Firstline Retevmo Improves Survival Rates Without Disease Progression in Select Patients With Thyroid Cancer

Compared with Cabometyx (cabozantinib) or Caprelsa (vandetanib), Retevmo (selpercatinib) improved progression-free survival (PFS; the time during and after treatment when a patient with cancer lives without disease worsening) and overall response rate (ORR; the percentage of patients who had a complete or partial response to treatment) in patients with advanced RET-mutant medullary thyroid cancer who have never been treated with a multikinase inhibitor, recent study findings demonstrated.

The data, which were presented during the 2023 ESMO Congress, showed that at a median follow-up of 12 months, the median PFS was not reached with Retevmo (meaning that more than half of patients did not experience this end point when it was assessed by researchers) versus 16.8 months in the kinase inhibitor arm, leading to a 72% reduction in the risk of disease progression or death.

“(Retevmo), a selective RET inhibitor, provides prolonged PFS, prolonged treatment failure-free survival, higher ORR, and a favorable safety profile as compared with multikinase inhibitors for the first-line treatment of patients with RET-mutant medullary thyroid carcinoma,” Dr. Julien Hadoux, lead study author, medical oncologist and attending physician at Gustave Roussy in Villejuif, France, said in a presentation during the meeting. “These results, therefore, support (Retevmo) as the first-line standard of care for patients with advanced RET-mutant medullary thyroid cancer.”

In the phase 3 LIBRETTO-531 trial, investigators sought to define the optimal first-line regimen for patients with advanced RET-mutant medullary thyroid cancer. To be eligible for enrollment, patients must have had unresectable locally advanced or metastatic RET-mutant medullary thyroid cancer who had progressive disease via RECIST v1.1 criteria that was documented in the 14 months prior to study enrollment. Patients could not have previously received a kinase inhibitor.

A total of 291 patients with advanced RET-mutant medullary thyroid cancer were randomized to receive Retevmo at 160 milligrams twice daily (193 patients) or physician’s choice of Cabometyx at 140 milligrams daily or Caprelsa at 300 milligrams daily (98 patients) in the first-line setting.

The primary end point was PFS. Secondary end points were treatment failure-free survival (TFFS) and investigator-assessed PFS, overall survival (OS; the time after treatment started when a patient with cancer is still alive) and safety.

Baseline characteristics showed that the median age between both arms was 54.6 years, with approximately one-fourth of patients at least 65 years old. A total 62.5% of patients had a RET M918T mutation.

Additional efficacy findings showed that the PFS benefit with the highly selective, potent RET inhibitor was also observed via investigator assessment. Retevmo also improved PFS across all prespecified subgroups, especially in those with a RET commutation beyond M918T.

At a median 15 months of follow-up, eight deaths occurred on the Retevmo arm versus 10 on the control arm; 94.8% and 85.7% of patients on each arm are alive, respectively. Hadoux cautioned that the data are immature due to a censoring date of 90% but highlighted that OS favored Retevmo. Of the 24 patients who crossed over to received Retevmo, 19 remained on treatment as of the data cutoff date.

TFFS was defined as the time from randomization to the first occurrence of progressive disease assessed, discontinuation due to treatment-related side effect or death. The median TFFS was not reached with Retevmo versus 13.9 months with Cabometyx or Caprelsa, which was also reported to be statistically significant. When assessed via investigator, the TFFS benefit with Retevmo was similar.

The ORR was 69.4% with Retevmo compared with 38.8% with the kinase inhibitor group. The complete response rate (the disappearance of all signs of cancer from treatment) was 11.9% with Retevmo versus 4.1% in the control group; partial response rates (a decrease in tumor size from treatment) were 57.5% and 34.7%, respectively. The median duration of response (the time from the onset of response to either progression or death) was not reached with Retevmo compared with 16.6 months with Cabometyx or Caprelsa.

Regarding safety, severe or worse common treatment-emergent side effects occurred in 52.8% and 76.3% of patients on Retevmo and Cabometyx/Caprelsa, respectively; severe or worse treatment-emergent side effects occurred in 52.8% and 76.3% of patients, respectively. The most common severe or worse treatment-emergent side effects with Retevmo were high blood pressure (19%), alanine aminotransferase increase (10%; indicating liver disease), aspartate aminotransferase increase (5%; indicating liver damage), fatigue (4%) and diarrhea (3%). In the control arm, these included high blood pressure (18%), mucosal inflammation (13%; inflammation of the membranes that line the mouth and the gastrointestinal tract), hand-foot syndrome (9%) and diarrhea (8%).

Dose reductions due to side effects occurred in 38.9%, 79.2% and 71.0% of patients on Retevmo, Cabometyx and Caprelsa, respectively; the discontinuation rates due to side effects occurred in 4.7% and 26.8% of patients, respectively. Four patients on Retevmo died due to side effects versus two on the control arm.

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