Oncology Overview: Selpercatinib for RET-Positive Metastatic Non-Small Cell Lung Cancer


Selpercatinib is an oral selective RET kinase inhibitor approved for the treatment of metastatic RET fusion-positive non-small cell lung cancer and for metastatic thyroid cancer.

The FDA approved selpercatinib (Retevmo) in 2020 for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) in adults. Selpercatinib received an accelerated approval based on the overall response rate (ORR) and duration of response (DoR) observed in the LIBRETTO-001 clinical trial. Selpercatinib is also approved for metastatic thyroid cancer.

NSCLC is 1 of 2 types of lung cancer—the other is small cell lung cancer (SCLC). NSCLC is more predominant than SCLC and its main subtypes are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. RET genes are one of the gene promoters of metastatic NSCLC.

Mechanism of Action

Selpercatinib is an oral selective RET kinase inhibitor. Chimeric RET fusion proteins can be continuously activated as a result of particular point mutations in RET or chromosomal rearrangements including in-frame fusions of RET.

Constitutive activation of chimeric RET fusion proteins act as oncogenic drivers that support uncontrolled tumor cell growth. Selpercatinib has anti-tumor activity in host cells of constitutive activation of RET proteins that are the result of gene fusions and mutations.

Trial Summary

LIBRETTO-001 was a multicenter, open-label, multi-cohort clinical trial. The study enrolled 105 patients 23 to 81 years of age.

All had advanced or metastatic RET fusion positive NSCLC and had progressed on platinum-based chemotherapy, with 39 patients aged 23 to 86 years with advanced or metastatic NSCLC without prior systemic therapy placed in separate cohorts. Patients were administered selpercatinib 160 mg twice daily until unacceptable toxicity or disease progression. According to the response evaluation criteria in solid tumors (RECIST) 1.1, a blinded independent review committee determined major efficacy outcomes measures as ORR and DoR.

In the cohort previously treated with platinum chemotherapy, 64% achieved ORR with 1.9% complete response and 62% partial response. The DoR in the pre-treated group was an average of 17.5 months with 81% of the patients achieving DoR for at least 6 months.

In the cohort without previous platinum chemotherapy treatments, 85% achieved ORR, which was partial response. The average DoR was not estimable but 58% of the patients achieved DoR for at least 6 months.

Adverse Events (AEs)

In the LIBRETTO-001 study, at least 15% of patients experienced severe AEs (grade 3-4) after selpercatinib exposure. AEs included high blood pressure occurring in 35% of patients, nausea, vomiting, diarrhea, constipation, trouble swallowing, exhaustion, abdominal pain, bleeding events, headache, rash, edema, and QT prolongation. Other common AEs were dry mouth and cough.

Laboratory abnormalities were also common in patients who received selpercatinib. These included increased liver enzymes and biomarkers; blood glucose fluctuations; decreased albumin; decreased calcium; increased creatinine; decreased platelets; increased total cholesterol; decreased sodium, magnesium, and/or potassium; and increased bilirubin.

Therapy modification is needed for concomitant administration with acid-reducing agents, moderate-strong CYP3A inhibitors or inducers or substrates and CYP2C8 substrates.

Warnings and Precautions

Patients prescribed selpercatinib are at risk of liver toxicity, high blood pressure, QTc prolongation, bleeding events, allergic reactions, decreased wound healing, and embryo-fetal toxicity. Individuals of reproductive potential should consider the risk of impaired fertility subsequent to selpercatinib. Women should not breastfeed during selpercatinib treatment and for 1 week after the final dose of selpercatinib.

Dosing, Administration, and Counseling

The usual dose of selpercatinib is weight-based. Patients should take selpercatinib twice daily until disease progression or unacceptable toxicity. Patients weighing less than 50 kg should receive 120 mg and patients who weigh 50 kg or more should receive 160 mg.

Pharmacists should remind patients to take selpercatinib doses approximately 12 hours apart, with or without food. If patients are taking proton pump inhibitors, they should take their doses with food.

Pharmacists should remind patients not to crush or chew selpercatinib. Patients should make up a missed dose within 6 hours of the scheduled administration time. If they vomit, they should not take another dose, but wait until the next scheduled dose.

About the Author

Dannoy Gibson is a 2024 PharmD candidate at the University of Connecticut.


Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC, Peled N, Weiss J, Kim YJ, Ohe Y, Nishio M, Park K, Patel J, Seto T, Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, Falchook G, Ebata K, Nguyen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg SM, Goto K, Subbiah V. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Aug 27;383(9):813-824. doi: 10.1056/NEJMoa2005653. PMID: 32846060; PMCID: PMC7506467.

Retevmo (selpercatinib) capsules. Prescribing information. Eli Lilly and Company; 2020. Accessed July 1, 2022. label (fda.gov)

Selpercatinib. Lexi-Drugs. Lexicomp. Wolters Kluwer. Updated June 29, 2022. Accessed July 1, 2022. Lexicomp (uconn.edu)

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