China's National Medical Products Administration (NMPA) recently approved Prugihua® (pralsetinib capsules) as a Class 1 New Drug Application for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is positive for transfection rearrangement (RET) gene fusions, who have previously received platinum-based chemotherapy. This marks the approval of the first selective RET inhibitor in China.
Pralsetinib Clinical Research
The ARROW study is a global clinical trial designed to evaluate the safety, tolerability, and efficacy of pralsetinib in patients with RET fusion-positive NSCLC, RET-mutant medullary thyroid carcinoma, and other RET fusion-positive advanced solid tumors.
Research data showed that pralsetinib demonstrated superior and durable antitumor activity in Chinese patients with RET fusion-positive NSCLC who had undergone platinum-based chemotherapy, with an overall response rate (ORR) of 56%, a median duration of response (DOR) that was not reached, and a 6-month DOR rate of 83%. The drug was well-tolerated and had good safety and tolerability, with no cases of treatment discontinuation or death due to pralsetinib-related adverse events.
Pralsetinib FDA Approved Indications
Pralsetinib is an oral, potent, selective RET inhibitor, marketed under the brand name Gavreto. It was first approved by the FDA in September 2020 for the treatment of lung cancer and in December 2020 for the treatment of thyroid cancer. In the United States, this drug is indicated for the treatment of:
(1) Adult patients with metastatic RET fusion-positive non-small cell lung cancer confirmed by an FDA-approved assay;
(2) Adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant medullary thyroid carcinoma requiring systemic therapy;
(3) Adult and pediatric patients aged 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer that is refractory to systemic therapy and radioactive iodine (if applicable).
Regarding RET Fusion-Positive Lung Cancer
Activating RET fusions and mutations are key disease drivers in many cancer types, including NSCLC and MTC. RET fusions are involved in approximately 1–2% of NSCLC patients and approximately 10–20% of papillary thyroid carcinoma (PTC) patients, while RET mutations are involved in approximately 90% of advanced MTC patients. In addition, low-frequency RET alterations have been observed in colorectal cancer, breast cancer, pancreatic cancer, and other cancers, and RET fusions have also been observed in drug-resistant, EGFR-mutant NSCLC patients.
About pralsetinib
In preclinical studies, pralsetinib consistently demonstrated sub-nanomolar potency against the most common RET gene fusions, activating mutations, and resistance mutations. Furthermore, pralsetinib exhibits significantly improved RET selectivity compared to approved multi-kinase inhibitors, with over 90-fold improved efficacy against VEGFR2. By inhibiting primary and secondary mutations, pralsetinib holds promise for overcoming and preventing the development of clinical resistance. This treatment approach is expected to achieve durable clinical remissions in patients carrying various RET variants, with a favorable safety profile.
