Augtyro (repotrectinib)

P1, N=24, Not yet recruiting, Bristol-Myers Squibb

P2, N=20, Not yet recruiting, MedSIR

In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.

The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.

In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.

No abstract available

This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.

P1/2, N=9, Terminated, Turning Point Therapeutics, Inc. | Phase classification: P1b/2 --> P1/2

Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

To the best of our knowledge, we reported the first case demonstrating anti-tumor activity of repotrectinib in a patient with AC carring an ETV6-NTRK3 gene fusion, indicating that repotrectinib may be an efficient therapeutic option for tumors with NTRK gene rearrangements.

P1/2, N=50, Recruiting, Memorial Sloan Kettering Cancer Center

P3, N=230, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRKs fusions tumors. Since this new era has begun, resistance to first-generation TRKi has been described and has opened the development of second-generation molecules, such as selitrectinib and repotrectinib. In this review, we provide a brief overview of the studies on NTRK alterations found in pediatric central nervous system tumors and first and second-generation TRKi useful in clinical practice.

Presently, larotrectinib and entrectinib are the only FDA-approved therapies for NTRK-mutated cancers...The treatment landscape for NTRK cancers is still being explored, with numerous new tyrosine kinase inhibitors currently in development or undergoing phase 1 and 2 clinical trials. In this review, we delve into both established and novel therapies targeting NTRK-mutated NSCLC.

Crizotinib was the drug most frequently linked to EPE (38%), followed by lorlatinib (26%), ceritinib (12%), entrectinib (8%), dabrafenib/trametinib (6%), repotrectinib (6%) and brigatinib (3%). Despite frequent EPE after TKI introduction, clinical pancreatitis are rare. Based on these results, we conclude that no routine assessment of pancreatic enzyme is required when introducing TKI treatment. To our knowledge, this is the first retrospective study about EPE linked to TKI in NSLC.

Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.

No abstract available

The tropomyosin receptor kinase inhibitors (TRKi) larotrectinib and entrectinib are among the first agents with tissue agnostic FDA approvals for cancer treatment, and additional TRKi are undergoing development...There are numerous ongoing studies investigating TRKi as frontline, adjuvant, and salvage therapy. It will be critical to continue to gather long term safety data on the use of these agents, particularly in children.

P3, N=230, Not yet recruiting, Bristol-Myers Squibb

In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

P1/2, N=500, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Dec 2024 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Feb 2028

P1/2, N=75, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Mar 2025 --> Sep 2027 | Trial primary completion date: Mar 2025 --> Sep 2026

Treatment discontinuation due to TEAEs was 7% in both subpopulations. Conclusions In TRIDENT-1, repotrectinib showed durable clinical activity, intracranial response, and manageable safety in both TKI-naïve and -pretreated pts from Asia, including pts from China.

Patients with NTRK+ solid tumors who were treated with repotrectinib generally experienced stable HRQoL as measured by the QLQ-C30. These results compliment the efficacy and safety profile of repotrectinib as a treatment option for patients with NTRK+ solid tumors.

P1, N=0, Withdrawn, Turning Point Therapeutics, Inc. | N=24 --> 0 | Recruiting --> Withdrawn

No abstract available

No abstract available

Repotrectinib safety at RP2D was manageable, consistent with prior reports. Table: 1372P Repotrectinib in NTRK+ solid tumors

With 14 months' minimum follow-up in TRIDENT-1, repotrectinib continued to demonstrate durable efficacy in patients with ROS1+ NSCLC, including intracranial activity, in both TKI-naïve and 1 prior TKI and no chemo cohorts. Safety in patients treated at RP2D was manageable, consistent with previous reports in all treated patients.

P1/2, N=75, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Sep 2025 --> Mar 2025

19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations...This was equally effective to the reference drug Repotrectinib (IC = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.

This event is organized and accredited by Research to Practice and supported through educational grants provided by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Lilly, Novocure Inc, Regeneron Pharmaceuticals Inc, and Takeda Pharmaceuticals USA Inc. Published data with alectinib, brigatinib or lorlatinib as first-line therapy for patients with NSCLC and ALK rearrangements; clinical factors in the selection of which to administer Differential CNS permeability and intracranial response rates observed with approved ALK-targeted agents; implications for selection of treatment for patients with brain metastases Indications for and implications of repeat biomarker testing for patients with progressive NSCLC with ALK rearrangements; selection of therapy for disease that is progressing on first-line ALK inhibition Principal efficacy and safety findings with entrectinib for NSCLC with a ROS1 rearrangement; integration into clinical practice Available data with, FDA breakthrough therapy designation for and ongoing evaluation of repotrectinib for NSCLC with a ROS1 rearrangement Key efficacy and safety results with selpercatinib or pralsetinib for patients with RET fusion-driven NSCLC, including those with previously untreated disease; optimal integration into therapy and selection between these agents Appropriate sequencing of immunotherapy for patients with metastatic NSCLC and targetable tumor mutations, including ALK, ROS1 and RET alterations

In TRIDENT-1, repotrectinib showed durable clinical activity in ROS1 TKI-naïve and -pretreated pts with or without BL CNS mets, including intracranial responses. Repotrectinib safety profile was similar in pts with ROS1+ NSCLC with or without CNS mets. Clinical trial information: NCT03093116.

P1, N=24, Recruiting, Turning Point Therapeutics, Inc.

P1, N=12, Recruiting, Turning Point Therapeutics, Inc.

P1b/2, N=9, Terminated, Turning Point Therapeutics, Inc. | Trial completion date: Jan 2024 --> Feb 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Feb 2023; Inability to achieve and optimize a dose that could provide a positive benefit risk profile

"Foundation Medicine, Inc...announced today, an expanded collaboration with Bristol Myers Squibb...to develop Foundation Medicine’s tissue-based test, FoundationOne^®CDx as a companion diagnostic for Bristol Myers Squibb’s investigational tyrosine kinase inhibitor, repotrectinib....'We’re proud to broaden our collaboration with Bristol Myers Squibb as they work to bring this exciting investigational therapy to patients living with ROS1 positive non-small cell lung cancer and NTRK positive solid tumors...'"

Osimertinib-resistant YU-1097 harboring EGFR resistance mutation (E19del/T790M/C797S) revealed sensitivity to BLU-945 (IC50, 108nM), a novel fourth-generation EGFR-TKI. A similar inhibition of cell viability was observed with repotrectinib (IC50, 21nM), a next-generation ROS1-TKI and lorlatinib (IC50, 9nM) in YU-1078 harboring CD74-ROS1, whereas more robust tumor regression was seen with repotrectinib in YU1078-derived xenograft model. Amivantamab, a EGFR-MET bispecific antibody, showed a robust activity in YU-1163 and YUO-036 in vitro and in vivo. PDC/PDO models can be utilized for evaluating activity of novel agents and will accelerate novel drug development in NSCLC.

Fifteen patients (10.7%) were enrolled in clinical trials or compassionate use program according to molecular profiling (DAY101 [BRAF inhibitor] in 3, selpercatinib in 3, palbociclib in 2, olaparib in 2, alectinib in 1, repotrectinib in 1, larotrectinib in 1, atezolizumab in 1 and erdafitinib in 1). Two (1.4%), one (0.7%) and one (0.7%) patients received vemurafenib, larotrectinib, and pembrolizumab with non-reimbursement... Application of NGS panel in pediatric cancer aid in diagnosis, treatment decision, clinical trial enrollment and germline risk determination. Although there are not many cases linked with molecular target-based therapy, it is leading to clinical benefits in pediatric patients and more understanding genomic profiling of pediatric cancer.