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EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
For the patients who progressed on prior ROS1-targeted therapies, nontargeted approaches can be utilized, including chemotherapy and immunotherapy. Investigational therapies are being tested in early-phase clinical trials in ROS1 NSCLC and include repotrectinib and DS-6051b [110, 111].
Targeted therapy of oncogenic-driven advanced non-small cell lung cancer: recent advances and new perspectives
Published in Expert Review of Respiratory Medicine, 2020
Carlo Genova, Giovanni Rossi, Marco Tagliamento, Erika Rijavec, Federica Biello, Luigi Cerbone, Lodovica Zullo, Francesco Grossi
Repotrectinib is a next-generation ROS1/TRKA-C/ALK inhibitor designed to overcome TKI resistance mutations, especially ROS1 G2032R, the most common resistance mutation of ROS1 after crizotinib. The TRIDENT-1 is a phase I/II trial including 33 patients with pretreated advanced cancers harboring ROS1/NTRAK1-3/ALK fusions. Efficacy data demonstrated that in TKI naïve population ORR was 82% (9/11), while in patients pretreated with crizotinib ORR was 57% (4/7); CNS activity was observed in both arms. All the 5 patients with ROS1 G2032R had a tumor regression with ORR of 40%. Repotrectinib demonstrated good activity with a manageable safety profile [60]. The most recent results of clinical trials involving ROS1 inhibitors are listed in Table 2.
Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)
Published in Expert Opinion on Therapeutic Patents, 2020
Yi-Min Liu, Chun-Nan Kuo, Jing-Ping Liou
Repotrectinib (9, TPX-0005) is a ROS1/TRK/ALK inhibitor. It was found with high activity against pan-TRK and ROS1 with the IC50 as <0.2 nM. In addition, repotrectinib shows good anti-cancer activity in Ba/F3 models harboring WT EML4-ALK variant1 with the value of IC50 as 27 nM, which is more potent than crizotinib and comparable to that of ceritinib. Moreover, repotrectinib can overcome resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK. Up to date, two phase I/II trial (NCT03093116 and NCT04094610) were under recruiting to investigate the safety and efficacy of repotrectinib [63].
Rare cancer, rare alteration: the case of NTRK fusions in biliary tract cancers
Published in Expert Opinion on Investigational Drugs, 2021
Alice Boilève, Loïc Verlingue, Antoine Hollebecque, Valérie Boige, Michel Ducreux, David Malka
Repotrectinib is a selective and highly potent MKI against ROS1, ALK and NTRK1-3 [75]. It has been designed to overcome acquired solvent front mutations, an on-target mechanism of resistance, and to target the ATP binding site (Figure 2). In preclinical models, repotrectinib exhibits anti-proliferative effects in cell lines and xenograft models [75]. Repotrectinib is currently being tested in a phase I/II dose escalation trial (NCT03093116) in MKI-naive or MKI-pretreated patients with advanced solid cancers harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 fusion.