SAN DIEGO–TP Therapeutics, a privately held, clinical-stage biopharmaceutical company developing oncology therapies with a focus on addressing drug resistance, today announced the publication in Cancer Discovery of preclinical and clinical proof-of-concept data for its lead investigational compound, Repotrectinib (TPX-0005), a next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1, TRKA-C and ALK fusion proteins, and overcome clinical resistance due to secondary kinase domain mutations.
The preclinical data show that repotrectinib can potently inhibit the wildtype fusion kinases and their solvent front mutations involving ROS1 (ROS proto-oncogene 1 receptor tyrosine kinase), TRKA-C (tropomyosin receptor kinases A, B, and C), and ALK (anaplastic lymphoma kinase). Proof-of-concept clinical data from the ongoing Phase 1/2 TRIDENT-1 study (www.clinicaltrial.govnumber NCT03093116) highlighted two patients with ROS1 or TRKC fusion-positive cancers who achieved confirmed partial responses after previously relapsing on earlier generation TKIs due to solvent front mutation-mediated resistance. One of the patients had brain metastases, which responded to treatment with repotrectinib.
“Targeted therapies have demonstrated remarkable efficacy in the treatment of various oncogene-driven solid tumors, yet patients invariably develop resistance which leads to clinical progression,” said Alice Tsang Shaw, MD, PhD, Professor of Medicine, Harvard Medical School; Attending Physician, Chief of Thoracic Oncology, Massachusetts General Hospital; and corresponding author of the Cancer Discovery publication. “What is unique about the preclinical and early clinical data with repotrectinib is the drug’s potency against the mutations that often drive clinical resistance. These early data are encouraging and suggest that repotrectinib could represent an effective treatment for patients with ROS1-, NTRK, or ALK-rearranged malignancies who have progressed on earlier generation TKIs.”
“Repotrectinib was intentionally designed with the goal to more effectively target and overcome solvent front mutations that ultimately hinder long-term effectiveness of other TKI therapies,” said Dr. J. Jean Cui, founder, President, and Chief Scientific Officer of TP Therapeutics. “With each patient our investigators treat, we learn more about Repotrectinib’s safety and efficacy profile and become more encouraged by its potential to ultimately help a broad range of cancer patients.”
The Cancer Discovery article may be found online at: http://cancerdiscovery.aacrjournals.org/content/early/2018/08/09/2159-8290.CD-18-0484?papetoc=
Preliminary data from the ongoing Phase 1 portion of the TRIDENT-1 clinical trial were previously presented in June 2018 at the annual meeting of the American Society of Clinical Oncology (ASCO).
Highlights of the findings published in Cancer Discovery include:
- In Ba/F3 models harboring wild type ROS1 fusion proteins, Repotrectinib was more potent (IC50 <0.2 nM) compared to all known or potential ROS1 inhibitors: crizotinib, ceritinib, brigatinib, ensartinib, cabozantinib, and lorlatinib.
- Repotrectinib was more potent than lorlatinib against the most common clinically acquired resistance mutation ROS1 G2032R with an IC50 of 3.3 nM, compared to an IC50 of 160.7 nM for lorlatinib.
- In Ba/F3 models harboring wild type TRKA-C fusion proteins, Repotrectinib was more potent (IC50 <0.2 nM) compared to larotrectinib and entrectinib, two TRK inhibitors in late stage clinical development.
- In Ba/F3 models, Repotrectinib retained potent activity against TRKA G595R (IC50 0.4 nM), TRKB G639R (IC50 0.6 nM), TRKC G623R (IC50 0.2 nM) and TRKC G623E (IC50 1.4 nM), whereas solvent front mutations (TRKA G595R, TRKC G623R) have been identified in patients who are resistant to larotrectinib and entrectinib.
- Repotrectinib treatment demonstrated a rapid, dramatic and durable confirmed partial response in a patient with an ETV6-TRKC G623E+ mammary analogue secretory carcinoma (MASC) within the first few days of administration who was previously treated with multiple TKIs.
- Repotrectinib treatment demonstrated a confirmed partial response and a response within metastases of the brain in a patient with CD74-ROS1 G2032R+ non-small cell lung cancer (NSCLC) previously treated with crizotinib who had progressed.
About repotrectinib (TPX-0005)
Repotrectinib (TPX-0005) is a potent and orally bioavailable investigational small molecule kinase inhibitor for ALK, ROS1, and TRK family. The clinical benefits of targeting ALK, ROS1, or TRK fusion kinase have been demonstrated with multiple kinase inhibitors already approved for the treatment of ALK+ non-small cell lung cancer (NSCLC), in addition to crizotinib for ROS1+ NSCLC, and larotrectinib and entrectinib in clinical studies for TRK+ cancers. The successes of these therapies are overshadowed by the development of acquired resistance. The acquired solvent front mutations including ALK G1202R, ROS1 G2032R, TRKA G595R and TRKC G623R render a common clinical resistance to the current ALK, ROS1, and TRK inhibitors.
Repotrectinib has demonstrated potency against wildtype and mutated ALK, ROS1 and TRK family kinases, especially the clinically significant solvent front mutations, gatekeeper mutations, and emerging compound mutations after multiple line treatments. Repotrectinib may provide a new opportunity to inhibit the abnormal signaling of ALK, ROS1, or TRK family in solid malignancies, and overcome multiple resistance mechanisms seen in refractory patients. Repotrectinib is currently being evaluated in a Phase 1/2, open-label, multi-center, first-in-human study of the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1, NCT03093116). For additional information about the repotrectinib trial, please refer to www.clinicaltrials.gov. Interested patients and physicians can also contact the TP Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email firstname.lastname@example.org.
Note: TPX-0005 had an initial generic name of “ropotrectinib,” which was later changed to repotrectinib and is now the accepted name by USAN and WHO INN.
About TP Therapeutics, Inc.
TP Therapeutics, Inc. (TP) is a clinical-stage structure-based oncology drug design company founded in October 2013 by Dr. J. Jean Cui, the lead inventor of Pfizer’s oncology drug crizotinib and lorlatinib. The TP team is focused on the design and development of novel chemical entities within oncology for established oncogene drivers with high incidence of secondary resistance mutations; newly identified disease-driven targets; and potential targets regulating the tumor microenvironment and tumor immunity. For more information, please visit us at www.tptherapeutics.com.