Clinical trialPhase 3Thyroid cancer

Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer

N Engl J Med · 2023291 patients

Hadoux J, Elisei R, Brose MS, et al. N Engl J Med. 2023. 389:1851-1861

Study type: Clinical trial
Study name: LIBRETTO-531
Phase: Phase 3
Design: Randomised open-label trial (2:1 randomisation, stratified by RET mutation type [M918T versus other] and intended control drug), comparing first-line selpercatinib with cabozantinib or vandetanib at the physician's choice; crossover to selpercatinib allowed after progression in the control group; prespecified interim analysis
Sample size: 291 patients
Source: N Engl J Med · 2023
Trial registration: NCT04211337

In plain words

Medullary thyroid cancer is a less common type of thyroid cancer, and in many patients with advanced disease it carries a mutation in the RET gene. Selpercatinib is a tablet that specifically targets this faulty protein. In this trial, selpercatinib was compared with older drugs (cabozantinib or vandetanib): the disease stayed under control for much longer, the tumour shrank in about 7 out of 10 patients, and fewer patients had to lower the dose or stop the drug because of side effects. Before using this drug, the RET mutation must first be confirmed by a genetic test of the tumour or blood.

Key results

Not reached vs 16.8 months

Median progression-free survival

HR 0.28; 95% CI 0.16–0.48; P<0.001; median follow-up 12 months

86.8% vs 65.7%

12-month progression-free survival

95% CI 79.8-91.6 vs 51.9-76.4

Median not reached vs 13.9 months

Treatment failure-free survival

HR 0.25; 95% CI 0.15–0.42; P<0.001; 12-month rate 86.2% vs 62.1%

69.4% vs 38.8%

Overall response

95% CI 62.4-75.8 vs 29.1-49.2

12% vs 4%

Complete response

FDA label; median duration of response: not reached vs 16.6 months

Immature at the interim analysis

Overall survival

FDA label: 18 deaths (14% of prespecified events)

Dose and schedule cards

Selpercatinib (LIBRETTO-531)

Advanced or metastatic RET-mutant medullary thyroid cancer requiring systemic therapy; or advanced RET fusion-positive thyroid cancer (in differentiated thyroid cancer: radioactive iodine-refractory or ineligible)Cycle length: ContinuousOn the page “Thyroid cancer” · Advanced or metastatic medullary thyroid cancer

Drug	Dose	Route	Schedule
Selpercatinib	120 mg (weight <50 kg) or 160 mg (≥50 kg)	Oral	Twice daily, continuously

Cycle length: Continuous
Duration: Until disease progression or unacceptable toxicity

Source: FDA label; LIBRETTO-531. ALT/AST before starting, every 2 weeks during the first 3 months and then monthly; monitor blood pressure and QTc. Avoid PPIs, H2 antihistamines and antacids; if unavoidable: take with food when on a PPI, 2 hours before or 10 hours after an H2 blocker, and 2 hours before or after an antacid.

On the page “Thyroid cancer” · Advanced or metastatic medullary thyroid cancer

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Selpercatinib

Oral selpercatinib 160 mg twice daily, continuously in 28-day cycles, until radiological progression, unacceptable toxicity, withdrawal or death. Adolescent dose (from age 12): 92 mg/m² twice daily (maximum 160 mg twice daily).

Note: the current FDA label sets the dose for adults and adolescents 12 years and older by weight: below 50 kg, 120 mg twice daily; 50 kg or more, 160 mg twice daily; the dose is reduced in severe hepatic impairment.

2Control group: cabozantinib or vandetanib at the physician's choice

The control drug was chosen before randomisation: oral cabozantinib 140 mg once daily, or oral vandetanib 300 mg once daily (starting dose 200 mg once daily if creatinine clearance was below 50 mL/min), both continuously in 28-day cycles until progression or unacceptable toxicity. Adolescent doses: cabozantinib 40 mg/m²; vandetanib by body surface area (0.7 to less than 0.9 m²: 100 mg every other day; 0.9 to less than 1.2: 100 mg daily; 1.2 to less than 1.6: 7-day schedule alternating 100 and 200 mg; 1.6 or more: 200 mg daily). Crossover to selpercatinib was allowed after progression confirmed by central review.

Source of the regimen details: ClinicalTrials.gov NCT04211337 (arms and adolescent dosing); LIBRETTO-531 trial design paper (Future Oncol 2022, PMC10652291; dose and schedule table: 28-day cycle and vandetanib dose at CrCl below 50); FDA label for selpercatinib (RETEVMO, DailyMed). The full text of the NEJM paper was not available in PMC.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 years and older (from age 12 where local regulations allowed) with unresectable, locally advanced and/or metastatic medullary thyroid cancer with a RET alteration (in tumour, germline DNA or blood sample), with no prior kinase inhibitor therapy for advanced disease, with radiological progression by RECIST 1.1 compared with an image from the previous 14 months (independent central assessment) and ECOG performance status 0 to 2. Measurable or non-measurable but evaluable disease was allowed (but not bone-only disease). Exclusion criteria: another valid oncogenic driver (such as a RAS or BRAF mutation or an NTRK fusion), symptomatic central nervous system metastases, significant active cardiovascular disease or infarction within 6 months, history of torsades de pointes, QTcF above 470 ms on more than one ECG (and above 450 ms for patients who would receive vandetanib if assigned to the control group) and active bleeding (criteria from ClinicalTrials.gov). According to the FDA label, 63% of patients had the M918T mutation, 98% were ECOG 0 to 1 and only 2.1% had one prior systemic therapy.

Endpoints

Primary endpoint at the prespecified interim analysis: progression-free survival by blinded independent central review. Alpha-controlled secondary endpoint: treatment failure-free survival (tested only if progression-free survival was significant). Other secondary endpoints: overall response and safety.

Safety and side effects

Adverse events led to dose reduction in 38.9% of the selpercatinib group versus 77.3% of the control group, and to treatment discontinuation in 4.7% versus 26.8% (abstract).

According to the FDA label (193 selpercatinib patients versus 97 control patients), grade 3 to 4 adverse events: hypertension 19% versus 18%, ECG QT prolongation 4.7% versus 2.1%, fatigue 4.1% versus 9%, diarrhoea 3.1% versus 8%, stomatitis 0.5% versus 13% and nausea 1.0% versus 5%; grade 3 to 4 ALT increase (laboratory) 16% versus 7%. Oedema (any grade, 33% versus 5%) and dry mouth (32% versus 10%) were more common with selpercatinib. In the selpercatinib group, serious adverse events occurred in 22% and fatal adverse events in 2.1%; dose interruption 49% and dose reduction 39%. Important label warnings: hepatotoxicity, interstitial lung disease/pneumonitis, hypertension, QT prolongation, haemorrhage, hypersensitivity, tumour lysis syndrome, impaired wound healing, hypothyroidism and slipped capital femoral epiphysis in adolescents.

Clinical significance and place in guidelines

The FDA had previously, in 2020, granted accelerated approval to selpercatinib (Retevmo) for RET-mutant medullary thyroid cancer; based on the LIBRETTO-531 results, traditional approval was granted on 27 September 2024 for adults and children 2 years and older with advanced or metastatic RET-mutant medullary thyroid cancer (detected by an FDA-approved test) who require systemic therapy. This trial was the first head-to-head comparison of a selective RET inhibitor with standard multikinase inhibitors and strengthened the place of selpercatinib as first-line therapy in these patients.

Limitations

The results are from an interim analysis with a median follow-up of 12 months and overall survival data were not yet mature; crossover of control-group patients to selpercatinib also complicates interpretation of overall survival. The design was open-label (unblinded), although the primary endpoint was assessed by blinded independent central review. The results apply only to patients with a RET mutation.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.