Re: "A Case Report of Poor Response to Selpercatinib in the Presence of a 632_633 RET Deletion" by Wijewardene Et Al.

ThyroidAhead of Print Open AccessCreative Commons licenseRe: “A Case Report of Poor Response to Selpercatinib in the Presence of a 632_633 RET Deletion” by Wijewardene et al.Sylwia Szymczak, Anna Szpurka, Zhao Hai Lu, and Jack A. DempseySylwia SzymczakAddress correspondence to: Sylwia Szymczak, PhD, Eli Lilly Polska, Department of Clinical Operations, Zwirki i Wigury 18a, 02-092 Warsaw, Poland E-mail Address: [email protected]https://orcid.org/0009-0001-5830-6446Eli Lilly Polska, Department of Clinical Operations, Warsaw, Poland.Search for more papers by this author, Anna SzpurkaEli Lilly and Company, Indianapolis, Indiana, USA.Search for more papers by this author, Zhao Hai LuEli Lilly and Company, Indianapolis, Indiana, USA.Search for more papers by this author, and Jack A. DempseyEli Lilly and Company, Indianapolis, Indiana, USA.Search for more papers by this authorPublished Online:22 Aug 2023https://doi.org/10.1089/thy.2023.0258AboutSectionsPDF/EPUB Permissions & CitationsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Dear Editor:In this letter to the editor, we wish to provide additional information and clarification relevant to the article by Wijewardene et al. entitled “A case report of poor response to selpercatinib in the presence of a 632_633 RET deletion” published in Thyroid in January 2023.1Experimental evidence and clinical observations from the LIBRETTO-0012 trial suggest that the RET p.632_633del mutation is neither rare in patients with medullary thyroid cancer (MTC) nor is it resistant to therapeutic intervention with the highly selective and potent REarranged during Transfection (RET)-inhibitor selpercatinib, a conclusion that is contrary to that presented in the mentioned case report. Findings by Elisei et al. show that such MTC-harboring somatic RET indels are common and can contribute to aggressive disease characteristics but respond to treatment with highly selective RET inhibitors.3Among 319 MTC patients enrolled in the LIBRETTO-001 study, 9 MTC patients harbored p.632_633del RET mutation at exon 11 (c.1894_1899 del GAGCTG), all of whom derived clinical benefit from selpercatinib treatment. Baseline Eastern Cooperative Oncology Group for all 9 patients was 0–1 and all patients were treated at a dose of 160 mg selpercatinib twice a day (BID). Before receiving selpercatinib, 6 of the 9 patients were pretreated with the multikinase inhibitor vandetanib, achieving a best overall response of 1 partial response (PR), 3 stable disease (SD), and 2 progressive disease.After treatment with selpercatinib, 7 of the 9 patients had a PR (78%), and 2 maintained SD for at least 16 weeks (44 and 144 weeks, respectively). Median duration of response (DOR) was 28 months (4–42). This median DOR is comparable with the DOR observed in the overall MTC population (Retsevmo SmPC4), as well as in MTC patients with other mutations in extracellular cysteine-rich domain (CRD) of RET (Fig. 1A). The time on treatment of patients with p.632_633del RET mutation ranged from 12 to 50 months (median 38 months). Median progression-free survival was 31 months (10–45).FIG. 1. (A) Median DOR in months for all MTC RET mutants affecting the extracellular cysteine-rich domain (exons 8–11) from LIBRETTO-001. The median DOR for all cysteine-rich domain mutants is shown by black bars. Median DOR for RET (E632_L633 del) is comparable with the DOR of the overall MTC population and MTC patients with other mutations in the extracellular cysteine-rich domain. (B) Various RET mutants or RET fusion KIF5B-RET-transformed Ba/F3 cells were treated with selpercatinib. (C) RET (E632_L633 del)-transformed Ba/F3 cells were treated with tyrosine kinase inhibitors. (D) IC50 value summary. To assess the growth inhibitory effect of kinase inhibitors, transformed Ba/F3 cells were treated with various concentrations of compound in IL-3-free medium for 96 hours. Cell viability was measured by CellTiter-Glo assay at the end of treatment, and IC50 values were generated for each compound with Prism GraphPad. Data are presented as mean ± SD. DMSO, dimethyl sulfoxide; DOR, duration of response; IC50, half-maximal inhibitory concentration; IL-3, interleukin-3; MTC, medullary thyroid cancer; RET, REarranged during Transfection; SD, standard deviation.As of January 9, 2023, 6 patients were alive, while 4 continued to receive selpercatinib. The study received approval from ethics committee(s) in respective institutions and was conducted in accordance with the Declaration of Helsinki 174 of 1964, and all applicable country and local regulations. All patients provided written informed consent for study participation. Clinical outcomes of MTC patients with other mutations in the extracellular CRD of RET enrolled to the LIBRETTO-001 study suggest that this receptor with a 6-base pair in-frame deletion responds to RET kinase inhibition in a manner similar to cysteine substitutions and other deletions and insertions in the CRD.These observations of clinical efficacy of selpercatinib in MTC patients with RET E632_L633del are supported by preclinical data from a functional assay on Ba/F3 cells transformed with RET (E632_L633del) or other relevant RET alterations. Results showed that interleukin-3 independent proliferation of RET (E632_L633del)-transformed Ba/F3 cells was potently inhibited by selpercatinib. The IC50 value for RET (E632_L633del) was consistently at ∼16 nM and was 4- to 5-fold higher than those for RET (M918T) and RET (C618R), but comparable with KIF5B-RET (Fig. 1A–C).At concentrations >33 nM, selpercatinib completely abolished RET kinase-driven Ba/F3 cell proliferation regardless which RET mutant was assessed. At the clinical dose of 160 mg, concentration of selpercatinib is estimated to reach and maintain at >100 nM, which is sufficiently higher than the maximal inhibitory concentration for RET (E632_L633del) as determined by this cell-based assay. Results further showed that selpercatinib was more active against RET (E632_L633del) than multityrosine kinase inhibitors such as cabozantinib, vandetanib, or lenvatinib in this assay (Fig. 1C, D).Based on this larger set of MTC patients harboring the p.632_633del RET mutation, we provide evidence that these patients received benefit from treatment with selpercatinib. Our results may dispute the proposed association between the p.632_633del RET mutation and poor selpercatinib response in the MTC patient presented in the report by Wijewardene et al.1Authors' ContributionsS.S. and A.S. contributed to conceptualization (equal), writing–original draft (equal), and review and editing (equal). Z.H.L. and J.A.D. were involved in methodology (equal) and review and editing (equal).Author Disclosure StatementAll authors are employees of Eli Lilly and Company.Funding InformationAll authors received funding from Eli Lilly and Company.References1. Wijewardene A, Bastard K, Wang B, et al. A case report of poor response to selpercatinib in the presence of a 632_633 RET deletion. Thyroid 2023;33(1):119–125; doi: 10.1089/thy.2021.0680. Link, Google Scholar2. National Library of Medicine (U.S.). A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). Identifier NCT03157128, 2017. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT03157128 [Last accessed: July 12, 2023]. Google Scholar3. Elisei R, Ciampi R, Matrone A, et al. Somatic RET indels in sporadic medullary thyroid cancer: Prevalence and response to selpercatinib. J Clin Endocrinol Metab 2022;107(8):2195–2202; doi: 10.1210/clinem/dgac325. Crossref, Medline, Google Scholar4. European Medicines Agency. Retsevmo Summary of Product Characteristics (SmPC). 2023. Available from: Retsevmo | European Medicines Agency (europa.eu) [Last accessed: June 22, 2023]. Google ScholarFiguresReferencesRelatedDetails Volume 0Issue 0 Information© Sylwia Szymczak et al. 2023; Published by Mary Ann Liebert, Inc.To cite this article:Sylwia Szymczak, Anna Szpurka, Zhao Hai Lu, and Jack A. Dempsey.Re: “A Case Report of Poor Response to Selpercatinib in the Presence of a 632_633 RET Deletion” by Wijewardene et al..Thyroid®.ahead of printhttp://doi.org/10.1089/thy.2023.0258creative commons licenseOnline Ahead of Print:August 22, 2023Online Ahead of Editing: June 27, 2023Open accessThis Open Access article is distributed under the terms of the Creative Commons License [CC-BY] ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PDF download