Selpercatinib Shifts Treatment Paradigm for MTC and NSCLC

The RET inhibitor selpercatinib (Retevmo; Lilly) could become standard-of-care therapy in patients with RET-altered medullary thyroid cancer (MTC) or non–small cell lung cancer (NSCLC) based on data from two phase III trials presented at the 2023 ESMO Congress in Madrid, Spain, October 20–24, and concurrently published in The New England Journal of Medicine. The findings highlight the need to sequence tumors to identify patients with RET-driven malignancies.

Oncologists typically turn to multikinase inhibitors, such as cabozantinib (Cabometyx; Exelixis) or vandetanib (Caprelsa; Genzyme), to treat advanced RET-mutant MTC, but adverse events (AE) have proven challenging for patients. In the LIBRETTO-531 study, researchers randomly assigned 291 patients newly diagnosed with MTC to receive either selpercatinib or physician's choice of either cabozantinib or vandetanib (N Engl J Med 2023 Oct 21 [Epub ahead of print]).

At a median follow-up of 12 months, the median progression-free survival (PFS) in the selpercatinib arm was not reached; the overall response rate (ORR) was 69.4%, and the complete response rate (CRR) was 11.9%. In the cabozantinib/vandetanib arm, the median PFS, ORR, and CRR were 16.8 months, 38.8%, and 4.1%, respectively, reported the study's presenter, Julien Hadoux, MD, PhD, of Gustave Roussy Hospital in Villejuif, France.

Treatment-related AEs of grade 3 or higher occurred in 37.3% of the patients in the selpercatinib arm versus 68% in the control arm, Hadoux said. AEs led to dose reductions in roughly half as many patients who received selpercatinib as those in the control arm—38.9% versus 79.2% for cabozantinib and 72% vandetanib. Just 4.1% of patients receiving selpercatinib discontinued treatment compared with 26.8% of those in the control group. Overall, the most common AEs were hypertension, diarrhea, and increased liver enzymes.

“This study highlights the importance of RET selectivity when treating patients and biomarker testing in our patients. These results support selpercatinib as the first-line standard of care for patients with advanced, RET-mutant medullary thyroid carcinoma,” said Hadoux.

Given the toxicity burden—and discontinuation rate—of cabozantinib and vandetanib, as well as the efficacy and targeted nature of selpercatinib, the RET inhibitor should be the new standard first-line treatment for patients with MTC and a RET alteration, said study discussant Laura Locati, MD, PhD, of the University of Pavia in Italy. It's a “paradigm shift.”

However, despite the impressive results, Locati and Hadoux cautioned that overall survival data are immature and longer follow-up is needed.

Similarly, the LIBRETTO-431 trial established the superiority of selpercatinib as a first-line treatment for RET fusion–positive NSCLC over standard platinum-based chemotherapy with or without pembrolizumab (N Engl J Med 2023 Oct 21 [Epub ahead of print]).

After a median follow-up of about 19 months, patients who received selpercatinib had a median PFS of 24.8 months versus 11.2 months for those who received chemotherapy. For selpercatinib, the ORR was 83.7% and the median duration of response was 24.2 months compared with 65.1% and 11.5 months, respectively, in the control group.

Although AEs related to grade 3 or higher liver enzyme changes were more prevalent in the selpercatinib group, “most of these side effects were well managed with dose modifications and dose reductions,” explained Herbert Loong, MBBS, of The Chinese University of Hong Kong, who presented the findings. The success of managing the AEs related to selpercatinib was highlighted by a crossover rate of 75% from the chemotherapy arm to selpercatinib, as well as the fact that patients treated with selpercatinib stayed on therapy about 70% longer than those in the control group.

Among patients who had measurable central nervous system (CNS) disease metastases, selpercatinib demonstrated a 12-month intracranial response rate (IRR) of 82.4% and a complete IRR of 35.3% compared with 58.3% and 16.7%, respectively, in the control group. Furthermore, in patients who did not have CNS metastases at the start of the trial, only 1.1% of those who received selpercatinib developed them compared with 14.7% in the control group.

“With this data in mind, I think it is reasonable to say that not only is selpercatinib active in patients who have brain metastases, but there's evidence of a preventive effect of development of brain metastases in patients with RET fusion–positive NSCLC,” said Loong. He concluded that “selpercatinib should be considered as a first-line standard of care in RET fusion–positive, advanced NSCLC.”

Discussant Benjamin Besse, MD, PhD, of Paris-Saclay University in France, agreed but noted that the European Medicines Agency (EMA) requirement to study selpercatinib in separate randomized controlled trials to confirm its superiority over standard chemotherapy to sustain its full approval—even after demonstrating overwhelmingly positive efficacy phase I/II trials—hurts patients. Payers can deny coverage of a treatment that works by citing regulators’ demand for more conclusive evidence.

He suggested that for rare cancers, like RET fusion–positive NSCLC, the EMA could follow the FDA's lead and require only additional patients and longer follow-up before an accelerated approval is converted to a full approval. This streamlined approach would allow patients to more quickly access a life-extending treatment. –Myles Starr