的3 - 4级不良事件：淋巴细胞减少（19/21例患者）和高血压（7/21例患者）。1例患者发生3级食管炎。无患者发生≥3级放射性肺炎。在分析时2例患者存活（分别随访24个月和26个月）。首次疾病进展的主要原因：远处转移±局部区域进展（12/21 [57.1%]例患者）。6例患者确诊/疑似卡氏肺孢子虫肺炎。
我们报告了在RP2D剂量下联合胸部放疗和司美替尼治疗的大多数患者预后不良且出现严重淋巴细胞减少，这导致了确诊/临床疑似卡氏肺孢子虫肺炎。这些结果表明不应在II期试验中采用这种联合方案。美国国立医学图书馆临床试验注册中心编号：NCT01146756。
