A Phase Ib Dose‐Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS

Lessons Learned Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents. The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. Background KRAS‐mutant tumors possess abnormal mitogen‐activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual‐action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen‐activated protein kinase (MEK) in KRAS‐mutant tumors may provide additive benefit. Methods Patients with KRAS‐mutant solid tumors were eligible for this phase Ib dose‐escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results Twenty‐three patients were enrolled. Dose‐limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment. 经验总结 • Cobimetinib和Duligotuzumab单药治疗或与其他药物联合治疗时均耐受良好。 Cobimetinib与Duligotuzumab联用在本试验患者人群中导致毒性增加（尤其是胃肠道毒性）, 且疗效有限。 摘要 背景. KRAS突变肿瘤中的丝裂原活化蛋白激酶（MAPK）通路信号传导异常, 从而导致细胞增殖失调。Cobimetinib可阻断MAPK信号传导。双重作用抗体Duligotuzumab（MEHD7945A）可同时抑制配体与表皮生长因子受体（EGFR）和人表皮生长因子受体3（HER3）的结合。在KRAS突变肿瘤中, 阻断EGFR/HER3并抑制丝裂原活化蛋白激酶（MEK）可能会产生叠加获益。 方法. KRAS突变实体瘤患者有资格参加本项Ib期剂量递增研究（包含一个计划扩展期）。Duligotuzumab以1 100 mg的剂量每2周一次（q2w）静脉注射（IV）给药, 而Cobimetinib以标准3 + 3设计口服给药, 据此确定二者的II期推荐剂量（RP2D）。主要研究目的是评估这一联合治疗方案的安全性和耐受性。 结果. 本研究入组了23例患者。剂量限制性毒性（DLT）包括4级低钾血症和3级黏膜炎症、乏力和痤疮样皮炎。70%的患者出现了≥3级不良事件（AE）。分别有5例（22%）和12例（52%）患者漏用至少1剂Duligot