Turning Point Therapeutics’ Kinase Inhibitors Show High Potency against Targeted Oncogene Drivers and Their Mutations

Two studies highlighted the higher potency of repotrectinib as compared to other proxy investigational and the currently approved ROS1 and TRK tyrosine kinase inhibitors (TKIs), Xalkori and Vitrakvi, against fusion ROS1s, wildtype TRK, and many resistance mutations, including solvent front, gatekeeper, and compound mutations.

Alexander Drilon, M.D., Clinical Director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and an investigator in the Phase 1 portion of the ongoing TRIDENT-1 study of repotrectinib, said, “As physicians adopt next-generation sequencing to identify genomic alterations in different cancers, there is an increased need for precision therapies that target specific oncogenes, such as TRK and ROS1. Repotrectinib was found to have 10-fold or higher increased potency when compared to proxy investigational and the currently approved TRK inhibitors against wildtype (WT) TRK fusions and solvent-front mutations. The findings -- while early -- are significant and warrant continued clinical study.”

Data for TPX-0022, a novel, internally developed MET/CSF1R/SRC inhibitor approaching IND submission in 1H 2019, were presented for the first time at the conference. TPX-0022 was designed to target MET-driven tumor cells, but also modulate the tumor microenvironment by inhibition of CSF1R. This dual modulation has demonstrated significant tumor growth inhibition in preclinical models.

The data shown in two posters highlighted the ability of TPX-0022 to potently inhibit MET-driven cancer cells and the associated signaling of known cancer pathways, inhibiting tumor growth and reducing tumor associated macrophages. This dual mechanism of action showed tumor regression and growth inhibition in multiple xenograft tumor models harboring MET amplification or MET exon 14 skipping mutations.

“We are excited to share why we believe our lead asset, repotrectinib, is a potential best-in-class ROS1 and TRK targeted TKI,” said Athena Countouriotis, M.D., chief executive officer. “This is based on multiple factors, including our ongoing Phase 1 TRIDENT-1 data and what we have shown at AACR in terms of preclinical potency against fusion ROS1s and resistance mutations, as well as WT and resistance mutations within TRKA-C. We remain encouraged by the potential for repotrectinib to make a difference in the lives of patients with a range of oncogene drivers, both patients who have yet to be treated with a kinase inhibitor, as well as those who have been treated with a prior kinase inhibitor and developed treatment resistance through a specific mutation.”

Turning Point Therapeutics plans to initiate a registrational Phase 2 portion of the TRIDENT-1 Study in the second half of 2019.

Dr. Countouriotis added: “While in late stage preclinical development, our MET/CSF1R/SRC kinase inhibitor, TPX-0022, has demonstrated promising preclinical activity in an important pathway for the regulation of tumor growth. We look forward to submitting our IND in the first half of 2019 and beginning our Phase 1 study in the second half of 2019.”

Additional highlights from the four studies include:

Title: Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations
Session: Sunday Mar 31, 2019, 1:00 PM - 5:00 PM
Abstract Number: 4000

Repotrectinib was shown to be more than 10-fold as potent as a LOXO-195 proxy against wildtype TRK fusions and solvent-front mutations, and more than 100-fold more potent against certain gatekeeper mutations. Repotrectinib was the only TRK inhibitor active against the compound mutation TRKA G595R/F589L (double mutation of solvent front and gatekeeper) in preclinical Ba/F3 cells. In xenograft tumor models, repotrectinib demonstrated significant tumor regression against wildtype or mutated TRK fusions. In the ongoing TRIDENT-1 clinical trial repotrectinib was active against the solvent front mutation ETV6-TRKC G623E in an entrectinib-resistant patient with a salivary gland tumor (-82%, confirmed partial response, RECIST v1.1). Tumor regression (-33%) was achieved in a larotrectinib-resistant cholangiocarcinoma patient with LMNA-TRKA G595R and F589L mutations.

Title: Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations
Session: Monday April 1, 2019, 8:00 AM - 12:00 PM
Abstract Number: 4832

Repotrectinib demonstrated higher potency as compared to other ROS1 inhibitors against multiple ROS1 fusions and mutations, especially the solvent front and gatekeeper mutations. In xenograft tumor models, repotrectinib treatment resulted in tumor regression against wildtype or solvent-front ROS1 fusion genes. Repotrectinib demonstrated a strong inhibition profile against wildtype and various mutated ROS1s across different fusion partners when compared to many other ROS1 TKIs.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling
Session: Monday April 1, 2019, 8:00 AM - 12:00 PM
Abstract Number: 3719

TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 (IC₅₀ < 0.2 nM) and SNU-5 (IC₅₀ < 0.2 nM) gastric cancer cells. TPX-0022 caused suppression of MET auto-phosphorylation at an IC₅₀ of approximately 0.3 nM in MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation of MET downstream signaling effectors, including AKT, ERK, STAT3 and PLCγ2 in a dose-dependent manner. In the cancer cell line and patient-derived xenograft tumor models from gastric, lung and liver cancers harboring MET amplification or MET exon14 skipping mutations, TPX-0022 caused dramatic tumor regression and tumor growth inhibition. The tumor inhibitory effect was associated with drastic inhibition of MET activity.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses
Session: Monday April 1, 2019, 8:00 AM - 12:00 PM
Abstract Number: 3749

TPX-0022 demonstrated potent CSF1R inhibitory activity and the ability to inhibit tumor growth and promote a pro-inflammatory anti-tumor microenvironment. In contrast, the potency of a proxy compound of the type II CSF1R inhibitor PLX-3397 demonstrated a strong dependency on the concentration of mouse CSF1, as the anti-proliferation IC₅₀ shifted from <0.1 nM to 146.4 nM when CSF1 concentration changed from baseline to 1 ng/mL. Finally, in the MC38 syngeneic mouse model, TPX-0022 effectively reduced tumor associated macrophages (TAM), altered the polarity of TAMs toward a more M1 phenotype, increased cytotoxic T cells and inhibited the growth of MC38 tumors.

About Repotrectinib

Repotrectinib (TPX-0005) is a potent and orally bioavailable investigational small molecule kinase inhibitor of ROS1, TRKs and ALK. The clinical benefits of targeting ROS1, TRK, or ALK fusion kinases have been demonstrated with multiple kinase inhibitors already approved or in clinical studies. The successes of these therapies are often overshadowed by the development of acquired resistance. The acquired solvent front mutations including ROS1 G2032R, TRKA G595R and TRKC G623R, and ALK G1202R render common clinical resistance to the current ROS1, TRK, and ALK inhibitors.

Repotrectinib has demonstrated potency against wildtype and mutated ROS1, TRK and ALK kinases, especially the clinically significant solvent front mutations, gatekeeper mutations, and emerging compound mutations after multiple lines of treatment. Repotrectinib may provide a new opportunity to inhibit the abnormal signaling of ROS1, TRK or ALK in solid malignancies, and overcome multiple resistance mechanisms seen in resistant 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 called TRIDENT-1 (www.clinicaltrial.gov number NCT03093116). Interested patients and physicians can also contact the TP Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email clinical@tptherapeutics.com.

About Turning Point Therapeutics Inc.

Turning Point Therapeutics is a clinical-stage precision oncology company with a pipeline of internally discovered investigational drugs designed to address key limitations of existing cancer therapies. The company’s lead program, repotrectinib, is a next-generation kinase inhibitor targeting genetic drivers of non-small cell lung cancer and advanced solid tumors. Repotrectinib has shown antitumor activity and durable responses among kinase inhibitor treatment-naïve and pre-treated patients, and is planned to enter a registrational Phase 2 study in the second half of 2019. Turning Point’s kinase inhibitors are designed to bind to their targets with greater precision and affinity than existing therapies, with a novel, compact structure that has demonstrated an ability to potentially overcome treatment resistance common with other kinase inhibitors. The company is driven to develop therapies that mark a turning point for patients in their cancer treatment. For more information, visit www.tptherapeutics.com.

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