Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Abstract
PMID
Authors Vivek Subbiah, Jun Zhong, Ying Lu, Yongbo Liu, Minchun Chen, Xiaohu Chen, Hao Wang, John Zhu, Shun Lu, Alexander E. Drilon
Title The development of APS03118, a potent next-generation RET inhibitor for treating RET-inhibitor-resistant patients.
Journal Journal of Clinical Oncology
Vol 40
Issue 16
Date June 1, 2022
URL https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.e15107
Abstract Text Background: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 < 15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited the proliferation of KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 < 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models at 10 mg/kg (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. The pharmacokinetic/pharmacodynamic relationship of APS03118 in Ba/F3 KIF5B-RET G810R and WT xenograft tumor model was investigated, and the sustained decrease of the phosphorylated RET were observed at 30 mg/kg with the plasma exposure exceed cell IC90. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. APS03118 has received IND approval and Fast Track Designation from FDA, and a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
APS03118 APS 03118|APS-03118 RET Inhibitor 47 APS03118 is a RET inhibitor with activity against RET fusions and gatekeeper mutations, potentially inhibiting phosphorylation, proliferation, and tumor growth (J Clin Oncol 40, no. 16_suppl (June 1, 2022)).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET G810C Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET G810C in an in vitro assay (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET V804E Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET V804E in an in vitro assay (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET C634W thyroid gland cancer predicted - sensitive APS03118 Preclinical - Cell line xenograft Actionable In a preclinical study, APS03118 treatment inhibited proliferation of a thyroid cancer cell line harboring RET C634W in culture and inhibited tumor growth in a xenograft model (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET M918T Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 treatment inhibited Ret phosphorylation in cells expressing RET M918T in culture (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET V804L Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET V804L in an in vitro assay (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET G810S Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Cell culture Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET G810S in an in vitro assay and inhibited proliferation of cells expressing RET G810S in culture (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET G810R Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Cell culture Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET G810R in an in vitro assay and inhibited Ret phosphorylation and proliferation of cells expressing RET G810R in culture (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...
RET V804M Advanced Solid Tumor predicted - sensitive APS03118 Preclinical - Biochemical Actionable In a preclinical study, APS03118 inhibited the enzymatic activity of RET V804M in an in vitro assay, inhibited Ret phosphorylation in cells expressing RET V804M in culture, and inhibited tumor growth in cell line xenograft models expressing RET V804M (J Clin Oncol 40, no. 16_suppl (June 1, 2022)). detail...