LBA3 - Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer

Background

Selpercatinib is a highly selective and potent RET inhibitor approved for treatment of advanced RET-mutant medullary thyroid carcinoma (MTC) but has not been directly compared with approved multikinase inhibitors (MKI).

Methods

LIBRETTO-531 (NCT04211337) is a randomized phase 3 study comparing first-line selpercatinib versus physician’s choice of cabozantinib or vandetanib. Eligible patients had kinase inhibitor-naïve progressive disease documented in the 14 months prior to enrollment. The pre-planned interim efficacy analysis occurred after 59 progression-free survival (PFS) events. The primary endpoint was blinded independent central review (BICR)-assessed PFS.

Results

In total, 291 patients were randomized. Baseline characteristics were well-balanced between study arms. At a median follow-up of 12 months, median PFS by BICR was not reached with selpercatinib remaining inestimable (95% CI: NE, NE) and was 16.8 months (95% CI: 12.2, 25.1) with control (HR: 0.280, 95% CI: 0.165, 0.475; P<.0001); by investigator assessment the HR was 0.187 (95% CI: 0.109, 0.321; P<.0001). BICR overall response rate (ORR) was 69.4% (95% CI: 62.4, 75.8) with selpercatinib compared to 38.8% (95% CI: 29.1, 49.2) with control (odds ratio 3.7, 95% CI, 2.2, 6.3; P<0.0001). At a median follow-up of 15 months, overall survival (OS) was better with selpercatinib (HR: 0.374, 95% CI: 0.147, 0.949). The most common treatment-emergent adverse events observed with selpercatinib were hypertension, dry mouth, and diarrhea; and with control, diarrhea, palmar-plantar erythrodysaesthesia syndrome, and hypertension. In total, 38.9% of patients treated with selpercatinib had a dose reduction (versus 77.3% in control) and 4.7% discontinued treatment due to an adverse event (versus 26.8% in control).

Conclusions

The study met the interim analysis criteria of efficacy. First-line selpercatinib delivered markedly prolonged PFS, improved ORR, and better OS compared with MKI. This study highlights the importance of selectivity in targeting RET-mutant MTC. Selpercatinib should be considered the preferred first-line standard of care for patients with advanced RET-mutant MTC.

Clinical trial identification

NCT04211337.

Editorial acknowledgement

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

J. Hadoux: Financial Interests, Personal, Advisory Board: IPSEN, Lilly, Pharma Mar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer; Financial Interests, Institutional, Advisory Board: EISAI, HRA pharma. R. Elisei: Financial Interests, Personal, Speaker, Consultant, Advisor, consulting fees: Eisai, Ipsen, Eli Lilly and Company, Loxo Oncology, Bayer, Roche; Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Eli Lilly and Company, Loxo Oncology, Bayer, Roche. M.S. Brose: Financial Interests, Institutional, Funding, grant funding: Eli Lilly and Company, Bayer/Loxo Oncology, Exelixis, Blueprint Medicines; Financial Interests, Personal, Speaker, Consultant, Advisor, consulting fees: Bayer, Eli Lilly and Company; Financial Interests, Personal, Advisory Board: Eli Lilly and Company, Bayer, Exelixis, Aadi. A. Hoff: Financial Interests, Personal, Advisory Board: Knight, Bayer; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Writing Engagement: Bayer; Financial Interests, Personal, Other, Libretto-531 - Steering Committee: Eli Lilly; Financial Interests, Institutional, Local PI, A Study of Selpercatinib (LY3527723) in Participants With RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531): Eli Lilly; Financial Interests, Institutional, Coordinating PI, A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects With Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed After Prior VEGFR-Targeted Therapy.: Exelixis; Financial Interests, Institutional, Local PI, Study of Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer.: Novartis; Other, Husband - President Oncologia D'OR: Oncologia D'OR. B. Robinson: Financial Interests, Personal, Leadership Role: Cochlear, Mayne Pharma; Financial Interests, Personal, Stocks or ownership: Cochlear, Mayne Pharma; Financial Interests, Personal, Advisory Board: Eisai, Loxo, Blueprint Medicines, Lilly; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Eisai. B. Jarzab: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting: EwoPharma, IPSEN; Financial Interests, Personal, Advisory Board: Sobi; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Amgen, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Oxigene, Pfizer, Elli Lilly; Financial Interests, Research Funding: AstraZeneca, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Pfizer, Elli Lilly; Financial Interests, Other, clinical trials: AstraZeneca, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Pfizer, Elli Lilly. K. Kopeckova: Financial Interests, Personal, Expert Testimony, Treatment of thyroid cancer: Eli Lilly; Financial Interests, Personal, Advisory Board, Systemic treatment of DTC: Ipsen; Financial Interests, Personal, Invited Speaker, Breast Cancer Treatment with PARP inhibitors: AstraZeneca; Financial Interests, Personal, Other, International collaboration for thyroid cancer: EISAI. J. Wadsley: Financial Interests, Institutional, Invited Speaker, Have regularly spoken at the invitation of Lilly, and attended advisory boards: Lilly; Financial Interests, Institutional, Invited Speaker, Have regularly spoken on behalf of AAA and attended advisory boards: Novartis (AAA); Financial Interests, Institutional, Invited Speaker: Bayer, Roche, AstraZeneca, Incyte; Financial Interests, Institutional, Invited Speaker, Have been invited to speak and to advisory boards: Eisai; Financial Interests, Institutional, Advisory Board: Ipsen; Financial Interests, Personal and Institutional, Invited Speaker, Funding received to run SELIMETRY trial: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, Funding received to support SELIMETRY trial: Sanofi Genzyme; Non-Financial Interests, Principal Investigator, Local PI for LIBRETTO 531 trial: Lilly. D. Führer: Financial Interests, Personal, Advisory Board, honoraria for advisory board: Lilly, Roche, Ipsen, Eisai, Novartis; Financial Interests, Personal, Speaker’s Bureau: Lilly, Roche, Ipsen, Eisai, Novartis. B. Keam: Financial Interests, Personal, Invited Speaker: Merck, Lily, MSD Oncology, AstraZeneca, Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Handok, TrialInformatics, ImmunOncia, NeoImmunetech, Beigen. E.J. Sherman: Financial Interests, Personal, Advisory Board: Eisai, Roche, Regeneron, Exelixis, Bayer; Financial Interests, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Regeneron; Financial Interests, Institutional, Invited Speaker, Also Local PI: Eli Lilly; Non-Financial Interests, Principal Investigator, PI of randomized study in thyroid cancer: Novartis. M. Tahara: Financial Interests, Personal, Advisory Board: Merck Biopharma, Ono pharma, Bristol- Myers Squibb, MSD, Pfizer, Bayer, Lilly, Rakuten Medical, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Ono Pharma, Novartis, Pfizer, Bristol-Myers Squibb, Loxo, GSK, Lilly, Rakuten Medical, Bayer; Financial Interests, Institutional, Research Grant: Bayer. M.I. Hu: Financial Interests, Steering Committee Member: Eli Lilly & Co; Financial Interests, Institutional, Local PI: Eli Lilly & Co; Other, Co-chair of writing committee for the update of the American Thyroid Association guidelines on systemic therapies for medullary thyroid cancer (non-financial): American Thyroid Association. Y. Lin: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. P. Maeda: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. L.J. Wirth: Financial Interests, Personal, Advisory Board: Bayer, Coherus, Eli Lilly, Eisai, Exelixis; Financial Interests, Personal, Other, Consultant: Curie Therapeutics, Morphic Therapeutics, Tome Biosciences; Financial Interests, Personal, Other, DMSC: PDS Biotherapeutics; Financial Interests, Institutional, Steering Committee Member: Novartis, Eli Lilly. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. All other authors have declared no conflicts of interest.