By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The Food and Drug Administration (FDA) has approved the first oncology treatment that targets rearranged during transfection (RET) alterations in the form of mutations or fusions of certain advanced lung and thyroid cancers.1 Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms, as well as vascular endothelial growth factors 1 and 3 (VEGFR1 and VEGFR3).2
The FDA greenlit selpercatinib under the accelerated approval pathway. The agency also approved priority review, breakthrough therapy, and orphan drug designations. It is marketed as Retevmo.
Indication
Selpercatinib is indicated for the treatment of adults with metastatic RET fusion-positive, non-small cell lung cancer (NSCLC) and pediatric patients (≥ age 12 years) and adults with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy.2
It also is indicated in advanced or metastatic RET fusion-positive thyroid cancer in patients who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). Accelerated approval was based on duration of response and overall response rate.2 Continued approval may be contingent on description and verification of clinical benefit in confirmatory trials.
Dosage
The recommended dose is 120 mg orally twice daily (< 50 kg body weight) or 160 mg twice daily (≥ 50 kg body weight).2 The drug should be taken until disease progression or unacceptable toxicity occurs. Dosage modifications are needed for adverse reactions, hepatic impairment, concomitant use of acid-reducing agents, and strong and moderate CYP3A inhibitors. Selpercatinib is available as 40 mg and 80 mg capsules.
Potential Advantages
Selpercatinimb is a selective and potent inhibitor of RET compared to other kinase (including multikinase) inhibitors.3 It is the first therapy approved that targets RET gene alterations. The drug showed response (i.e., tumor shrinkage) in patients with NSCLC, MTC, and thyroid cancer (e.g., papillary thyroid cancer [PTC]), with overall response rates of 64% to 79% in previously treated patients and 73% to 100% for those naïve to treatment.1,2
Potential Disadvantages
Selpercatinib can cause serious hepatotoxicity, hypertension, hemorrhagic events, and embryo-fetal toxicity.2 It also can cause concentration-dependent QT prolongation and increase the risk of impaired wound healing. Common adverse reactions (more than 30%) include dry mouth, diarrhea, hypertension, fatigue, and edema; higher aspartate transaminase/alanine aminotransferase, glucose, creatinine, alkaline phosphatase, and total cholesterol levels; and lower albumin and leukocytes levels.2
Comments
Selpercatinib was evaluated in open-label trials in the three types of cancer and stratified by treatment-experienced and treatment-naïve status.2 The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by a blinded, independent review committee.
In patients with advanced RET fusion-positive NSCLC, previously treated with platinum chemotherapy (55% underwent prior anti-PD-1/PDL-1 therapy; n = 105), ORR was 64%, of which 62% were partial response. Median duration of response was 17.5 months.
For treatment-naïve patients (n = 39), ORR was 85% (all partial), and DOR has not been determined. For RET-mutant MTC previously treated with multikinase inhibitors (cabozantinib or vandetanib; n = 55), ORR was 69% (9% complete, 60% partial), with DOR yet to be determined. However, 76% had DOR ≥ 6 months. For treatment-naïve patients (n = 88), ORR was 73% (11% complete, 61% partial). For RET fusion-positive thyroid cancer (78% PTC) previously treated (n = 19), ORR was 79% (5% complete, 74% partial) and DOR of 18.4 months. For treatment-naïve patients (n = 8), ORR was 100% (12% complete, 88% partial) and 75% with DOR ≥ 6 months.
Clinical Implications
RET is a transmembrane receptor protein-tyrosine kinase (proto-oncogene) required for normal tissue development and maturation. The RET rearrangement (i.e., chromosomal rearrangement) gene has been associated with 30% of papillary thyroid cancers and 1-2% of NSCLC, particularly in patients who never smoked or who had lung adenocarcinoma.4-6 Current therapies are limited in efficacy, with ORR for NSCLC ranging from 18% to 32%.5 Similarly, for MTC, the ORR is 28% with cabozantinib, a multikinase inbibitor.7
Selpercatinib is a first-of-its-kind drug that provides the first effective targeted treatment (in this case, RET) rather than targeting the site (i.e., organ) of the tumor, with ORR of 60% to 100%, including previously treated NSCLC, MTC, and PTC. Approval was based on a small number of patients, but these new gene-based therapies offer potential benefit to patients who previously had few options. The National Comprehensive Cancer Network (Version 5.2020) now lists selpercatinib as the preferred treatment for NSCLC with RET rearrangement. It has not been updated for MTC or PTC. The cost is $20,600 for a 30-day supply at 320 mg/day.
REFERENCES
- Food and Drug Administration. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. May 8, 2020.
- Eli Lilly. Retevmo prescribing information. Revised May 2020.
- Subbiah V, Velcheti V, Tuch BB, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 2018;29:1869-1876.
- Zhang Q, Xu C, Wang W, et al. Comparison of rearranged during transfection (RET) gene rearrangements in primary versus metastatic non-small cell lung cancer (NSCLC). Med Sci Monit 2018;24:8207-8212.
- Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET Registry. J Clin Oncol 2017;35:1403-1410.
- Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2017;13:27-45.
- Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary. Thyroid Cancer J Clin Oncol 2013;31:3639-3646.
Selpercatinib should be prescribed to treat metastatic rearranged during transfection (RET) fusion-positive, non-small cell lung cancer and advanced or metastatic RET-mutant medullary thyroid cancer.
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