enbezotinib (TPX-0046) / BMS - LARVOL DELTA

Genomic mechanisms of RET inhibitor resistance in RET-fusion positive NSCLC (AACR 2024) - "We engineered a panel of Ba/F3 cells expressing various RET fusion partners and breakpoints observed in clinical cases of NSCLC and evaluated their drug sensitivity profile against a panel of RETi including selpercatinib, pralsetinib, TPX-0046, lovatinib, zeteletinib and ponatinib. Collectively, we show that individual RET fusion variants have distinct drug sensitivity profiles and that secondary resistance mutations are non-overlapping between RETi. The comprehensive characterization of RET-dependent mechanisms of resistance to RETi may provide therapeutic guidance for treating RET-fusion driven NSCLC and provide structural insights that can guide the development of new therapeutic regimens."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KIF5B • RET

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2 | N=41 | Terminated | Sponsor: Turning Point Therapeutics, Inc. | Trial completion date: Nov 2023 ➔ May 2023 | Active, not recruiting ➔ Terminated; Adverse change in the risk/benefit.

Metastases • Trial completion date • Trial termination • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Genomic mechanisms of RET inhibitor sensitivity and resistance in RET-fusion positive cancer cells. (ASCO 2023) - "To investigate the drug sensitivity profile of individual RET fusion variants, we generated a panel of Ba/F3 cells expressing various RET fusion variants and evaluated in vitro sensitivity to RETi including selpercatinib, pralsetinib, vandetinib, cabozantinib, TPX-0046, lovatinib, and ponatinib... Taken together, these data indicate that individual RET fusion variants with diverse fusion partner breakpoints have distinct drug sensitivity profiles and that secondary resistance mutations may be non-overlapping between RETi. These findings support the need to comprehensively characterize RET-dependent mechanisms of resistance in order to provide therapeutic recommendations for treating RET-fusion driven cancers."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • KIF5B • NCOA4 • RET

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2 | N=41 | Active, not recruiting | Sponsor: Turning Point Therapeutics, Inc. | N=462 ➔ 41 | Trial completion date: Nov 2026 ➔ Nov 2023 | Trial primary completion date: Dec 2025 ➔ Jul 2023

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Precious Gene: The Application of RET-Altered Inhibitors. (PubMed, Molecules) - "Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy."

Journal • Review • Endocrine Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • RET

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2 | N=462 | Active, not recruiting | Sponsor: Turning Point Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046. (PubMed, Invest New Drugs) - "We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings."

Journal • Oncology • ALK • ROS1

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2 | N=462 | Recruiting | Sponsor: Turning Point Therapeutics, Inc. | Trial completion date: Mar 2025 ➔ Nov 2026 | Trial primary completion date: May 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

"Is TPX 0046 effective against gatekeeper RETV804M/L mutation?" (@RenoHemonc)

[VIRTUAL] The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models. (ASCO 2020) - P1/2 | "Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391). Research Funding: Turning Point Therapeutics"

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • Thyroid Gland Carcinoma • CCDC6 • KIF5B • RET

Expert Answers to Frequently Asked Questions About Selective RET Inhibition in RET-Driven Cancers (Clinical Care Options) - "In this commentary, I answer the most common questions on the use of selective RET inhibitors in the management of patients with RET-altered cancers posed by the audience during a series of live CCO webinars presented in early 2021....The standard of care outside of the confines of a clinical trial for patients with advanced RET fusion–positive NSCLC who progress through first-line selective RET inhibitor therapy is to stop the RET inhibitor and give platinum-doublet chemotherapy. That said, I typically continue the RET inhibitor and graft on chemotherapy, as I think patients benefit from continuation of the tyrosine kinase inhibitor, even though this is off-label use."

Online posting

Next-Generation RET Inhibitor Achieves Preliminary Activity in RET-Driven Cancers (Targeted Oncology) - "'RET-driven cancers affect nearly 10,000 patients annually in the United States and European Union, and patients who progress following treatment with a selective RET inhibitor remain particularly underserved,' said Alexander Drilon, MD...stated in a statement. 'While we continue to evaluate TPX-0046, the initial preliminary data are encouraging, with a generally tolerable safety profile and early signals of activity.'"

Media quote

Turning Point Therapeutics Announces Initial Clinical Data From Phase 1/2 SWORD-1 Study of RET Inhibitor TPX-0046 (GlobeNewswire) - P1/2, N=362; SWORD-1 (NCT04161391); Sponsor: Turning Point Therapeutics; "Turning Point...plans to revise the study protocol to include Phase 1 expansion cohorts at the recommended Phase 2 dose...Of 5 RET TKI-naïve patients, 4 showed tumor regressions of -42%, -37%, -23%, and -3%, including 2 patients dosed at 30 mg QD who achieved confirmed partial responses with duration of responses of 5.6 and 5.8+ months, respectively...Of 9 TKI-pretreated patients, 3 patients (2 treated with only 1 prior selective RET TKI) achieved tumor regressions of -44%, -27% and -17%."

Clinical protocol • P1 data • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Thyroid Gland Carcinoma

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2; N=350; Recruiting; Sponsor: Turning Point Therapeutics, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations (clinicaltrials.gov) - P1/2; N=350; Not yet recruiting; Sponsor: Turning Point Therapeutics, Inc.

Clinical • New P1/2 trial • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Turning Point Therapeutics Reports Fourth-Quarter and Full-Year Financial Results, Provides Operational Updates (GlobeNewswire) - "Key milestones anticipated in 2021 include: TPX-0046: Report early interim data from initial patients enrolled in the dose finding portion of the TPX-0046 Phase 1 study in the second quarter."

P1 data • Oncology • Solid Tumor

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

Turning Point Therapeutics Reports Second-Quarter Financial Results, Provides Operational Updates (GlobeNewswire) - "Key milestones anticipated into early 2021 include: Early interim data from approximately 30 to 40 patients across multiple TRIDENT-1 Phase 2 cohorts in the third quarter. Additional preclinical data highlighting the potential for repotrectinib to increase the effectiveness of KRAS-G12C inhibitors in the fourth quarter. Early interim data from initial patients treated with TPX-0022 in the fourth quarter. Submitting the IND for TPX-0131 by early 2021. Early interim data from initial patients treated with TPX-0046 in early 2021."

IND • P1 data • P1/2 data • P2 data • Preclinical • Oncology • Solid Tumor

Turning Point Therapeutics presents preclinical data for novel RET inhibitor candidate, TPX-0046 (GlobeNewswire) - "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...'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....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..."

Enrollment open • Media quote • Preclinical • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Cancer

Turning Point Therapeutics reports first-quarter financial results, provides update on operations and COVID-19 response (GlobeNewswire) - "Key milestones anticipated through 2020 include: Presenting preclinical data for TPX-0046, the company’s novel RET/SRC inhibitor, as a poster presentation during the ASCO virtual annual meeting on May 29; Early interim data from initial patients treated with TPX-0022 during the second half of the year."

P1 data • Preclinical • Oncology • Solid Tumor

TPX-0046 (RET) (IASLC-LCTT 2020) - No abstract available

"TPX-0046 is next gen selective RET inhibitor. Designed to tackle the solvent front mutations arising from first gen selective RET inhibitors in pre-clinical models." (@VivekSubbiah)

Turning Point Therapeutics Initiates Phase 1/2 Clinical Study of TPX-0046, a Novel RET/SRC Inhibitor (GlobeNewswire, Turning Point Therapeutics, Inc.) - "Turning Point Therapeutics, Inc...announced initiation of a Phase 1/2 clinical study of its drug candidate TPX-0046 in patients with advanced solid tumors harboring RET genetic alterations. TPX-0046 is a compact tyrosine kinase inhibitor (TKI) designed to target tumors with RET alterations and potentially overcome resistance that may develop in patients previously treated with other RET inhibitors."

Clinical • New P1/2 trial

Turning Point Therapeutics Announces FDA Clearance of Investigational New Drug Application for TPX-0046, a Novel RET/SRC Inhibitor (GlobeNewswire, Turning Point Therapeutics, Inc.) - "SAN DIEGO, Sept 30, 2019 (GLOBE NEWSWIRE) -- Turning Point Therapeutics, Inc (NASDAQ: TPTX), a precision oncology company developing novel drugs to address treatment resistance, today announced clearance by the U.S. Food and Drug Administration (FDA) of its investigational new drug application (IND) for TPX-0046, a novel therapy targeting solid tumors with abnormal RET genes by inhibiting RET and SRC kinases. The phase 1 portion will have a dose-finding design, including intra-patient dose escalation to assess the safety, tolerability, and preliminary clinical activity of TPX-0046 in patients with advanced or metastatic solid tumors harboring oncogenic RET fusions or mutations. “Similar to our lead asset, repotrectinib, our preclinical work supports a potential role for TPX-0046 in both TKI-naïve and TKI-pretreated patients, and we look forward to initiating our Phase 1/2 study later this year. Preclinical studies of TPX-0046 demonstrate potent..."

New trial • Preclinical • Regulatory

TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers (ESMO 2019) - "Two multi-kinase RET inhibitors vandetanib and cabozantinib have been approved for thyroid cancer...TPX-0046 is potent against the SFM G810R in Ba/F3 cell proliferation assay with a mean IC50 of 17 nM, whereas comparable proxy molecules for BLU-667 and LOXO-292 have IC50s >500 nM... TPX-0046 is a novel next generation RET/SRC inhibitor with favorable pharmaceutical properties and possesses potent in vitro and in vivo activity against diverse RET alterations, including the SFM G810R. The novel macrocyclic structure may provide opportunities to overcome treatment resistance from current RET inhibitors. TPX-0046 is currently in IND-enabling studies."