FDA Grants Pembrolizumab Priority Review for TMB-High Tumors
April 07, 2020 04:24pm
By Lisa Astor
The FDA has approved selpercatinib capsules for the treatment of patients with lung cancer or thyroid cancer harboring RET alterations. This marks the first treatment approved to target RET gene alterations.
The FDA has approved selpercatinib (formerly known as LOXO-292; Retevmo) capsules for the treatment of patients with lung cancer or thyroid cancer harboring RET alterations.1,2 This marks the first treatment approved to target RET gene alterations.
Specifically, the approval is for the following indications:
"In the clinical trial, we observed that the majority of [patients with] 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 and lead investigator for LIBRETTO-001, in a statement.2 "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. I am pleased that patients with these RET-driven cancers have this newly approved option."
The RET inhibitor was approved under the FDA’s Accelerated Approval program based on positive findings from the phase I/II LIBRETTO-001 trial, the largest trial to date of patients with RET-driven cancers. Continuation of the approval is contingent, however, on the verification of clinical benefit in confirmatory trials.
“Innovations in gene-specific therapies continue to advance the practice of medicine at a rapid pace and offer options to patients who previously had few,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in a statement.1 “The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer.”
In the LIBRETTO-001 trial, patients with RET-altered solid tumors and MTC received treatment with 160 mg selpercatinib orally twice daily. Among the evaluable adult patients with RET fusion-positive NSCLC treated in the trial were 105 who had previously received platinum chemotherapy and 39 who were treatment naïve. In the previously treated subgroup, the objective response rate (ORR) was 64%, with 81% of these patients maintaining their response for at least 6 months. The median duration of response (DOR) was 17.5 months. In the treatment-naïve group, the ORR was 84% with 58% of these responses lasting for at least 6 months. The median DOR was not reached in this subgroup.
Eleven patients with RET fusion-positive NSCLC who had measurable brain metastases at baseline had an intracranial response, with 10 of these patients experiencing an intracranial DOR of at least 6 months.
The MTC subgroup consisted of 143 patients 12 years and older with advanced or metastatic disease harboring RET mutations. Fifty-five of these patients had been previously treated with cabozantinib (Cabometyx), vandetanib (Caprelsa), or both. The ORR in the previously treated group was 69% with 76% of these responses lasting for at least 6 months. The median DOR was not reached. In the treatment naïve MTC group, the ORR was 73% and 61% of these patients maintained their response for at least 6 months; the median DOR was 22 months.
An additional 27 patients, adult and pediatric, with RET fusion–positive thyroid cancer were treated in the study. Nineteen of these patients were refractory to RAI and had received other prior systemic therapy. The ORR in this previously treated subgroup was 79% with 87% of responders maintaining a response for at least 6 months. The median DOR was 18.4 months. The other 8 patients with RET fusion–positive thyroid cancer were RAI-refractory and had not received additional therapy. The ORR in this subgroup was 100% with 75% of these patients still in response after at least 6 months; the median DOR was not reached.
"RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of other thyroid cancers. For patients living with these cancers, the approval of selpercatinib means they now have a treatment option that selectively and potently inhibits RET," said Lori J. Wirth, MD, medical director of head and neck cancers, Massachusetts General Hospital Cancer Center, in a statement.
Common adverse events (AEs) with selpercatinib included increased aspartate aminotransferase and alanine aminotransferase enzymes in the liver, increased blood sugar, decreased white blood cell count, decreased albumin in the blood, decreased calcium in the blood, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, swelling in the body or limbs, low blood platelet count, increased cholesterol, rash, constipation, and decreased sodium in the blood.
Serious AEs possible with selpercatinib include hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions. The FDA noted that in the event of hepatotoxicity, the dose of selpercatinib should be reduced, treatment should be interrupted, or discontinued permanently. The FDA also cautioned regarding treatment with selpercatinib when undergoing surgery and in pregnant and breastfeeding women.1
LIBRETTO-001 (NCT03157128) is an ongoing open-label, multicenter trial exploring the safety, tolerability, pharmacokinetics, and antitumor activity of selpercatinib in patients with advanced solid tumors—including RET-fusion-positive solid tumors—MTC, and other tumors with RET activation.
Previously the FDA granted selpercatinib with both a breakthrough therapy designation and a priority review for the treatment of patients with advanced RET fusion–positive NSCLC, RET-mutant MTC, and RET fusion–positive thyroid cancer.