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Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer
Julien Hadoux1, Rossella Elisei1, Marcia S Brose1
1From the Service d'oncologie endocrinienne, département d'imagerie, Gustave Roussy and ENDOCAN-TUTHYREF Network, Villejuif (J.H.), and the Nuclear Medicine Department and Thyroid Unit, Centre François Baclesse, Caen (S.B.) - both in France; the Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (R.E.); the Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia (M.S.B.); the Department of Endocrinology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, and Instituto D'Or de Pesquisa e Ensino - both in São Paulo (A.O.H.); Sydney Medical School, University of Sydney, Sydney (B.G.R.); the Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China (M.G.); the Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology, Gliwice Branch, Poland (B.J.); Federal State Institution Medical Radiology Research Center, Obninsk, Russia (P.I.); the Department of Oncology, 2nd Faculty of Medicine of Charles University and Motol University Hospital, Prague, Czech Republic (K.K.); the Clinical Oncology Department, Weston Park Cancer Center, NHS Foundation Trust, Sheffield, United Kingdom (J.W.); the Department of Endocrinology Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (D.F.); the Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea (B.K.); the Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (E.J.S.); the Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan (M.T.); the Endocrine Neoplasia and Hormonal Disorders Department, University of Texas M.D. Anderson Cancer Center, Houston (M.I.H.); Eli Lilly, Indianapolis (R.S., Y.L., V.S., J.W., B.L., P.M.); the Medical Oncology Department, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona (J.C.); and the Cancer Center, Massachusetts General Hospital, Boston (L.J.W.).
Background:
Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear.
Methods:
We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.
Results:
A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.
Conclusions:
Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).
Insights
Selpercatinib significantly improved progression-free survival and treatment failure-free survival in patients with advanced RET-mutant medullary thyroid cancer compared to standard therapies. This RET inhibitor offers a superior treatment option for this rare cancer.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Advanced RET-mutant medullary thyroid cancer (MTC) presents a therapeutic challenge.
- Selpercatinib is a selective RET inhibitor with demonstrated efficacy in MTC.
- Comparative efficacy against approved multikinase inhibitors was previously unclear.
Purpose of the Study:
- To compare the efficacy of selpercatinib with cabozantinib or vandetanib as first-line therapy for advanced RET-mutant MTC.
- To evaluate progression-free survival (PFS) as the primary endpoint.
- To assess treatment failure-free survival (TFFS), overall response, and safety.
Main Methods:
- Phase 3, randomized trial design.
- 291 patients with progressive RET-mutant MTC randomized to selpercatinib or physician's choice of cabozantinib/vandetanib.
- Primary endpoint: PFS by blinded independent central review. Secondary endpoints: TFFS, overall response, safety.
Main Results:
- Selpercatinib demonstrated superior PFS (not reached vs. 16.8 months) and TFFS (not reached vs. 13.9 months) compared to control (P<0.001 for both).
- 12-month PFS was 86.8% for selpercatinib vs. 65.7% for control.
- Overall response rates were 69.4% for selpercatinib vs. 38.8% for control, with fewer dose reductions and discontinuations due to adverse events.
Conclusions:
- Selpercatinib significantly improves PFS and TFFS in patients with RET-mutant MTC.
- Selpercatinib represents a superior first-line treatment option compared to cabozantinib or vandetanib.
- The safety profile of selpercatinib was more favorable, with lower rates of dose modification and treatment discontinuation.
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