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Home Roche's RET Inhibitor Gavreto (Pralsetinib) Receives Positive CHMP Opinion for First-Line Treatment of RET Fusion-Positive Advanced NSCLC in EU; Already Approved in China

Roche's RET Inhibitor Gavreto (Pralsetinib) Receives Positive CHMP Opinion for First-Line Treatment of RET Fusion-Positive Advanced NSCLC in EU; Already Approved in China

Sep 21, 2021 02:32 CST Updated 02:32
Roche

Oncology Drug Research, Development, and Manufacturing

Committee for Medicinal Products for Human Use

Committee for Medicinal Products for Human Use (CHMP)The Committee for Medicinal Products for Human Use (CHMP) is the committee within the European Medicines Agency (EMA) responsible for human medicines. The CHMP replaced the former Committee for Proprietary Medicinal Products (CPMP) in May 2004.The CHMP plays a vital role in the authorization of medicines in the European Union (EU). In the centralized procedure, the CHMP is responsible for: 1) conducting initial assessments of marketing authorization applications across the EU; assessing modifications or extensions to existing marketing authorizations (“variations”); considering recommendations from the Agency’s Pharmacovigilance Risk Assessment Committee regarding the safety of medicines on the market, and, where necessary, advising the European Commission to amend the marketing authorization of a medicinal product, or to suspend or withdraw it from the market.The CHMP also evaluates medicines authorized at the national level that are referred to the EMA, with the aim of maintaining a harmonized position throughout the EU.Furthermore, the CHMP and its working groups promote the development of medicines and pharmaceutical regulation by: providing scientific advice to companies researching and developing new medicines; developing scientific and regulatory guidelines to assist pharmaceutical companies in preparing marketing authorization applications for human medicines; and collaborating with international partners to harmonize regulatory requirements.


September 20, 2021 /BioonBIOON/ -- Roche recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending approvalPrecisionTumorDrug — the RET kinase inhibitor Gavreto (Chinese trade name: Pujihua®, generic name: pralsetinib), as a monotherapy for the treatment of adult patients with RET fusion-positive advanced non-small cell lung cancer (NSCLC) who are RET inhibitor-naïve.

The CHMP opinion will now be submitted to the European Commission (EC) for review, which typically renders a final decision within two months. If approved, Gavreto will become the first and only targeted therapy indicated for the first-line treatment of advanced RET fusion-positive non-small cell lung cancer (NSCLC) in the European Union. The CHMP’s positive opinion is based on results from the Phase 1/2 ARROW study, with data showing:Gavreto demonstrated rapid, potent, and durable clinical responses in patients with advanced RET fusion-positive NSCLC.

Gavreto is an oral, once-daily, potent and highly selective RET inhibitor designed and developed by Blueprint Medicines to inhibit RET alterations (fusions and mutations, including predicted resistance mutations) that drive multiple cancers.Gavreto has demonstrated efficacy in treating multiple types of solid tumors, reflecting its tumour-agnostic potential.

Levi Garraway, M.D., Chief Medical Officer and Head of Global Product Development at Roche, stated: “The CHMP’s positive opinion of Gavreto represents another important step toward our goal of providing effective treatments targeting the genetic drivers of the disease to as many cancer patients as possible. Advances in personalized medicine also highlight# TumorThe importance of genomic analysis in identifying patients who may benefit from targeted therapy.”


RET fusions and activating mutations are key oncogenic drivers in many cancer types, including NSCLC and MTC. RET fusions occur in approximately 1–2% of NSCLC patients and 10–20% of patients with papillary thyroid carcinoma (PTC), while RET mutations are implicated in approximately 90% of patients with advanced MTC. Additionally, in colorectal cancer,Breast cancer、Low-frequency RET alterations have also been observed in pancreatic cancer and other cancers, and RET fusions have also been observed in patients with drug-resistant, EGFR-mutated NSCLC.

Pralsetinib was designed by the research team at Blueprint Medicines based on its proprietary compound library. 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 enhanced selectivity for RET compared with approved multikinase inhibitors, demonstrating more than a 90-fold greater potency for RET relative to VEGFR2. By inhibiting both primary and secondary mutations, pralsetinib holds promise for overcoming and preventing the development of clinical resistance. This therapeutic approach is expected to achieve durable clinical responses in patients harboring various RET alterations, while maintaining a favorable safety profile.

In July 2020, Roche and Blueprint entered into a $1.7 billion license and collaboration agreement, under which Roche obtained exclusive rights to Gavreto outside the United States (excluding Greater China) and co-commercialization rights in the U.S. market.Pursuant to the agreement previously signed with Blueprint, CStone Pharmaceuticals holds the exclusive license for Gavreto in Greater China.

In the United States, Gavreto has been approved for 3 indications.: (1) Indicated for the treatment ofFDAadult patients with metastatic RET fusion-positive NSCLC confirmed by an approved test; (2) for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; (3) for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if applicable).

In China, Gavreto® (pralsetinib) has been approved by the National Medical Products Administration (NMPA) for the treatment of adult patients with locally advanced or metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) who have previously received platinum-based chemotherapy.. The new indication application for Gavreto® (pralsetinib) for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) requiring systemic therapy, and for advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy and radioactive iodine-refractory (if radioactive iodine is appropriate), was also accepted by the NMPA in April and included in the priority review program.

Chemical Structure of Pralsetinib (Image source: wikimedia.org)

ARROW is an ongoing, open-label, phase 1/2 clinical study designed to evaluate the safety, tolerability, and efficacy of once-daily oral Gavreto in the treatment of RET fusion-positive NSCLC, RET-mutant MTC, RET-altered thyroid cancer, and other RET-altered solid tumors. The latest updates from this study were presented at the 2021 ASCO Annual Meeting.

Data show that,Among 126 patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy, the overall response rate (ORR) to Gavreto treatment was 62% (95% CI: 53%, 70%), the clinical benefit rate (CBR) was 74% (95% CI: 65%, 81%), the disease control rate (DCR) was 91% (95% CI: 85%, 96%), and the median progression-free survival (PFS) was 16.5 months (95% CI: 10.5 months, 24.1 months).

In 68 patients who had not previously received treatment (treatment-naive), the confirmed ORR was 79% (95% CI: 68%, 88%), CBR was 82% (95% CI: 71%, 91%), DCR was 93% (95% CI: 84%, 98%), and median PFS was 13.0 months (95% CI: 9.1 months, not reached [NR]). In 25 treatment-naive patients enrolled after the revision of eligibility criteria (which allowed platinum-based chemotherapy), the confirmed ORR was 88% (95% CI: 69%, 98%), CBR was 88% (95% CI: 69%, 98%), and DCR was 96% (95% CI: 80%, 100%).In the study, Gavreto was well tolerated; among 471 patients in the ARROW trial, various types of RET alterationsTumorAmong patients, the most common (≥25%) treatment-related adverse events included neutropenia, elevated liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]),Anemia、Decreased white blood cell count、Hypertensionand lack of energy (fatigue).

It is worth noting that,Eli Lilly's Retevmo (selpercatinib) is the first approved RET inhibitor.This drug is manufactured byEli LillyDeveloped by its oncology subsidiary, Loxo Oncology, and received US approval in May 2020.FDAApproved, for the treatment of three types with RET gene alterations (mutations or fusions)`Tumor`Patients: non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other types of thyroid cancer.

Regarding administration, Retevmo is taken orally twice daily, with or without food. Retevmo is the first therapy specifically approved for the treatment of cancer patients harboring RET gene alterations. The drug is indicated for the treatment of: (1) adult patients with advanced or metastatic NSCLC; (2) patients aged ≥12 years with advanced or metastatic MTC requiring systemic therapy; (3) patients aged ≥12 years with advanced RET fusion-positive thyroid cancer requiring systemic therapy and who are radioactive iodine-refractory or ineligible for radioactive iodine therapy. Notably, up to 50% of patients with RET fusion-positive NSCLC may have# TumorBrain metastases: In patients with baseline brain metastases, Retevmo demonstrated robust efficacy, with a central nervous system objective response rate (CNS-ORR) of 91% (n=10/11). (Bioon.com)