The role of RET inhibitors in cancer management

Receptor tyrosine kinase (RET) is involved in the physiological development of a number of organ systems, including the nervous, hematopoietic, gastrointestinal, and genitourinary systems.^[] The RET proto-oncogene can be activated by gene fusion and point mutation.

While RET has been investigated as a therapeutic target in a number of malignancies, focus is warranted as to its place and treatment in MTC and NSCLC.

Initial inhibition of RET: multikinase inhibitors

The first agents (eg, multikinase inhibitors [MKI]) thought to inhibit RET included vandetanib, cabozantinib, lenvatinib, and sorafenib—and while axitinib does not have activity against RET, axitinib has been shown to be active in RET-altered thyroid cancers.^[]

Vandetanib and cabozantinib are MKIs with nonselective RET activity approved by the FDA for the treatment of symptomatic or progressive MTC in locally advanced or metastatic disease and locally advanced or metastatic differentiated thyroid cancer, respectively.

However, their nonselective RET activity may lead to significant off-target adverse effects (eg, nausea, hypertension, diarrhea) that limit their efficacy or even lead to drug discontinuation. As a result, clinical research led to the discovery of more potent and more selective RET inhibitors: pralsetinib and selpercatinib.

Pralsetinib facts

Pralsetinib is a kinase inhibitor that received accelerated approval by the FDA for the treatment of:

• Adult patients with metastatic RET fusion-positive NSCLC as detected by an FDA-approved test

• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC who require systemic therapy

• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

The recommended dosage in patients 12 years of age and older is 400 mg orally QD on an empty stomach. Pralsetinib may be associated with constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea; laboratory abnormalities may include decreased lymphocytes, neutrophils, hemoglobin, and platelets, as well as increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

Concomitant administration with strong CYP3A inhibitors and CYP3A inducers should be avoided. Pralsetinib should be discontinued in patients with severe hemorrhage or recurrent interstitial lung disease (ILD)/pneumonitis. Patients should be monitored for hypertension and hepatotoxicity.

The safety and efficacy of pralsetinib for RET-altered thyroid cancer and RET-fusion NSCLC were established in the ARROW trials. In patients with RET-mutant MTC, overall response rates were 71% and 60% in treatment-naïve patients and those previously receiving cabozantinib or vandetanib or both, respectively; response rates were 89% in patients with RET fusion-positive thyroid cancer.^[]

In patients with RET fusion NSCLC, overall responses were observed in 61% and 70% of patients who had prior platinum-based chemotherapy or were treatment-naïve, respectively.^[]

Tumor shrinkage was observed in all treatment-naïve patients and 97% of patients with prior platinum-based chemotherapy; median progression-free survival (PFS) was 13.0 and 16.5 months in treatment-naive and previously-treated patients, respectively. Importantly, median duration of response (at efficacy cutoff) had not been reached for treatment-naive patients and was 22.3 months for previously-treated patients.^[]

Selpercatinib facts

Selpercatinib is a kinase inhibitor approved by the FDA under accelerated approval for the treatment of:

• Adult patients with metastatic RET fusion-positive NSCLC

• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC who require systemic therapy

• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory

The recommended dosage in patients 12 years of age and older is based on weight:

• Less than 50 kg: 120 mg orally BID

• 50 kg or greater: 160 mg orally BID

Selpercatinib may be associated with dry mouth, diarrhea, fatigue, edema, constipation, and hypertension; increased AST, ALT, glucose, total cholesterol, creatinine, and alkaline phosphatase; and decreased leukocytes, albumin, calcium, platelets, and sodium.

Concomitant administration with strong CYP3A inhibitors and CYP3A inducers should be avoided. Selpercatinib should be discontinued in patients with severe or life-threatening hemorrhage. Patients should be monitored for hepatotoxicity, hypertension, and QT interval prolongation in those at risk of developing QTc prolongation.

The safety and efficacy of selpercatinib for RET-altered thyroid cancer and RET fusion NSCLC were established in the LIBRETTO-001 trials. In patients with RET-mutant MTC, the response rate was 69% and 73% in those previously receiving vandetanib, cabozantinib, or both and those who did not, respectively; 1-year PFS was 82% and 92% in previously-treated patients and treatment-naive patients, respectively.^[]

The response rate was 79% in those with previously treated RET fusion-positive thyroid cancer. In patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy, 64% achieved an objective response, while 85% of treatment-naïve patients achieved an objective response.^[] In patients with CNS metastasis, 91% achieved an objective intracranial response.