zeteletinib (BOS-172738) / Boston Pharma, Daiichi Sankyo - LARVOL DELTA

Real-world evidence of resistance mechanisms, subsequent genome-guided treatments and late presenting adverse events in patients with RET-altered tumours on selective RET inhibitors (ESMO 2025) - "Results 53 pts (48 selpercatinib, 1 BOS172738, 1 selpercatinib & pralsetinib, 3 BOS172738 & pralsetinib) started RET TKI in Mar 2018 - Sep 2023 were included: 47 NSCLC (98% fusion; 2% exon 11 intron), 6 thyroid cancer (50% M918T, 33% fusion, 17% G634R/G533C). Optimal strategy for LPAE will be discussed. Legal entity responsible for the study The authors."

Adverse events • Clinical • HEOR • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • MET • NTRK

BOS172738, a selective RET inhibitor, for the treatment of patients with RET-altered tumors including RET-fusion-positive non-small-cell lung cancer and RET-mutant medullary thyroid cancer: a phase I dose-escalation/expansion multicenter study. (PubMed, ESMO Open) - "BOS172738 showed preliminary efficacy and a manageable safety profile in RET-altered tumors, including those resistant to prior therapies and in patients with brain metastases."

Clinical • Journal • P1 data • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1 | N=117 | Completed | Sponsor: Boston Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Aug 2024 ➔ Sep 2023 | Trial primary completion date: Mar 2024 ➔ Sep 2023

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: Boston Pharmaceuticals | Trial completion date: Apr 2023 ➔ Aug 2024 | Trial primary completion date: Apr 2023 ➔ Mar 2024

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: Boston Pharmaceuticals | Trial completion date: Dec 2022 ➔ Apr 2023 | Trial primary completion date: Dec 2022 ➔ Apr 2023

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

[VIRTUAL] BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results. (ASCO 2021) - P1 | "BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases . BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors."

P1 data • Anemia • Constipation • Endocrine Cancer • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Hypertension • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Medullary Carcinoma • KDR • RET

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: Boston Pharmaceuticals | Trial completion date: Jun 2022 ➔ Dec 2022 | Trial primary completion date: Jun 2022 ➔ Dec 2022

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1; N=117; Active, not recruiting; Sponsor: Boston Pharmaceuticals; Trial primary completion date: Dec 2021 ➔ Jun 2022

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

A Phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer. (ASCO 2019) - P1; "The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517"

Clinical • P1 data

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1; N=117; Active, not recruiting; Sponsor: Boston Pharmaceuticals; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2021 ➔ Jun 2022

Clinical • Enrollment closed • Trial completion date • Endocrine Cancer • Hematological Malignancies • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

[VIRTUAL] Lambert-Eaton-Myasthenic-Syndrome as an adverse effect of RET inhibitor therapy: a case report (EAN 2021) - " Case report After lymph node disease progression in 2019, a 28 year-old woman with metastatic medullary thyroid carcinoma diagnosed in 2012, received treatment with BOS172738 (a selective RET inhibitor)... As far as we know, this is the first described case suggesting an association between RET inhibitor therapy, a novel treatment for advanced tumors with RET gene alterations, and LEMS. Physicians should be aware of this possible adverse effect in patients who develop muscle weakness while undergoing RET inhibitor therapy."

Adverse events • Clinical • Cardiovascular • Endocrine Cancer • Gastrointestinal Disorder • Heart Failure • Hypertension • Musculoskeletal Pain • Myasthenia Gravis • Neuroendocrine Tumor • Oncology • Pain • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1; N=114; Recruiting; Sponsor: Boston Pharmaceuticals

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1; N=114; Recruiting; Sponsor: Boston Pharmaceuticals; Trial completion date: Jun 2021 ➔ Nov 2021; Trial primary completion date: Dec 2020 ➔ Nov 2021

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

Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors (clinicaltrials.gov) - P1; N=114; Recruiting; Sponsor: Boston Pharmaceuticals; Trial completion date: Nov 2020 ➔ Jun 2021; Trial primary completion date: May 2020 ➔ Dec 2020

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

BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development (AACR 2019) - "...BOS172738 (formerly DS-5010) is an orally available small-molecule RET kinase inhibitor that has previously been shown to have potent in vitro RET inhibitor activity and in vivo potency against transfected allograft and xenograft models...To confirm this selectivity in vitro, BOS172738 was compared to ponatinib, a multikinase inhibitor with potent activity against both KDR and RET... These results support that BOS172738 is a potent and selective RET kinase inhibitor, with strong antitumor activity against a range of RET fusion proteins, as well as resistant RET active site mutations. BOS172738 is currently being evaluated in a Phase 1 clinical study."

Clinical • P1 data