Abstract 1652P
Background
Medullary thyroid cancer (MTC) is a rare subtype of thyroid cancer characterized by a high frequency of molecular alteration (MA) in the RET oncogene. Recently, Ret specific inhibitors (RETi) have emerged as an effective treatment in phase I/II trial. However, resistance almost invariably occurs.
Methods
Monocentric retrospective study of MTC patients (pts) who discontinued RETi and were included in a personalized medicine study (NCT04932525). The cause of RETi discontinuation, baseline RET mutational status, molecular profile (MP) and pathology specimen pre and post RETi when available were analyzed. MP were obtained by next generation sequencing analysis performed on either tissue or blood.
Results
Among 47 MTC pts who started RETi between March 2018 and March 2022, 19 pts (7 females, median age 63) discontinued RETi because of progression (PD) (n=12), death (4) and toxicity (2), one patient was lost to follow-up and excluded. RET mutations (2 germline and 16 somatic) were: p.M918T (12), p.C634F/R/W (4), p.C611W (1), p.V804L (1) and p.A883F (1). Pts received RETi after a median number of 1 treatment line (range 0-6) and 83% had received vandetanib (V) prior to RETi. Under RETi, there were 44% partial responses (n=8), 28% stable disease (n=5) and 28% non-evaluable (4 MTC-related death and 1 toxicity arrest). The median duration of RETi was 10.5 months (range 0.6-42). Baseline MP were obtained after a median of 32.5 months from first line therapy and 7 months, in median before RETi. Comparison of baseline and post RETi MP, available in 10/18 pts, revealed an acquired MA, potentially related to a mechanism of resistance in all 8 pts who discontinued because of PD: KRAS p.G12D (n=4), HRAS p.A59T, RET p.G810N, RET p.G810S (co-occurred with KRAS p.G12D), RET p.Y806C and MYC p.P44L. Serial longitudinal tumor samples at thyroidectomy, post V and post RETi, available for 6 pts, showed an increase of the mean Ki67-index of 7%, 17% and 40%, respectively (p=0.042) and a more aggressive poorly differentiated histology post RETi in 3 pts.
Conclusions
By-pass resistance MA may be the most frequent mechanism of PD under RETi and more aggressive histology may arise following PD; these results warrant further explorations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Hadoux: Financial Interests, Personal, Advisory Board: Ipsen, Lilly, PharmaMar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer. L. Lamartina: Financial Interests, Personal, Advisory Board: Eisai, Bayer; Financial Interests, Institutional, Invited Speaker: Exelixis, Eisai, Sanofi, bayer. M. Aldea: Financial Interests, Institutional, Research Grant: Sandoz; Financial Interests, Institutional, Funding: Sandoz. L. Friboulet: Financial Interests, Institutional, Research Grant: Debiopharm, Incyte, Relay Therapeutics, Nuvalent. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. E. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis - AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. All other authors have declared no conflicts of interest.