A landmark phase 3 randomized clinical trial has demonstrated the superiority of selpercatinib, a highly selective RET inhibitor, over standard multikinase inhibitors for the first-line treatment of advanced RET-mutant medullary thyroid cancer. The study, known as LIBRETTO-531, was published on November 16, 2023 in The New England Journal of Medicine.
This global, open-label trial enrolled 291 patients across 176 centers in 19 countries. Participants had progressive, locally advanced or metastatic RET-mutant medullary thyroid cancer and had not previously received treatment with kinase inhibitors. The study was funded by Loxo Oncology, a subsidiary of Eli Lilly.
The primary purpose of the trial was to compare the efficacy and safety of selpercatinib to the current standard of care - either cabozantinib or vandetanib - as first-line therapy. Patients were randomized in a 2:1 ratio to receive either selpercatinib (160 mg twice daily) or the treating physician's choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily).
To be eligible for the study, patients had to be at least 12 years old (where permitted by local regulations; otherwise 18 or older) with pathologically confirmed, unresectable, locally advanced or metastatic medullary thyroid cancer. They were required to have radiologic evidence of disease progression within the previous 14 months, as confirmed by blinded independent central review. A key inclusion criterion was the presence of a prospectively identified pathogenic RET alteration, either somatic or germline.
The demographic characteristics of the participants were well-balanced between the treatment arms, with a few exceptions. The median age was 56 years in the selpercatinib group and 54 years in the control group. Most patients were male (59.6% in the selpercatinib group and 69.4% in the control group), white (60.1% and 53.1% respectively), and younger than 65 years old. The most common RET mutation was M918T, present in about 62% of patients in both groups.
The primary endpoint of the study was progression-free survival as assessed by blinded independent central review. At a median follow-up of 12 months, the results were striking. The median progression-free survival was not reached in the selpercatinib group, compared to 16.8 months in the control group. This translated to a hazard ratio for disease progression or death of 0.28 (95% CI, 0.16 to 0.48; P<0.001), indicating a 72% reduction in the risk of disease progression or death with selpercatinib.
The 12-month progression-free survival rate was 86.8% in the selpercatinib group versus 65.7% in the control group. At 24 months, these rates were 76.4% and 37.2% respectively, demonstrating a sustained benefit with selpercatinib.
A key secondary endpoint was treatment failure-free survival, which accounted for both disease progression and treatment discontinuation due to adverse events. This endpoint also strongly favored selpercatinib, with a hazard ratio of 0.25 (95% CI, 0.15 to 0.42; P<0.001).
The overall response rate was significantly higher with selpercatinib (69.4%) compared to the control group (38.8%). Notably, 11.9% of patients in the selpercatinib group achieved a complete response, versus 4.1% in the control group.
The safety profile of selpercatinib was generally more favorable than that of the multikinase inhibitors. The incidence of grade 3 or higher adverse events was 52.8% with selpercatinib compared to 76.3% in the control group. Adverse events leading to dose reduction occurred in 38.9% of patients on selpercatinib versus 77.3% in the control group. Treatment discontinuation due to adverse events was also lower with selpercatinib (4.7% vs 26.8%).
The most common adverse events with selpercatinib were hypertension, dry mouth, diarrhea, and increased alanine aminotransferase levels. In the control group, the most frequent adverse events were diarrhea, palmar-plantar erythrodysesthesia syndrome, and hypertension.
While the results of this trial are highly promising, there are some limitations to consider. The open-label design could potentially introduce bias, although this was mitigated by the use of blinded independent central review for the primary endpoint assessment. Additionally, the availability of vandetanib fluctuated during the trial, leading to a restriction in the control arm to cabozantinib for later enrollees. This resulted in fewer patients receiving vandetanib than initially planned.
The authors concluded that selpercatinib demonstrated superior efficacy and a more favorable safety profile compared to standard multikinase inhibitors in patients with RET-mutant medullary thyroid cancer. They emphasized that these results highlight the importance of selective RET inhibition in treating this patient population.
The potential clinical impact of this study is significant. It provides strong evidence to support selpercatinib as a new standard of care for first-line treatment of advanced RET-mutant medullary thyroid cancer. The marked improvement in progression-free survival, coupled with a more manageable side effect profile, could translate to meaningful benefits for patients in terms of both survival and quality of life.
Furthermore, this trial underscores the importance of biomarker-driven treatment approaches in oncology. The authors stressed the need for timely biomarker testing to detect actionable RET mutations in all patients with advanced medullary thyroid cancer, as this information can now directly inform first-line therapy decisions.
It's worth noting that selpercatinib is already approved in several regions, including the United States, European Union, and Japan, for the treatment of RET-altered cancers. This new data from a randomized phase 3 trial provides the highest level of evidence to date supporting its use in RET-mutant medullary thyroid cancer.
As with any new therapy, long-term follow-up will be important to assess the durability of response and any potential late-onset adverse effects. Additionally, future research may explore combination strategies or sequencing of therapies to further improve outcomes for patients with this challenging disease.
In conclusion, the LIBRETTO-531 trial represents a significant advance in the treatment of RET-mutant medullary thyroid cancer. It demonstrates the power of precision medicine approaches in oncology and offers new hope for patients with this rare but aggressive form of thyroid cancer. As these results are disseminated and incorporated into clinical practice guidelines, they are likely to reshape the standard of care for this patient population.
References
Hadoux J, Elisei R, Brose MS, et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N Engl J Med. 2023;389(20):1851-1861. doi:10.1056/NEJMoa2309719
