^
    24d
    Discovery of new non-macrocyclic TRK inhibitors based on conformational flexibility and scaffold hopping to overcome clinical acquired resistance. (PubMed, Bioorg Chem)
    The best TRK inhibitor 5c had IC50 values of 0.75 and 0.96 nM against TRKAG595R and TRKAG667C, showing better potency than drugs larotrectinib (approximately 87- and 46-fold improvement) and selitrectinib (approximately 10- and 13-fold improvement). More importantly, 5c demonstrated favorable in vivo pharmacokinetic properties and antitumor efficacy (tumor growth inhibition (TGI) of 91% at 30 mg/kg and 115% at 60 mg/kg with 4 of 6 partial regression) in a BaF3-TMP3-TRKAG667C xenograft mouse model, which is greatly superior to that of selitrectinib (TGI of 2% at 30 mg/kg). Compound 5c exhibits significant potential to overcome clinical acquired multiple resistance to TRK inhibitors.
    Preclinical • Journal
    |
    NTRK (Neurotrophic receptor tyrosine kinase)
    |
    NTRK fusion
    |
    Vitrakvi (larotrectinib) • selitrectinib (BAY 2731954)
    1m
    Repotrectinib in NTRK fusion-positive advanced solid tumors: a phase 1/2 trial. (PubMed, Nat Med)
    These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .
    P1/2 data • Journal
    |
    ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    NTRK positive • NTRK fusion
    |
    Augtyro (repotrectinib)
    1m
    Study to Evaluate the Effect of Repotrectinib on the Drug Levels of Transporter and CYP P450 Probe Substrates in Healthy Adult Participants (clinicaltrials.gov)
    P1, N=32, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Augtyro (repotrectinib) • metformin • omeprazole
    2ms
    Effectiveness and cost-effectiveness of first-line versus second-line use of repotrectinib in the treatment of ROS1 fusion-positive advanced NSCLC. (PubMed, Expert Rev Anticancer Ther)
    Repotrectinib is not cost-effective at current prices, but first-line use is consistently more economically favorable than second-line therapy. Price reductions or shorter treatment durations could improve its cost-effectiveness.
    Journal • HEOR • Cost-effectiveness
    |
    ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ROS1 fusion • ROS1 positive
    |
    Augtyro (repotrectinib)
    3ms
    Phase II Study of REPotrectinib With or Without Fulvestrant in Patients With Hormone Receptor-positive Human Epidermal Growth Factor 2-negative Metastatic Invasive LObular Carcinoma Who Received a Prior Endocrine Therapy in Combination With Cyclin-dependent Kinase 4 and 6 Inhibitor (REPLOT Trial) (clinicaltrials.gov)
    P2, N=6, Terminated, M.D. Anderson Cancer Center | N=58 --> 6 | Trial completion date: Dec 2027 --> Dec 2025 | Recruiting --> Terminated | Trial primary completion date: Dec 2027 --> Dec 2025; <75% Participation
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date
    |
    fulvestrant • Augtyro (repotrectinib)
    4ms
    A Study of Repotrectinib Versus Crizotinib in Participants With Locally Advanced or Metastatic Tyrosine Kinase Inhibitor (TKI)-naïve ROS1-positive Non-Small Cell Lung Cancer (NSCLC) (TRIDENT-3) (clinicaltrials.gov)
    P3, N=190, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Mar 2027 --> Mar 2026
    Trial primary completion date
    |
    Xalkori (crizotinib) • Augtyro (repotrectinib)
    4ms
    Study to Evaluate the Effect of Repotrectinib on the Drug Levels of Transporter and CYP P450 Probe Substrates in Healthy Adult Participants (clinicaltrials.gov)
    P1, N=32, Not yet recruiting, Bristol-Myers Squibb
    New P1 trial
    |
    Augtyro (repotrectinib) • metformin • omeprazole
    4ms
    Larotrectinib for the Treatment of NTRK Amplification Positive, Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
    P2, N=13, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2025 --> Nov 2027 | Trial primary completion date: Nov 2025 --> Nov 2027
    Trial completion date • Trial primary completion date • Pan tumor
    |
    NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
    |
    Vitrakvi (larotrectinib)
    5ms
    A Study to Assess the Drug Levels of Repotrectinib in Healthy Participants and Participants With Moderate and Severe Hepatic Impairment (clinicaltrials.gov)
    P1, N=18, Completed, Bristol-Myers Squibb | Recruiting --> Completed
    Trial completion
    |
    Augtyro (repotrectinib)
    5ms
    A Study of Repotrectinib Versus Crizotinib in Participants With Locally Advanced or Metastatic Tyrosine Kinase Inhibitor (TKI)-naïve ROS1-positive Non-Small Cell Lung Cancer (NSCLC) (TRIDENT-3) (clinicaltrials.gov)
    P3, N=190, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    Xalkori (crizotinib) • Augtyro (repotrectinib)