Dataset Information

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naive and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer.

ABSTRACT:

Purpose

Although first-line crizotinib treatment leads to clinical benefit in ROS1⁺ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1^G2032R) 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 ROS1^G2032R 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 ROS1^G2032R. 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 ROS1^G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.

SUBMITTER: Yun MR

PROVIDER: S-EPMC10283448 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer.

Yun Mi Ran MR Kim Dong Hwi DH Kim Seok-Young SY Joo Hyeong-Seok HS Lee You Won YW Choi Hun Mi HM Park Chae Won CW Heo Seong Gu SG Kang Han Na HN Lee Sung Sook SS Schoenfeld Adam J AJ Drilon Alexander A Kang Seok-Gu SG Shim Hyo Sup HS Hong Min Hee MH Cui J Jean JJ Kim Hye Ryun HR Cho Byoung Chul BC

Clinical cancer research : an official journal of the American Association for Cancer Research 20200408 13

<h4>Purpose</h4>Although first-line crizotinib treatment leads to clinical benefit in <i>ROS1<sup>+</sup></i> lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1<sup>G2032R</sup>) 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 <i>ROS1<sup>+</sup></i> patient-derived preclinical models.<h4>Experi ...[more]

PMID: 32269053

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Project description:BackgroundHead-to-head evidence comparing repotrectinib against other approved ROS1 tyrosine kinase inhibitors (TKIs) is not currently available. The objective of this study was to indirectly compare progression-free survival (PFS), the objective response rate (ORR), and the duration of response (DoR) for repotrectinib vs. crizotinib and vs. entrectinib in patients with TKI-naïve ROS1+ locally advanced or metastatic non-small-cell lung cancer (aNSCLC).MethodsUsing evidence from a systematic literature review, unanchored matching-adjusted indirect comparisons (MAICs) were used to estimate population-adjusted hazard ratios (HRs) for PFS and DoR and odds ratios (ORs) for ORR for repotrectinib vs. crizotinib and vs. entrectinib among patients with TKI-naïve aNSCLC. The MAICs were adjusted for imbalances in baseline patient characteristics that were pre-specified as being prognostic or predictive of treatment effects. Weighted Cox (for PFS and DoR) and logistic (for ORR) regression models were fit. Supplementary analyses (SAs) explored the impact of missing data and modeling assumptions on effect estimates.ResultsThe evidence base was formed by TRIDENT-1 EXP-1 (repotrectinib; N = 71), a pooled set of five trials involving crizotinib (N = 273), and the pooled ALKA-372-001/STARTRK-1 and -2 trials (entrectinib; N = 168). After population adjustment, repotrectinib was associated with statistically significant improvements in PFS relative to crizotinib (HR = 0.44; 95% confidence interval [CI]: 0.29, 0.67) and entrectinib (HR = 0.57; 95% CI: 0.36, 0.91). Differences in ORR and DoR were not statistically significant but numerically favored repotrectinib. SAs were consistent with the main analyses across all comparisons.ConclusionsThe analysis demonstrated the strong benefits of repotrectinib in PFS, which was robust across different SAs and supported by numerically favorable results for DoR (where available) and ORR. These results, alongside the published TRIDENT-1 clinical data, further support repotrectinib as a potential new standard of care for TKI-naïve patients with ROS1+ aNSCLC.