Roche RET inhibitor Gavreto (Platinib) is about to be approved in EU

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Roche RET inhibitor Gavreto (Platinib) is about to be approved in EU: the treatment of RET fusion-positive lung cancer

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Roche RET inhibitor Gavreto (Platinib) is about to be approved in EU: the treatment of RET fusion-positive lung cancer. 

Roche recently announced that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive review suggesting the approval of the precision oncology drug-RET kinase inhibitor Gavreto (generic name: pralsetinib, general Latinib), as a monotherapy, is used to treat adult patients with RET fusion-positive advanced non-small cell lung cancer (NSCLC) who have not previously been treated with RET inhibitors.

Now, CHMP’s opinions will be submitted to the European Commission (EC) for review, which usually makes a final review decision within 2 months. If approved, Gavreto will become the first and only targeted drug in the European Union to be included in the first-line treatment of RET fusion-positive advanced NSCLC.

The positive opinions of CHMP, based on the results of the Phase I/II ARROW study, data show that Gavreto shows 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 changes (fusions and mutations, including predicted drug-resistant mutations) that cause a variety of cancers. Gavreto has shown efficacy in the treatment of various types of solid tumors, reflecting the potential of tumor-agnostic.

Levi Garraway, MD, Roche’s Chief Medical Officer and Head of Global Product Development, said: “CHMP’s positive evaluation of Gavreto represents another step towards providing effective treatments to as many cancer patients as possible for disease gene drivers. An important step. Advances in personalized medicine also emphasize the importance of tumor genome analysis to identify patients who may benefit from targeted therapy.”

RET-activated fusions and mutations 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 patients with papillary thyroid carcinoma (PTC), and RET mutations involve about 90% of patients with advanced MTC.

In addition, low-frequency RET changes have also been observed in colorectal cancer, breast cancer, pancreatic cancer and other cancers, and RET fusion has also been observed in patients with drug-resistant, EGFR-mutated NSCLC.

pralsetinib is designed by the research team of Blueprint Medicines based on its proprietary compound library. In preclinical studies, pralsetinib has always shown sub-nanomolar titers against the most common RET gene fusions, activating mutations and resistance mutations.

In addition, the selectivity of pralsetinib for RET is significantly improved compared with approved multi-kinase inhibitors. Among them, the effectiveness of pralsetinib is more than 90-fold higher than that of VEGFR2. By inhibiting primary and secondary mutations, pralsetinib is expected to overcome and prevent the occurrence of clinical drug resistance.

This treatment method is expected to achieve long-lasting clinical remission in patients with different RET variants, and has good safety.

In the United States, Gavreto has been approved for 3 indications:

(1) For the treatment of adult patients with metastatic RET fusion-positive NSCLC confirmed by FDA-approved testing methods; (

2) For the treatment of advanced or metastatic RET-mutated medullary thyroid carcinoma (MTC) adults and children 12 years and older who require systemic treatment;

(3) For the treatment of adults and children with advanced or metastatic RET fusion-positive thyroid cancer that require systemic treatment and are refractory to radioactive iodine (if applicable).

Pratinib-pralsetinib chemical structure (picture source: wikimedia.org)

ARROW is an ongoing Phase 1/2 open-label human study aimed at evaluating the safety of Gavreto in the treatment of RET fusion-positive NSCLC, RET mutant MTC, RET-prone thyroid cancer, and other RET-altered solid tumors. Tolerability and effectiveness. The latest progress of this research will be announced at the 2021 ASCO conference.

The data showed that among 126 patients with RET fusion-positive NSCLC who had previously received platinum-containing chemotherapy, the overall response rate (ORR) of Gavreto treatment was 62% (95% CI: 53%, 70%) and the clinical benefit rate (CBR) It 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).

Among 68 patients who had not previously received treatment (treatment-naive), the confirmed ORR was 79% (95%CI: 68%, 88%), and the CBR was 82% (95%CI: 71%, 91%), DCR was 93% (95%CI: 84%, 98%), median PFS was 13.0 months (95%CI: 9.1 months, did not reach [NR]).

Among the 25 patients who were enrolled after the revision of the eligibility criteria (allowed to receive platinum-containing chemotherapy) patients, the confirmed ORR was 88% (95%CI: 69%, 98%), and the CBR was 88% (95%CI: 69%, 98%), DCR was 96% (95%CI: 80%, 100%).

In the study, Gavreto was well tolerated; among 471 patients in the ARROW trial, among the various types of tumor patients with RET changes, the most common (≥25%) treatment-related adverse events included neutropenia, Elevated liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), anemia, decreased white blood cell count, high blood pressure, and lack of energy (fatigue).

It is worth mentioning that Eli Lilly Retevmo (selpercatinib) is the first approved RET inhibitor. The drug was developed by Loxo Oncology, an oncology company under Eli Lilly, and was approved by the US FDA in May 2020 for the treatment of patients with 3 types of tumors with genetic alterations (mutations or fusions) in the RET gene: non-small cell lung cancer (NSCLC) , Medullary Thyroid Cancer (MTC), other types of thyroid cancer.

In terms of medication, Retevmo is taken orally twice a day, with or without food. Retevmo is the first therapeutic drug approved specifically for cancer patients carrying RET gene alterations. This medicine is suitable for the treatment of:

(1) Adult patients with advanced or metastatic NSCLC; (2) Patients with advanced or metastatic MTC who are ≥12 years old and require systemic treatment;

(3) Patients with advanced RET fusion-positive thyroid cancer who are ≥12 years old, require systemic treatment, have stopped responding to radioactive iodine therapy, or are not suitable for radioactive iodine therapy.

It is particularly worth mentioning that up to 50% of RET fusion-positive NSCLC patients may have tumor brain metastases. Among patients with baseline brain metastases, Retevmo has shown a strong effect, with intracranial remission (CNS-ORR) as high as 91% (n =10/11).

Original source: Roche receives positive CHMP opinion for Gavreto® (pralsetinib) for the treatment of adults with RET fusion-positive advanced non-small cell lung cancer

(source:internet, reference only)

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