EU Approves Roche’s RET Inhibitor Gavreto (Pralsetinib) for First-Line Treatment of RET Fusion-Positive Advanced NSCLC; Now Available in China

Roche recently announced that the European Commission (EC) has granted conditional approval for precisionTumorStudy Drugs——RET Kinase Inhibitor Gavreto (Chinese Trade Name: Pulzhen®, Generic Name: Pralsetinib): As a monotherapy, it is used to treat adult patients with RET fusion-positive advanced non-small cell lung cancer (NSCLC) who have not previously received RET inhibitor treatment. Notably,Gavreto is the first and only precision therapy approved by the EU for frontline treatment of RET fusion-positive advanced NSCLC.

Gavreto is an orally administered, 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 various cancers. Gavreto has demonstrated efficacy in treating multiple types of solid tumors, reflecting tumor-agnostic potential.

This approval is based on the results of the Phase I/II ARROW study, which showed that Gavreto demonstrated rapid, potent, and durable clinical responses in patients with advanced RET fusion-positive NSCLC: (1)In 75 patients who had not previously received treatment (treatment-naive), the overall response rate (ORR) was 72.0% (95% CI: 60.4%, 81.8%), the median duration of response (DOR) has not been reached (95% CI: 9.0 months, NR); (2)In 136 patients previously treated with platinum-based chemotherapy, the ORR was 58.8% (95% CI: 50.1%, 67.2%), with a median DOR of 22.3 months.(95% CI: 15.1 months, NR). In this study, Gavreto was generally well-tolerated with a low discontinuation rate; common grade 3-4 adverse events reported by patients included:Adverse ReactionsFor neutropenia (20.1%),Anemia(17.6%) andHypertension（16.1%）。

Levi Garraway, MD, Chief Medical Officer and Head of Global Product Development at Roche, stated: "Today's approval represents an important step in providing targeted therapies to patients with RET fusion-positive advanced non-small cell lung cancer. These patients have historically had limited treatment options. By utilizing cancer genomic profiling upfront, healthcare professionals can identify specific genetic alterations and predict the clinical benefit of first-line treatment options such as Gavreto."

RET activation fusions and mutations are key disease drivers in many cancer types, including NSCLC and MTC. RET fusions occur in approximately 1-2% of NSCLC patients, about 10-20% of papillary thyroid carcinoma (PTC) patients, while RET mutations are implicated in roughly 90% of advanced MTC patients. Additionally, in colorectal cancer,Breast CancerLow-frequency RET alterations have also been observed in pancreatic cancer and other cancers, and RET fusions have been observed in resistant, EGFR-mutant NSCLC patients.

Pralsetinib (Pralsetinib) was designed by the research team of Blueprint Medicines based on their proprietary compound library. In preclinical studies, pralsetinib consistently demonstrated sub-nanomolar potency against the most common RET gene fusions, activating mutations, and resistance mutations. Moreover, the selectivity of pralsetinib for RET has significantly improved compared to approved multi-kinase inhibitors, with over 90 times greater efficacy for RET than for VEGFR2. By inhibiting primary and secondary mutations, pralsetinib is expected to overcome and prevent the occurrence of clinical resistance. This treatment is anticipated to achieve durable clinical responses in patients with various RET alterations while maintaining a favorable safety profile.

In July 2020, Roche entered into a $1.7 billion licensing and collaboration agreement with Blueprint, securing exclusive rights to Gavreto outside the United States (excluding Greater China) and co-commercialization rights in the U.S. market. According to the previous agreement signed with Blueprint,CStone Pharmaceuticals has exclusive rights to Gavreto in Greater China.

In the United States, Gavreto has been approved for three indications: (1) for the treatment of...FDA(1) Approved testing methods confirm adult patients with metastatic RET fusion-positive NSCLC; (2) For the treatment of advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adult and pediatric patients aged 12 years and older requiring systemic therapy; (3) For the treatment of advanced or metastatic RET fusion-positive thyroid cancer in adult and pediatric patients aged 12 years and older requiring systemic therapy and who are radioactive iodine-refractory (if applicable).

Pralsetinib Chemical Structure (Image Source: wikimedia.org)

In China, Gavreto (Pralsetinib, brand name: Puljia®) has been approved by the National Medical Products Administration (NMPA) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for rearranged during transfection (RET) gene fusions and have previously received platinum-based chemotherapy. The new indication applications for Gavreto (Puljia®, Pralsetinib) for the treatment of advanced or metastatic medullary thyroid carcinoma (MTC) with RET mutations requiring systemic therapy, and for advanced or metastatic RET fusion-positive thyroid cancer that requires systemic therapy and is radioactive iodine-refractory (if radioactive iodine is applicable), were accepted by the NMPA in April and included in the priority review.

In September this year,Gavreto (Pralsetinib, Brand name: Pulzhen) has been included in the 2021 edition of the Chinese Society of Clinical Oncology (CSCO).TumorTreatment Guidelines Medication Recommendations. Gavreto® Included for the First Time in Medication Recommendations for Two Cancer Types:(1) Second-line treatment for RET fusion gene-positive Stage IV non-small cell lung cancer (NSCLC) (Grade II recommendation); (2) Systemic treatment for RET fusion gene-positive radioactive iodine-refractory recurrent metastatic differentiated thyroid cancer (DTC) (Grade II recommendation).

Source of Original Text:European Commission approves Roche’s Gavreto (pralsetinib) for the treatment of adults with RET fusion-positive advanced non-small cell lung cancer