Introduction

MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial.

Methods

Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay.

Results

Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression.

Conclusion

The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

中文翻译：

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Trametinib 和帕尼单抗治疗 RAS/RAF 野生型转移性结直肠癌的 II 期试验

介绍

MEK 抑制可以克服RAS野生型 (wt) 转移性结直肠癌 (mCRC)患者对 EGFR 抑制的抗性。我们在 II 期试验中评估了曲美替尼（MEK1/2 抑制剂）与帕尼单抗（EGFR 单克隆抗体）的抗肿瘤活性。

方法

既往接受过 5-FU、伊立替康、奥沙利铂、+/- 贝伐单抗治疗且未接受过抗 EGFR 治疗的KRAS、NRAS和BRAF wt mCRC 患者接受每天口服 1.5 mg 曲美替尼和每 2 周静脉注射 4.8 mg/kg 帕尼单抗治疗。主要终点是 RECIST v1.1 的临床受益率（CB；CR、PR 或 SD ≥24 周）。使用 2 阶段极小极大设计。使用 Oncomine Lung cfDNA 测定收集和分析系列血浆循环游离 DNA (cfDNA)。

结果

14 名患者于 2015 年 11 月至 2019 年 4 月入组。CB 率为 38% (5/13)，中位无进展生存期 (PFS) 为 4.4 个月 (95% CI, 2.9-7.1)。确认的总体响应率为 38% (5/13)。治疗相关 AE (trAE) 包括痤疮样皮疹 (85%)、腹泻 (62%)、斑丘疹 (54%)、粘膜炎 (46%) 等。曲美替尼的剂量调整和中断发生在 69% 的患者中，帕尼单抗发生在 54% 的患者中。由于耐受性和反应持续时间短，该试验没有进入 II 阶段。RAS或BRAF突变 cfDNA 在 3/13 患者 (23%) 中检测到放射学疾病进展前。

结论

在帕尼单抗中添加曲美替尼导致RAS/RAF wt 转移性结直肠癌的肿瘤缩小率很高，由于皮肤毒性的高发生率，耐受性差。在历史对照数据中，中位 PFS 与单独使用帕尼单抗相似。