FDA Approves Selpercatinib for Advanced RET-Driven Lung and Thyroid Cancers

By Adam Hochron
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The FDA recently approved selpercatinib as the first therapy specifically designed for patients with RET-driven lung and thyroid cancers. 

The approval is for patients with RET fusion-positive non-small cell lung cancer (NSCLC), adults and children over the age of 12 with advanced or metastatic RET-mutant medullary thyroid cancer who need systematic therapy, or advanced or metastatic RET fusion-positive thyroid cancer patients who need systematic therapy and are radioactive-iodine refractory, according to a release from the manufacturer. 

The approval follows the LIBRETTO-001 Phase 1/2 trial reaching its endpoints of objective response rate and duration of response. The release from the manufacturer noted that the trial was the “largest clinical trial of patients with RET-driven cancers treated with a RETinhibitor.” Phase 1 of the trial included a dose-escalation, while phase 2 involved a dose expansion.  

“In the clinical trial, we observed that the majority of metastatic lung cancer patients experienced clinically meaningful responses when treated with selpercatinib, including responses in difficult-to-treat brain metastases,” said Alexander Drilon, MD, acting chief of early drug development at Memorial Sloan Kettering Cancer Center. “The approval of selpercatinib marks an important milestone in the treatment of NSCLC, making RET-driven cancers now specifically targetable in the same manner as cancers with activating EGFR and ALK alterations, across all lines of therapy.” 

For patients with RET Fusion-Positive NSCLC, 85% of patients who were systemic treatment naïve achieved an overall response rate, while 64% of patients who were treatment-experienced an overall response rate. Seventy three percent of RET-Mutant MTC who were cabozantinib/vandetanib naïve achieved overall response rate, compared to 69% who had received those drugs in the past. 

The smallest group in the trial were patients with RET fusion-positive thyroid cancers, including papillary, Hurthle cell, anaplastic, and poorly differentiated. All eight of the systemic treatment naïve arm achieved an overall response rate, compared to 79% in the treatment-experienced arm. The median duration of response for all three groups was between 12 and 22 months, although some groups did not reach that level. 

The labeling for selpercatinib includes warnings and precautions for several conditions, including hepatoxicity, hypertension, hemorrhagic events, and risk of impaired wound healing. Five percent of patients in the LIBRETTO-001 trial discontinued treatment due to adverse reactions. The most common adverse reactions in the trial included increased alanine aminotransferase, dry mouth, diarrhea, and hypertension. The most frequent adverse reaction, occurring in more than 2% of patients, was pneumonia. 

“RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of thyroid cancers,” said Lori J. Wirth, MD, medical director of head and neck cancers at Massachusetts General Hospital Cancer Center. “For patients living with these cancers, the approval of selpercatinib means they now have a treatment option that selectively and potentially inhibits RET.” 

Selpercatinib had previously been granted orphan drug designation by the FDA for the treatment of RET fusion-positive NSCLC and RET fusion-positive and RET-mutant thyroid cancers, including poorly differentiated, undifferentiated, or anaplastic thyroid cancer, MTC and locally advanced or metastatic follicular or papillary thyroid cancer. 

Two confirmatory Phase 3 trials for selpercatinib are currently enrolling patients, according to the release.


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