On may 8, 2020, selpercatinib was granted accelerated approval for the following indications:

• Adult patients with metastatic RET fusion-positive non–small cell lung cancer (NSCLC)
• Adult and pediatric patients ≥ 12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy
• Adult and pediatric patients ≥ 12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate).^1,2

In the clinical trial setting, identification of a RET gene alteration was determined in local laboratories using next-generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization.

Supporting Efficacy Data

Approval was based on findings in the multicenter, multicohort phase I/II LIBRETTO-001 trial in patients with tumors with RET alterations.² Patients received oral selpercatinib at 160 mg twice daily until disease progression or unacceptable toxicity. The main efficacy measures were overall response rate and response duration as determined on blinded independent review committee assessment using Response Evaluation Criteria in Solid Tumors, version 1.1.

RET Fusion-Positive NSCLC

Among 105 adult patients previously treated with platinum-containing chemotherapy (55% also receiving anti–programmed cell death protein 1/programmed cell death ligand 1 therapy), the objective response rate was 64% (95% confidence interval [CI] = 54%–73%); median response duration was 17.5 months, with 81% of responders having response lasting at least 6 months. Evaluation of an additional 39 patients who were treatment-naive showed an overall response rate of 85% (95% CI = 70%–94%); median response duration was not reached, with 58% of responders having a response lasting at least 6 months.

RET-Altered Thyroid Cancer

Evaluation of 55 adult or pediatric patients aged ≥ 12 years with advanced or metastatic RET-mutant medullary thyroid cancer previously treated with cabozantinib, vandetanib, or both showed an overall response rate of 69% (95% CI = 55%–81%); median response duration was not reached, with 76% of responders having a response lasting at least 6 months. Evaluation of an additional 88 adult or pediatric patients aged ≥ 12 years not previously treated with an approved therapy for medullary thyroid cancer showed an overall response rate of 73% (95% CI = 62%–82%); median response duration was 22 months, with 61% of responders having a response lasting at least 6 months.

Efficacy for RET fusion–positive thyroid cancer was evaluated in adults and pediatric patients ≥ 12 years of age. Among 19 patients who were radioactive iodine–refractory (if radioactive iodine was appropriate) and had received another prior systemic treatment, the overall response rate was 79% (95% CI = 54%–94%); median response duration was 18.4 months, with 87% of responders having a response lasting at least 6 months. Among an additional eight radioactive iodine–refractory treatment-naive patients, overall response rate was 100% (95% CI = 63%–100%); median response duration was not reached, with 75% of
responders having a response lasting at least 6 months.

How It Works

Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms, as well as VEGFR1 and VEGFR3; in other enzyme assays, selpercatinib also inhibited FGFR1, FGFR2, and FGFR3 at higher but clinically achievable concentrations. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and FGFR2 and approximately 8-fold lower concentrations than VEGFR3.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins; these proteins can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated antitumor activity in cells harboring constitutive activation of RET protein resulting from gene fusions and mutations, including RET CCDC6, RETKIF5B, RET V804M, and RET M918T. Selpercatinib also showed antitumor activity in mice intracranially implanted with a patient-derived RET fusion–positive tumor.

How It Is Used

Patients should be selected for treatment with selpercatinib based on the presence of a RET gene fusion (NSCLC or thyroid cancer) or specific RET-gene mutation (medullary thyroid cancer) in tumor specimens or plasma. A U.S. Food and Drug Administration–approved test for the detection of RET-gene fusions and RET-gene mutations is not currently available.

The recommended dosage of selpercatinib based on body weight is 120 mg twice daily in patients weighing < 50 kg and 160 mg twice daily in those weighing ≥ 50 kg, with treatment continuing until disease progression or unacceptable toxicity.

Prescribing information provides recommended dosages for three dose reductions for adverse reactions according to initial dose based on body weight. Treatment should be discontinued if further dose reduction is required. Concomitant use of proton pump inhibitors, histamine-2 receptor antagonists, or locally acting antacids should be avoided. Concomitant use of strong and moderate CYP3A inhibitors and CYP2C8 and CYP3A substrates should be avoided. Prescribing information provides instructions on selpercatinib administration when concomitant use with these agents cannot be avoided as well as instructions on dosage modification in patients with severe hepatic impairment.

Prescribing information provides instructions on dosage modification for and management of adverse reactions, including hepatotoxicity, hypertension, QT interval prolongation,
hemorrhagic events, hypersensitivity reactions, and grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for grade 4 hypertension, grade 4 QT interval prolongation, and severe or life-threatening hemorrhagic events.

Safety Profile

The safety data are derived from 702 patients receiving selpercatinib monotherapy at 160 mg twice daily in the LIBRETTO-001 trial. Overall, 65% of patients received selpercatinib for at least 6 months and 34% for more than 12 months.

The most common adverse events of any grade (≥ 25% of patients, including laboratory abnormalities) were increased aspartate aminotransferase (AST; 51%), increased alanine aminotransferase (ALT; 45%), increased glucose (44%), decreased leukocytes (43%), decreased albumin (42%), decreased calcium (41%), dry mouth (39%), diarrhea (37%), increased creatinine (37%), increased alkaline phosphatase (36%), hypertension (35%), fatigue (35%), edema (33%), decreased platelets (33%), increased total cholesterol (31%), rash (27%), decreased sodium (27%), and constipation (25%). The most common grade 3 or 4 adverse event was diarrhea (3%). Hemorrhage of any grade occurred in 15% and was grade 3 or 4 in 2% of patients. The most common grade 3 or 4 laboratory abnormalities were increased ALT (9%) and increased AST (8%).

Serious adverse events occurred in 33% of patients, including pneumonia in ≥ 2%. Adverse events led to dosage interruption in 42% (increased ALT, increased AST, hypertension, diarrhea, pyrexia, and QTinterval prolongation in > 2% each) and to dosage reduction in 31% (increased ALT, increased AST, QT interval prolongation, and fatigue in > 2% each).

Permanent treatment discontinuation due to an adverse event occurred in 5% of patients, with causes including increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%). Fatal adverse events occurred in 3% of patients, with those occurring in more than one patient consisting of sepsis, cardiac arrest, and respiratory failure in three patients each.

Selpercatinib has warnings/precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryofetal toxicity.

ALT and AST should be monitored prior to initiating selpercatinib, every 2 weeks during the first 3 months, monthly thereafter, and as clinically indicated. Treatment should not be started in patients with uncontrolled hypertension; blood pressure should be optimized prior to initiating treatment and monitored after 1 week, at least monthly thereafter, and as clinically indicated. Patients who are at significant risk of developing QTc prolongation must be monitored, with assessment of QT interval, electrolytes, and thyroid-stimulating hormone at baseline and periodically during treatment. QT interval should be monitored more frequently when selpercatinib is given concomitantly with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval.

Selpercatinib should be withheld for at least 7 days prior to elective surgery and not given for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming treatment after resolution of wound healing complications has not been established. Patients should be advised not to breastfeed while taking selpercatinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. Accessed May 18, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Retevmo (selpercatinib) capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf. Accessed May 18, 2020.