Clinical Cancer Research Highlights Potent Antitumor Activity of Repotrectinib in Treatment-Naïve and Solvent-Front Mutation Ros1-Positive Non-Small Cell Lung Cancer
SAN DIEGO, April 16, 2020 (GLOBE NEWSWIRE) -- Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, today announced the publication of preclinical data and patient case studies from the Phase 1 portion of its TRIDENT-1 clinical study for its lead investigational drug, repotrectinib.
Among the findings published in the American Association of Cancer Research peer-reviewed journal, Clinical Cancer Research, repotrectinib demonstrated potent in vitro and in vivo activity in patient-derived preclinical models compared with proxy chemical compounds for other tyrosine kinase inhibitors (TKIs) against ROS1 and the ROS1 G2032R solvent-front mutation. The central nervous system (CNS) activity of repotrectinib was studied in an in vivo model and demonstrated significant reduction of metastatic brain lesions with longer survival compared to a proxy chemical compound for entrectinib.
“Our findings provide encouraging support for repotrectinib as a potential first-line treatment in ROS1-positive non-small cell lung cancer, and later-line use after progression from a prior ROS1 TKI,” said Dr. Byoung Chul Cho, Division of Medical Oncology, Yonsei Cancer Center at Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea and corresponding author of the paper. “In addition, these preclinical data as presented initially at the annual AACR conference in 2019 and now expanded upon in the publication suggest repotrectinib may prevent or delay the emergence of the G2032R solvent-front mutation and subsequent compound mutations, potentially improving clinical outcomes.”
In preclinical studies, repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1-downstream signaling in treatment-naïve models compared with proxy chemical compounds for crizotinib, ceritinib, and entrectinib. Compared to a lorlatinib proxy chemical compound in a xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. In addition, repotrectinib induced anti-tumor activity in the CNS. Repotrectinib also showed selective and potent in vitro and in vivo activity against the ROS1 G2032R solvent-front mutation.
Patient case studies (from the previously reported July 22, 2019 data cut-off) included in the manuscript highlighted the potential for repotrectinib to prevent or delay ROS1 kinase domain resistance mutations.
“The emergence of resistance mutations and disease progression in the CNS are characteristics of ROS1-positive non-small cell lung cancer and represent a high unmet medical need given the lack of approved therapies,” said Dr. Mohammd Hirmand, chief medical officer of Turning Point Therapeutics. “These findings highlighted in Clinical Cancer Research build on prior preclinical studies of repotrectinib and data we have shown from the Phase 1 portion of TRIDENT-1, and are encouraging for repotrectinib as a potential treatment for both TKI-naïve and -pretreated ROS1-positive non-small cell lung cancer patients.”
Approximately 50 to 60 percent of crizotinib-resistant mutations are found within the ROS1 kinase, of which the ROS1 G2032R solvent-front mutation is the most common. In addition, it is estimated that approximately 50 percent of patients treated with ROS1-TKIs experience disease progression due to CNS metastases.
The Clinical Cancer Research article may be found online at https://clincancerres.aacrjournals.org/content/early/2020/04/08/1078-0432.CCR-19-2777
More information about the ongoing TRIDENT-1 study of repotrectinib may be found by searching clinical trial identifier NCT03093116 at https://clinicaltrials.gov.
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