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.
Academic Article
Overview
abstract
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.
