Gavreto (pralsetinib) - 2 indications

Scroll down for more information on each indication:

• for metastatic rearranged during transfection (RET) fusion- positive non-small cell lung cancer; approved September 2020
• for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer; approved December 2020

General Information

Gavreto (pralsetinib) is a kinase inhibitor.

Gavreto is specifically indicated for the following:

• adult patients with metastatic rearranged during transfection (RET) fusion- positive non-small cell lung cancer as detected by an FDA approved test;
• adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) 

Gavreto is supplied as a capsule for oral administration. The recommended dose is 400 mg orally once daily on an empty stomach. No food should be taken for at least 2 hours before and at least 1 hour after taking Gavreto. 

Mechanism of Action

Gavreto (pralsetinib) is a kinase inhibitor of wild-type RET and oncogenic RET fusions and mutations. Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations.

Side Effects

Adverse effects associated with the use of Gavreto may include, but are not limited to, the following:

• fatigue
• constipation
• musculoskeletal pain
• hypertension
• laboratory abnormalities

Indication 1 - metastatic rearranged during transfection (RET) fusion- positive non-small cell lung cancer

approved September 2020

Clinical Trial Results

Gavreto was approved under the FDA's accelerated approval program, based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

The FDA approval of Gavreto for NSCLC was based on ARROW, a multicenter, non-randomized, open-label, multi-cohort phase 1/2 trial. The study enrolled, in separate cohorts, patients with metastatic RET fusion positive NSCLC who had progressed on platinum-based chemotherapy and treatment-naïve patients with metastatic NSCLC. Patients received Gavreto 400mg orally once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to RECIST v1.1. Efficacy was evaluated in 87 patients with RET fusion-positive NSCLC with measurable disease who were previously treated with platinum chemotherapy enrolled into a cohort of ARROW. Gavreto demonstrated an overall response rate (ORR) of 57% and complete response (CR) rate of 5.7% in the 87 people with NSCLC previously treated with platinum-based chemotherapy, and the median duration of response (DoR) was not reached. In the 27 people with treatment-naïve NSCLC, the ORR was 70%, with an 11% CR rate. 

Indication 2 - advanced or metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer

approved December 2020

Clinical Trial Results

The FDA accelerated approval of Gavreto for RET-mutant medullary thyroid cancer was based on the Phase I/II ARROW study. The open-label study was designed to evaluate the safety, tolerability and efficacy of Gavreto, administered orally in people with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancers and other RET-altered solid tumors. The trial consists of two parts: a dose escalation portion, which is complete, and an expansion portion in people treated with 400 mg of Gavreto, once-daily.  Treatment with Gavreto led to an overall response rate (ORR) of 60% in 55 people with RET-mutant metastatic MTC previously treated with cabozantinib and/or vandetanib, and the median duration of response (DoR) was not reached. In 29 people with RET-mutant advanced MTC who were cabozantinib and vandetanib treatment-naïve, the ORR was 66% and the median DoR was not reached. In nine people with RET fusion-positive metastatic thyroid cancer, Gavreto demonstrated an ORR of 89% and the median DoR was not reached.