FDA approves RET inhibitor Gawreto to treat RET fusion positive lung cancer
Last Update: 2021-03-02
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Foundation Pharmaceuticals partner Blueprint Pharmaceuticals recently announced that the U.S. Food and Drug Administration (FDA) has approved the precision oncology drug, RET kinase inhibitor Gawreto (pralsetinib), for the treatment of adult patients with metastasis non-small cell lung cancer (NSCLC) that has been confirmed to be RET fusion-positive.
On the same day, the FDA also accepted Gawreto's application for a new drug to treat RET mutant thyroid myelin cancer (MTC) and RET fusion-positive thyroid cancer (NDA), which will be reviewed through the Real-Time Oncology Review (RTOR) pilot project. The FDA has granted the NDA priority review, with a target date of February 28, 2021 for the Prescription Drug User Charge Act (PDUFA).
It is worth mentioning that Gavreto is the only reT-targeted therapy that is orally available once a day, showing long-lasting efficacy and high total remission rates in PATIENTs with RET fusion-positive NSCLC. The approval, based on tumor mitigation data from the I/II ARROW study, showed that Gavreto was effective in patients with RET fusion-positive NSCLC, regardless of the RET fusion partner or whether the central nervous system was affected, and that some of the patients were in complete remission.
Under the partnership with Roche, Blueprint will commercialize Gawreto with Roche's Genentek in the U.S. market. In July, the two sides signed a $1.7 billion licensing and cooperation agreement in which Roche acquired Gawreto's exclusive rights outside the U.S. (excluding Greater China) and joint commercialization rights to the U.S. market. Keystone Pharmaceuticals owns Gawreto's exclusive license in Greater China.
Gavreto is a daily oral RET targeted therapy designed and developed by Blueprint Pharmaceuticals to selectively and powerfully inhibit RET changes (fusion and mutations, including predicted drug-resistant mutations), including about 1-2% of NSCLC patients. Currently, RET is one of seven NSCLC biomarkers that can be targeted with FDA-approved precision oncology drugs.
Gavreto is 100 mg tablets and the recommended starting dose is 400 mg once a day. RET biomarker testing is the only way to identify whether patients with metastasis NSCLC are eligible for Gawreto treatment. RET fusion can be identified by available biomarker detection methods, including next-generation sequencing of tumor tissue or liquid biopsies. In the ARROW test, next-generation sequencing, FISH, or other methods were used to detect RET fusion.
Based on tumor mitigation data from the I/II ARROW study, Gavreto received accelerated FDA approval, and continued approval of the drug's adaptation will depend on the validation and description of clinical benefits in validated clinical trials. In the study, patients with RET fusion-positive NSCLC were treated at a daily dose of 400 mg with Gawreto. Data show that: (1) In 87 patients who have received platinum-containing chemotherapy, the objective remission rate (ORR) is 57% (95% CI: 46-68%), the full remission rate (CR) is 5.7%, and the medium remission duration (DOR) has not yet reached (95% CI: 15.2 months, not to be estimated). (2) In 27 patients who had not received primary treatment with platinum chemotherapy, ORR was 70% (95% CI: 50-86%), CR was 11%, and the medium DOR was 9.0 months (95% CI: 6.3 months, not to be estimated). Gavreto's drug label contains warnings and precautions regarding interstitial pulmonary disease/pneumonia, hypertension, hepatotoxicity, bleeding events, risk of damage to wound healing, and risk of embryo-fetal toxicity.
RET-activated fusion and mutation are key disease drivers for many cancer types, including NSCLC and MTC. RET fusion involves about 1-2% of NSCLC patients, about 10-20% of thyroid papyroid cancer (PTC) patients, and RET mutations involve about 90% of advanced MTC patients. In addition, low-frequency RET changes were observed in colorectal, breast, pancreatic and other cancers, and RET fusion was observed in drug-resistant, EGFR-mutated NSCLC patients.
Pralsetinib was designed by Blueprint Medicines' research team based on its proprietary compound library. In preclinical studies, pralsetinib consistently showed the effect of subnamor levels for the most common RET gene fusion, activation mutations, and drug-resistant mutations. In addition, pralsetinib's selectivity to RET is significantly higher than that of approved multi-kinase inhibitors, where the effectiveness of RET is more than 90 times higher than that of VEGFR2. By inhibiting primary and secondary mutations, pralsetinib is expected to overcome and prevent the occurrence of clinical resistance. This treatment is expected to achieve long-lasting clinical remission and good safety in patients with different RET variants.
It is worth mentioning that Lilly Retevmo (selpercatinib) was the first approved RET inhibitor. Developed by Lilly's oncology company Loxo Oncology, the drug was approved by the FDA in May to treat patients with three types of tumors with genetic changes (mutations or fusions) in the RET gene: non-small cell lung cancer (NSCLC), thyroid myelin cancer (MTC), and other types of thyroid cancer.
In terms of medication, Retevmo is available or or without food twice a day. Retevmo is the first drug approved specifically for cancer patients with RET gene changes. The drug is suitable for treatment: (1) adult patients with advanced or metastatic NSCLC; (2) patients with advanced or metastatic MTC who are ≥ 12 years of age and require systematic treatment; and (3) patients with advanced RET fusion-positive thyroid cancer who are ≥12 years of age, need systematic treatment, stop responding to radioactive iodine therapy, or are not suitable for radioiodine therapy. In particular, up to 50% of RET fusion-positive NSCLC patients may have tumor brain metastasis, and in patients with baseline brain metastasis, Retevmo showed strong efficacy, with intracranial remission (CNS-ORR) up to 91% (n-10/11). (Bio Valley Bioon .com)
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