TPX-0131 / BMS - LARVOL DELTA

Preclinical Prediction of Resistance Mutations and Proposal of Sequential Treatment Strategies for ALK-positive Lung Cancer Using Next-generation ALK Inhibitors. (PubMed, Pharm Res) - "• A PCR-based mutation prediction system was successfully applied to fourth-generation ALK inhibitors. • Neladalkib showed efficacy against G1202R-positive relapses with minimal evidence of secondary resistance mutations. • Sequential combinations of gilteritinib with either neladalkib or ensartinib may sustain efficacy and delay resistance in I1171N-positive relapses."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Prediction of potential drug-resistant ALK mutations against fourth-generation inhibitors NVL-655 and TPX-0131. (PubMed, Int J Biol Macromol) - "Specifically, V1180W, M1199W, and L1256S are the common mutations with decreased binding free energy concerning both inhibitors. These findings highlight important residues and mutations that may impact the clinical efficacy of NVL-655 and TPX-0131, and this pipeline provides an efficient and accurate framework to predict drug-resistant mutations and facilitate the rational design of next-generation ALK inhibitors."

Journal • Oncology • ALK

In-depth theoretical modeling to explore the mechanism of TPX-0131 overcoming lorlatinib resistance to ALKL1196M/G1202R mutation. (PubMed, Comput Biol Med) - "The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c. (PubMed, Mol Pharm) - "Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC)...ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities...Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors."

Journal • Preclinical • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • ALK • CYP3A4 • SLCO1C1

An ultra-fast green ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of zotizalkib in human liver microsomes. (PubMed, J Sep Sci) - "Zotizalkib (ZTK, TPX-0131) is a fourth-generation highly effective inhibitor of wild-type anaplastic lymphoma kinase (ALK) and ALK-resistant mutations that can penetrate the central nervous system...ZTK and encorafenib were separated using an Agilent C8 column (Eclipse Plus) and an isocratic mobile phase...The in vitro half-life (t1/2) and intrinsic clearance (Clint) of ZTK were determined to be 15.79 min and 51.35 mL/min/kg, respectively that suggests the ZTK exhibits characteristics similar to those of a medication with a high extraction ratio. These approaches are crucial for the progress of novel pharmaceutical development, especially in improving metabolic stability."

Journal • Preclinical • Oncology • ALK

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. (PubMed, Front Mol Biosci) - " 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."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov) - P1/2 | N=11 | Terminated | Sponsor: Turning Point Therapeutics, Inc. | Trial completion date: Aug 2026 ➔ Apr 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2025 ➔ Apr 2023; Adverse change in the risk/benefit.

Metastases • Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. (PubMed, Transl Lung Cancer Res) - "Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4 generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALK

The influence of the ABCB1, ABCG2 and OATP1 transporters and the CYP3A enzyme on the bioavailability and tissue distribution of TPX-0131 (ESMO-TAT 2023) - "Conclusions TPX-0131 might be a substrate for the ABCB1 and ABCG2 transporters. However, TPX-0131 is probably not a substrate for the OATP1 transporter(s) or the CYP3A enzyme."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • CYP3A4 • SLCO1C1

A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov) - P1/2 | N=11 | Active, not recruiting | Sponsor: Turning Point Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | N=210 ➔ 11

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

[VIRTUAL] A phase I/II study of TPX-0131, a novel oral ALK tyrosine kinase inhibitor, in patients with ALK+ advanced/metastatic NSCLC (ESMO 2021) - P1/2 | "CNS endpoints will be assessed in patients with measurable brain metastases. Phase I will be enrolling in Australia, USA, and South Korea."

Clinical • IO biomarker • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors. (PubMed, Target Oncol) - "We developed a PCR-based system for predicting drug resistance mutations. When this system was applied to repotrectinib and ensartinib, the results suggested that these drugs can be used for the second-line treatment of ALK-positive NSCLC. Predicting resistance mutations against TKIs will provide useful information to aid in the development of effective therapeutic strategies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • FLT3

TPX-0131, a Potent CNS-Penetrant, Next-Generation Inhibitor of Wild-Type ALK and ALK-Resistant Mutations. (PubMed, Mol Cancer Ther) - "Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer...The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations)...Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies."

Journal • Lung Cancer • Oncology • Solid Tumor • ALK

Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? (PubMed, Transl Oncol) - "How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities ("singe mutant active" versus "double mutant active") rather than the loosely-defined "generational" (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs."

Clinical • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Turning Point Therapeutics Provides Updates and Anticipated 2022 Clinical and Discovery Pipeline Milestones (GlobeNewswire) - "The dose finding portion of the Phase 1/2 FORGE-1 study is ongoing. The company anticipates providing early interim data from initial patients treated in the dose-finding portion of the FORGE-1 study in the fourth quarter of 2022 or early 2023."

P1/2 data • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov) - P1/2; N=210; Recruiting; Sponsor: Turning Point Therapeutics, Inc.; Initiation date: Mar 2021 ➔ Aug 2021

Clinical • Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

[VIRTUAL] TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations (AACR 2021) - "Cell proliferation assays of WT, single mutations, and compound mutations were used to evaluate TPX-0131 relative to previous generations of ALK inhibitions (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib). In contrast, lorlatinib (5 mg/kg BID) caused 31% TGI in the G1202R/L1198F model and did not have statistically significant TGI in the G1202R/L1196M model. Taken together, TPX-0131 is a next generation ALK inhibitor that has preclinical potency against WT ALK as well as a broad spectrum of acquired resistance mutations, especially compound mutations, which currently lack any effective ALK inhibitor therapy."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EML4

Turning Point Therapeutics Initiates Global Phase 1/2 Forge-1 Clinical Study of TPX-0131, a Next-Generation ALK Inhibitor (GlobeNewswire) - "Turning Point Therapeutics...announced initiation of its Phase 1/2 FORGE-1 study of TPX-0131, a potent inhibitor of the anaplastic lymphoma kinase (ALK) and multiple resistant mutations of ALK...The study was initiated in Australia, with U.S. site activations now planned...The Phase 1 dose finding portion of the FORGE-1 study will enroll patients with locally advanced or metastatic TKI-pretreated ALK-positive NSCLC."

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Phase update (GlobeNewswire) - Preclinical➔P2, NSCLC

Phase shift • Non Small Cell Lung Cancer

Turning Point Therapeutics Announces New Preclinical Data for Three Drug Candidates (GlobeNewswire) - "For its ALK-inhibitor, TPX-0131, Turning Point will present preclinical data showing its potential to cross the blood-brain barrier and its potency against wild type ALK and a broad spectrum of acquired ALK resistance mutations, including the G1202R solvent front mutation, L1196M gatekeeper mutation, and the G1202R/L1196M and /L1198F compound mutations."

Preclinical • Oncology

A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov) - P1/2; N=210; Recruiting; Sponsor: Turning Point Therapeutics, Inc.

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Turning Point Therapeutics to Present New Preclinical Data For Three Drug Candidates at American Association For Cancer Research Annual Meeting (GlobeNewswire) - "Turning Point Therapeutics...announced today that four abstracts featuring three of its drug candidates will be presented at the American Association for Cancer Research (AACR) annual meeting...For lead drug candidate, repotrectinib, two poster presentations will highlight new preclinical combination data with MEK and MEK/Raf inhibitors, as well as repotrectinib’s potency against wildtype and TRKC A/B/C as compared to approved TRK inhibitors. For MET/SRC/CSF1R inhibitor, TPX-0022, the company will present preclinical data demonstrating potential utility in combination with immune checkpoint inhibitors. For its newest drug candidate, ALK-inhibitor TPX-0131, Turning Point will present preclinical potency data against ALK resistance mutations and in-vivo data demonstrating brain tissue penetration."

Preclinical • Oncology

Turning Point Therapeutics Reports Fourth-Quarter and Full-Year Financial Results, Provides Operational Updates (GlobeNewswire) - "Key milestones anticipated in 2021 include: TPX-0131: (i) Submit the IND for TPX-0131 in the first quarter; (ii) Initiate the Phase 1/2 clinical study of TPX-0131 focused on ALK-positive TKI-pretreated advanced NSCLC patients in the second quarter."

IND • New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Turning Point Therapeutics Announces 2021 Milestone Targets (GlobeNewswire) - "2021 Milestone Target:...Report early interim data from initial patients enrolled in the dose finding portion of the TPX-0046 Phase 1 study in the first half; Submit the IND for TPX-0131 in the first quarter; Initiate a Phase 1 clinical study of TPX-0131 in the first half"

IND • New P1 trial • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology

[VIRTUAL] TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors (AACR-II 2020) - "Second generation ALK inhibitors alectinib, ceritinib, and brigatinib were able to overcome the majority of ALK resistant mutations (L1196M, G1269A and F1174L) acquired with crizotinib...Lorlatinib, a third generation ALK inhibitor, can overcome G1202R resistance with moderate IC50 values of 40 - 60 nM in cell-based assays...Taken together, TPX-0131 is a next generation ALK inhibitor that can overcome a broad spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations (e.g. L1196M/G1202R). The nonclinical pharmacology profile of TPX-0131 warrants further preclinical investigation."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Thoracic Cancer • ALK • EML4