Binimetinib联合厄洛替尼治疗具有KRAS或EGFR激活突变的NSCLC患者I/IB期试验

SCI

31 July 2023

A Phase I/IB Trial of Binimetinib in Combination with Erlotinib in NSCLC Harboring Activating KRAS or EGFR Mutations

(Lung Cancer, IF: 5.3)

Andreas N. Saltos, Ben C. Creelan, Tawee Tanvetyanon, Alberto A. Chiappori, Scott J. Antonia, Michael R. Shafique, Milijana Ugrenovic- Petrovic, Samer Sansil, Anthony Neuger, Hilal Ozakinci, Theresa Boyle, Jongphil Kim, Eric B. Haura, Jhanelle E. Gray

CORRESPONDENCE TO: andreas.saltos@moffitt.org

Background 背景

Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation.

EGFR或KRAS的激活突变在NSCLC中非常普遍，共享MAPK通路的激活，可能适合联合治疗以防止负反馈激活。

Methods 方法  

In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1. The primary objective was to evaluate the safety of binimetinib plus erlotinib and establish the RP2D.

在这项1/1B期试验中，我们在至少既往接受一线治疗的晚期非小细胞肺癌患者中测试了binimetinib和厄洛替尼的联合用药（除非有EGFR突变并且未曾接受过治疗）。随后的1B期扩展积累的EGFR-或KRAS突变患者使用源于1期的推荐的2期剂量（RP2D）。主要目的是评估binimetinib加厄洛替尼的安全性，并建立RP2D。

Results 发现  

43 patients enrolled (dose-escalation = 23; expansion = 20). 17 harbored EGFR mutation and 22 had KRAS mutation. The RP2D was erlotinib 100 mg daily and binimetinib 15 mg BID x 5 days/week. Common AEs across all doses included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%), and were primarily grade 1/2. Among KRAS mutant patients, 1 (5%) had confirmed partial response and 8 (36%) achieved stable disease as best overall response. Among EGFR mutant patients, 9 were TKI-naïve with 8 (89%) having partial response, and 8 were TKI-pretreated with no partial responses and 1 (13%) stable disease as best overall response.

总计有43名患者入选（剂量增加=23人；扩展=20人）。其中17例存在EGFR突变，22例存在KRAS突变。RP2D为每日100 mg厄洛替尼和15 mg binimetinib BID x 5天/周。所有剂量小组中的常见AE包括腹泻（69.8%）、皮疹（44.2%）、疲劳（32.6%）和恶心（32.6%），分级为1/2级。在KRAS突变患者中，1例（5%）已确认部分缓解，8例（36%）病情稳定，为最佳总体缓解。在EGFR突变患者中，在9例从未既往接受TKI治疗的患者中，8例（89%）有部分反应，8例TKI预处理无部分反应，1例（13%）病情稳定为最佳总体反应。

Conclusions 结论  

Binimetinib plus erlotinib demonstrated a manageable safety profile and modest efficacy including one confirmed objective response in a KRAS mutant patient. While clinical utility of this specific combination was limited, these results support development of combinations using novel small molecule inhibitors of RAS, selective EGFR- and other MAPK pathway inhibitors, many of which have improved therapeutic indices.

Binimetinib加厄洛替尼在KRAS突变患者中显示出可控的安全性和适度的疗效，包括一个已证实的治疗反应。虽然这种特定组合的临床实用性有限，但这些结果支持开发使用新型RAS小分子抑制剂、选择性EGFR-和其他MAPK途径抑制剂的组合，其中许多已经改善了治疗指标。

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