On May 29, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported at the ASCO (Free ASCO Whitepaper) Annual Meeting presented a preclinical update for its novel, clinical-stage, selective RET-inhibitor drug candidate, TPX-0046 (Press release, Turning Point Therapeutics, MAY 29, 2020, View Source [SID1234564371]).

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In the updated preclinical studies comparing proxy molecules for approved and investigational RET inhibitors, TPX-0046 demonstrated potent in vitro and in vivo activity against a range of RET alterations, including greater potency against solvent-front mutations, G810S, G810R, G810C and G810N.

A phase 1/2 trial of TPX-0046 in RET TKI-naïve and -pretreated patients is ongoing.

"TPX-0046 was designed as a potent RET inhibitor with the potential to address TKI-naïve and RET inhibitor-resistant RET-dependent cancers," said Alexander Drilon, M.D., medical oncologist and acting chief of the Early Drug Development Service, Memorial Sloan Kettering Cancer Center, and a principal investigator for the TPX-0046 clinical study. "Specifically, in preclinical studies, TPX-0046 inhibited RET solvent front mutations that have been observed in biopsies from patients with progression on a prior RET inhibitor. Developing a next-generation RET inhibitor is an unmet need."

In enzymatic and cellular assays presented at ASCO (Free ASCO Whitepaper), TPX-0046 was potent against wildtype RET and multiple RET mutations and fusions.TPX-0046 also demonstrated antitumor activity in RET-driven cell-derived and patient-derived xenograft tumor models, including those that harbor a RET G810R solvent-front mutation.

The ongoing Phase 1/2 open-label, single-arm, multi-center clinical study of TPX-0046 is enrolling TKI-naïve and -pretreated patients with RET-altered non-small-cell lung, thyroid, and other advanced cancers in a Phase 1 dose escalation study of approximately 50 patients, and Phase 2 expansion study of approximately 300 patients with multiple cohorts, to assess safety, tolerability, pharmacokinetics (PK) and clinical activity. The study design allows intra-patient dose escalation based on tolerability. For more information, visit clinicaltrials.gov and search NCT04161391.

"The preclinical studies we are presenting today support a potential role for TPX-0046 in both TKI-naïve and TKI-pretreated patients," said Athena Countouriotis, M.D., president and chief executive officer of Turning Point Therapeutics. "With a compact design, and lower molecular weight than other investigational or approved RET inhibitors, TPX-0046 has shown encouraging preclinical activity against multiple RET G810 mutations, where there are currently no approved therapeutic options for patients."

TPX-0046 is a multi-targeted RET and SRC kinase inhibitor with a novel three-dimensional macrocyclic structure that is smaller and structurally distinguished from other approved or investigational RET inhibitors. Activation of RET– a receptor tyrosine kinase –through gain-of-function mutations or fusions has been found in multiple tumor types, including non-small-cell lung and thyroid cancers. In preclinical studies TPX-0046 spared vascular endothelial growth factor (VEGF) receptors 1, 2 and 3. According to research published in the European Journal of Cancer1, hypertension was the most common adverse effect (up to 46 percent) among multiple anti-cancer therapeutics that inhibit VEGF. Dual inhibition of RET and SRC represents a novel therapeutic strategy to target abnormal RET signaling in cancers. Inhibition of SRC family kinases has the potential to reduce bypass resistance from signaling through multiple receptor tyrosine kinases and therefore has the potential to increase the therapeutic effect of TPX-0046.