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Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged
Mi Ran Yun1,2, Dong Hwi Kim3, Seok-Young Kim3
1JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea. cbc1971@yuhs.ac nobelg@yuhs.ac FORTUNE@yuhs.ac.
Purpose:
Although first-line crizotinib treatment leads to clinical benefit in ROS1 lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1 patient-derived preclinical models.
Experimental Design:
Antitumor activity of repotrectinib was evaluated in ROS1 patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.
Results:
Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.
Conclusions:
Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.
Insights
Repotrectinib demonstrates potent antitumor activity against ROS1 lung cancer, including resistant mutations and brain metastases. This next-generation tyrosine kinase inhibitor shows promise for both initial treatment and overcoming resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Crizotinib is a first-line treatment for ROS1 lung cancer but faces challenges with resistance mutations like ROS1-G2032R and central nervous system (CNS) progression.
- Developing novel therapies is crucial to overcome resistance and improve outcomes in ROS1-positive non-small cell lung cancer.
Purpose of the Study:
- To investigate the antitumor activity of repotrectinib, a next-generation ROS1/TRK/ALK tyrosine kinase inhibitor (TKI), in preclinical models of ROS1 lung cancer.
- To evaluate repotrectinib's efficacy against treatment-naïve and crizotinib-resistant ROS1 mutations, including the ROS1-G2032R mutation.
- To assess repotrectinib's central nervous system (CNS) penetration and activity in a brain metastasis model.
Main Methods:
- Evaluation of repotrectinib's antitumor activity in patient-derived preclinical models, including treatment-naïve and ROS1-G2032R models.
- Assessment of intracranial antitumor activity in a brain-metastasis mouse model.
- Clinical evaluation in patients enrolled in a Phase I/II clinical trial (NCT03093116).
Main Results:
- Repotrectinib demonstrated potent inhibition of in vitro and in vivo tumor growth and downstream signaling in treatment-naïve models compared to existing TKIs.
- Repotrectinib showed comparable tumor regression to lorlatinib but significantly delayed recurrence after drug withdrawal.
- Repotrectinib exhibited significant antitumor activity in the CNS, with efficient blood-brain barrier penetration, and potent activity against the ROS1-G2032R mutation.
- Clinical data from the ongoing trial supported the observed systemic and intracranial activity.
Conclusions:
- Repotrectinib is a potent and selective next-generation ROS1 TKI with improved activity against treatment-naïve and ROS1-G2032R mutations.
- Efficient CNS penetration makes repotrectinib a promising therapeutic option for ROS1 lung cancer with brain metastases.
- Repotrectinib may be effective as both a first-line treatment and after progression on prior ROS1 TKIs.
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