Medullary Thyroid Carcinoma (MTC)


Gavreto™ (pralsetinib) is an effective treatment for advanced medullary thyroid cancer (MTC) in adults and children older than 12 years of age. This prescription drug is used to treat cancers caused by an abnormal rearranged during transfection (RET) gene. Gavreto is administered to persons with MTC orally or by injection as part of systemic therapy after the failure of prior treatment with radioactive iodine. Healthcare providers must perform a test to be sure that Gavreto will be an appropriate treatment for a patient with MTC.1  

Gavreto
Credit: PubChem

Clinical Pharmacology

Gavreto is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET M918T, RET V804L, RET V804M). It has half-maximum inhibitory concentrations (IC50) of less than 0.5 nM. In cellular assays, Gavreto inhibits RET at 12-, 14-, and 40- fold lower concentrations than JAK2, FGFR2, and VEGFR2. In purified enzyme assays, Gavreto inhibits TRKC, FLT3, JAK1-2, TRKA, DDR1, VEGFR2, FGFR1, and PDGFRB at higher concentrations that were clinically achievable at Cmax. RET fusion proteins can drive tumorigenic potential through hyperactivation of downstream signaling pathways. leading to uncontrolled cell proliferation. Gavreto has demonstrated antitumor activity in animal tumor implantation models and in cultured cells harboring RET fusions and mutations, including RET C634W, RET V804L, RET V804M, RET M918T, and RET C634W. The exposure-response relationship and time course of the pharmacodynamics of Gavreto are not fully characterized. The QT interval prolongation associated with Gavreto was assessed in 34 patients with RET fusion-positive tumors who received Gavreto at the recommended dose. No large mean increase in the QTc interval (>20 ms) was detected in the study.2    

Safety Information

Gavreto can cause severe or life-threatening inflammation of the lungs during treatment, which may lead to death. Patients must inform their healthcare provider if they experience new or worsening symptoms, such as fever, cough, and shortness of breath. Hypertension may develop after Gavreto administration, and blood pressure must be monitored regularly. Patients should tell their healthcare provider if they have observed an increase in their blood pressure measurements or symptoms of high blood pressure, such as headache, chest pain, shortness of breath, and dizziness. Liver problems have developed in some patients, and serum liver enzymes may be elevated after the administration of Gavreto. Healthcare providers should assess patients’ liver function during treatment with Gavreto. Patients may experience yellowing of the skin or sclera of the eye (jaundice), tea-colored urine, pain in the upper abdomen, nausea or vomiting, bleeding or bruising, and sleepiness. Gavreto can cause bleeding, which is a serious health risk and may cause death. Patients should inform their healthcare provider about any signs or symptoms of bleeding, including vomit that looks like coffee grounds, unusual vaginal bleeding, pink or brown urine, nose bleeding, and red or black (tarlike) stools.3 

Get detailed prescribing information on the Gavreto monograph page at MPR.

Clinical Trials in Patients With Thyroid Cancers

In clinical studies such as ARROW, Gavreto demonstrated durable and potent antitumor activity in patients with RET fusion-positive or RET-mutant thyroid cancers. Patients with RET-mutant MTC (V804X, C634X, M918T) or RET fusion-positive papillary thyroid carcinoma (CCDC6, NCOA4) were treated with Gavreto. The dosage varied from 30 to 600 mg once or twice daily in the phase 1 dose escalation. The dose of Gavreto can be increased to 400 mg daily according to the phase 2 escalation. In a therapeutic trial, 79 patients were found to have RET-mutant MTC. Of these, 61% had M918T mutations, 28% had C634X mutations, 8% had other mutations, and 4% had V804X mutations. The overall response rate was 65% (51 of 79 patients). The partial response rate was 59%, inclusive of 1 pending confirmation, and the complete response rate was 5%.4 

RET Inhibitor Therapy for Medullary Thyroid Cancer

Gavreto is a novel, highly selective rearranged during transfection (RET) inhibitor that is being investigated for the therapy of RET-altered solid tumors. It is highly efficacious, and durable responses have been seen in patients with tumors of the central nervous system. Gavreto is also known as BLU-667. In a clinical study, a patient with metastatic MTC underwent somatic testing. A commercial assay revealed the RET M918T mutation. The variant allele frequency (VAF) of this mutation was 38%. The patient provided informed consent and was enrolled in a phase 1/1b study of Gavreto. Previously, the patient had been treated with vandetanib for 2 months. This drug was discontinued because of disease progression. The patient was then treated with cabozantinib for 8 months. This drug also was discontinued because of the patient’s inability to tolerate the drug and disease progression. The patient was then treated with selpercatinib for 12 months. A partial response was noted and the selpercatinib was well tolerated, but it was ultimately discontinued because of disease progression.5 

The patient then chose to undergo salvage therapy with a selective RET inhibitor (Gavreto) in preference to cytotoxic chemotherapy. Initially, the patient’s symptoms and liver metastases improved; however, at 6 weeks after the start of therapy, sudden and rapid deterioration of his symptoms developed, with worsening liver metastases. Mixed changes were revealed by tumor markers. The RET M918T mutation (VAF, 28%), RET G810S mutation (VAF, 11.9%), and RET V804M mutation (VAF, 22%) were confirmed with next-generation sequencing of a tumor biopsy obtained at enrollment (before pralsetinib and after selpercatinib therapy). Clinical studies show that highly selective RET inhibitor therapy is not efficacious in all patients with MTC previously treated with another highly selective RET inhibitor. Loss of heterozygosity is observed in the RET M918T mutation with a VAF of 38%. The studies concluded that pralsetinib and selpercatinib have inhibitory activity against the RET V804M mutation and that clinical resistance is mediated by the emergent RET G810S mutation.5

References

  1. Gavreto™ (pralsetinib). Genentech. Accessed August 20, 2021. 
  2. Gavreto capsules, for oral use. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213721s000lbl.pdf.. Revised December 2020. Accessed August 20, 2021.
  3. Gavreto for RET+ advanced thyroid cancer. Genentech. Accessed August 20, 2021.
  4. Markham A. Pralsetinib: first approval. Drugs. 2020;80(17):1865-1870. doi:10.1007/s40265-020-01427-4
  5. Bruce JY, Bible KC, Chintakuntlawar AV. Emergence of resistant clones in medullary thyroid cancer may not be rescued by subsequent salvage highly selective rearranged during transfection-inhibitor therapy. Thyroid. 2021;31(2):332-333. doi:10.1089/thy.2020.0449

Reviewed by Harshi Dhingra, MD, on 8/30/2021.

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