USP1 Inhibitor in Metastatic Solid Tumors

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The first-in-class ubiquitin-specific peptidase 1 (USP1) inhibitor RO7623066 showed a positive safety profile as a single agent and signs of early antitumor activity in patients with advanced solid tumors, according to preliminary data from a new first-in-human phase I trial presented by Yap et al at the 2024 ASCO Annual Meeting (Abstract 3005).

RO7623066 is an oral, selective, small molecule targeting USP1—a deubiquitinating enzyme that regulates the translesion synthesis and Fanconi Anemia DNA repair pathways.

Study Methods and Results

In the new trial, researchers assigned 70 heavily pretreated patients with advanced solid tumors to receive RO7623066 as a single agent, in combination with the PARP inhibitor olaparib, and in combination with the chemotherapy carboplatin. The three arms of the trial comprised dose-escalation studies.

The researchers observed a partial response in one patient with advanced fallopian tube cancer. Further, 17% (n = 5/29) of patients achieved stable disease for over 16 weeks. Pharmacokinetic and pharmacodynamic data suggested the drug effectively targeted USP1 in a near dose-proportional exposure. When RO7623066 was combined with olaparib, preliminary clinical antitumor activity was associated with BRCA1 mutation status. The findings were consistent with preclinical data.

The most common side effect of RO7623066 as a single agent and in combination with olaparib was anemia. The most common grade 3 or higher adverse events of RO7623066 as a single agent and in combination with olaparib were hyponatremia and anemia, respectively. Both dose interruption and discontinuation rates were low.


“RO7623066 has demonstrated a manageable safety profile in combination with olaparib, with early signals of antitumor activity in patients with metastatic solid tumors,” said lead study author Timothy Yap, MBBS, PhD, Professor of Investigational Cancer Therapeutics as well as Vice President and Head of Clinical Development in the Division of Therapeutics Discovery at The University of Texas MD Anderson Cancer Center, Houston. “Further evaluation of the combination of RO7623066 and olaparib currently is ongoing to determine the recommended dose for expansion and recommended phase II dose,” he continued.

The examination of RO7623066 in combination with olaparib is currently ongoing—with additional measures introduced to address the occurrence of anemia.

Disclosure: The research in this trial was supported by Roche and KSQ Therapeutics. For full disclosures of the study authors, visit

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