The FDA granted accelerated approval to the selective RET kinase inhibitor selpercatinib (Retevmo, Lilly) for patients with certain non-small cell lung cancer (NSCLC) and thyroid cancers whose tumors have alterations in the RET gene.

The following indications were approved:
• adults with metastatic RET fusion–positive NSCLC;
• adults and children at least 12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and
• adults and children at least 12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI)-refractory, if RAI is appropriate.

“RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of other thyroid cancers,” according to Lori J. Wirth, MD, the medical director of head and neck cancers at Massachusetts General Hospital Cancer Center, in Boston, who has studied selpercatinib in patients with 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,” noted Dr. Worth, adding, “Based on the published data for this new medicine, as well as my personal experience treating patients, this may be a good treatment option.”

The approval was based on results from the single-arm, multicenter, multicohort, open-label, phase 1/2 LIBRETTO-001 trial of patients with RET-driven cancers (N=702). The trial enrolled  treatment-naive patients and heavily pretreated patients with a variety of advanced solid tumors, including RET fusion–positive NSCLC,  RET fusion–positive thyroid cancer, RET-mutant MTC, and certain other solid tumors with RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next-generation sequencing, polymerase chain reaction or fluorescence in situ hybridization. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) assessed by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified secondary end points included central nervous system (CNS) ORR and CNS DOR.

Efficacy for advanced or metastatic RET-mutant MTC was investigated in adults and children at least 12 years of age. The trial enrolled patients previously treated with cabozantinib (Cometriq, Exelixis), vandetanib (Caprelsa, Genzyme) or both, and patients who had not received these drugs. The ORR for the 55 patients who were treated previously was 69% (95% CI, 55%-81%), with 76% of responding patients had responses lasting six months or longer. The ORR for treatment-naive patients (n=88) was 73% (95% CI, 62%-82%), with 61% of responding patients having responses lasting six months or longer.

Efficacy for RET fusion–positive thyroid cancer was evaluated in adults and children at least 12 years of age. The trial enrolled 19 patients who were RAI refractory, if appropriate, and had received another prior systemic treatment, and eight patients who were RAI refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79% (95% CI, 54%-94%), with 87% of responding patients having responses lasting six months or longer. All eight patients who received RAI and no other subsequent therapy responded (95% CI, 63%-100%), and 75% had responses lasting six months or longer.

Efficacy for RET fusion–positive NSCLC was evaluated in 105 adults previously treated with platinum-based chemotherapy. The ORR was 64% (95% CI, 54%-73%), with 81% of responses lasting six months or longer. The ORR for 39 treatment-naive patients was 85% (95% CI, 70%-94%), with 58% of responses lasting six months or longer.

“In the clinical trial, we observed that the majority of metastatic lung cancer patients experienced clinically meaningful responses when treated with selpercatinib,” noted LIBRETTO-001 lead investigator Alexander Drilon, MD, the acting chief of early drug development at Memorial Sloan Kettering Cancer Center, in New York City. This included responses in patients with metastases, which occur in up to half of patients with RET fusion–positive NSCLC (J Thorac Oncol 2018;13[10]:1595-1601).

Among previously treated NSCLC patients with measurable brain metastases, 10 out of 11 patients observed intracranial responses, with all 10 patients experiencing a CNS DOR of at least six months.

The most common adverse events (AEs) observed during the trial included constipation, decreased albumin, diarrhea, edema, fatigue, hypercholesterolemia, hyperglycemia, hypertension, hypocalcemia, hyponatremia, increased alkaline phosphatase, increased aspartate and alanine aminotransferases, increased creatinine, leukocytopenia, rash, thrombocytopenia and xerostomia.

The most frequent serious AE occurring in at least 2% of patients was pneumonia. 

The labeling for selpercatinib contains warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk for impaired wound healing and embryo–fetal toxicity.

The recommended dose of selpercatinib is weight based: 120 mg for patients less than 50 kg, and 160 mg for those 50 kg or greater. Selpercatinib is taken orally twice daily with or without food, or with food when coadministered with a proton pump inhibitor.

For more information, see the full prescribing information for selpercatinib.

—Clinical Oncology News Staff

Based on press releases from the FDA and Lilly.