RET V804M

Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease.

Coexistence of MTC and PTC in germline RET mutation is an uncommon association and more information is required to understand common features, risk factors, phenotype and cancer aggressiveness in these patients. At this point it cannot be concluded that the association is a mere coincidence.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.

Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. 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. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.

Despite the controversy and the heterogeneous presentation of patients with RET p.V804M mutation, our study and review of the literature suggest that this seemingly "low" risk mutation is associated with late-onset but potentially aggressive MTC. This indicates the need for follow-up and timely intervention based on calcitonin level elevation.

This study is active and recruiting, with planned enrollment of 400 participants at ~150 sites in 21 countries. In response to the global COVID-19 pandemic, mitigations for patient safety are included in the protocol.

Currently, several approved multikinase inhibitors such as vandetanib and cabozantinib demonstrate clinical activity in patients with RET-rearranged or RET-mutant cancers...Herein, we designed and synthesized a series of RET inhibitors based on the structure of selective RET inhibitor BLU-667 and investigated their biological activities...In mouse xenograft models, compound 9 repressed tumor growth driven by KIF5B-RET-Ba/F3 cells in a dose-dependent manner. Based on its exceptional kinase selectivity, good potency and high exposure in tumor tissues, compound 9 represents a promising lead for the discovery of RET directed therapeutic agents and the study of RET-driven tumor biology.

Previous studies in pts treated with selpercatinib or pralsetinib have reported the shared emergence of recurrent RET G810 mutations at the solvent front of the ATP pocket, which lead to a steric clash and loss of binding potency for both drugs. These data suggest that LOX-18228, as well as closely related compounds, represent promising next-generation RET inhibitor candidates that could be used to further extend durable disease control for pts with RET-altered cancers following the development of acquired resistance to current agents. An IND is planned for 2021.

In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.

Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.

This global, open-label, randomized, controlled, phase III trial will compare selpercatinib to physician choice of cabozantinib or vandetanib in pts with MKI-naïve progressive advanced or metastatic RETmut MTC...Funding: Eli Lilly and Company. Clinical trial identification: NCT04211337.

Among the primary analysis set of patients with RET-mutant MTC previously treated with cabozantinib and/or vandetanib (N=55), the investigator-assessed objective response rate (ORR) per RECIST 1.1 was 56% (95% CI 42.3-69.7, n=31/55)...As previously reported, selpercatinib was well tolerated with an acceptable safety profile (1). These results indicate broad anti-tumor activity for selpercatinib in patients with RET-mutant MTC irrespective of the specific RET mutation, and support implementation of RET mutation testing for patients with advanced MTC, including somatic testing, to identify patients who may benefit from selpercatinib.