The US Food and Drug Administration (FDA) has granted accelerated approval to pralsetinib (Gavreto™; Blueprint Medicines) for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved companion diagnostic test.

The approval is based on data from the Phase I/II, multicentre, open-label, multi-cohort ARROW clinical trial, which showed efficacy for pralsetinib in patients with RET fusion-positive NSCLC with or without prior therapy, and regardless of RET fusion partner or central nervous system involvement.

The approval was granted accelerated approval based on ORR and response duration. Continued approval may be contingent upon verification of clinical benefit in a confirmatory trial.

RET-activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and medullary thyroid cancer (MTC), and treatment options that selectively target these genetic alterations are limited. In NSCLC, RET fusions represent approximately 1-2% of patients.[1]

Oral treatment
Pralsetinib is a once-daily oral RET-targeted therapy designed to selectively and potently inhibit RET alterations that drive many cancer types, including approximately 1 to 2% of patients with NSCLC. Currently, RET is one of seven NSCLC biomarkers that can be targeted with an FDA-approved therapy.

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Under Blueprint Medicines’ collaboration with Roche, Blueprint Medicines and Genentech, a member of the Roche Group, will co-commercialize pralsetinib in the U.S.

This makes pralsetinib the sixth FDA-approved lung cancer drug in the Genentech/Roche portfolio for lung cancer. In addition to pralsetinib, the company’s portfolio also includes  the immuno-oncology drug atezolizumab (Tecentriq®), approved as a first-line treatment for adults with metastatic NSCLC, entrectinib (Rozlytrek™), indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive, alectinib (Alecensa®), indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (mNSCLC) as detected by an FDA-approved test, bevacizumab (Avastin™), prescribed in combination with carboplatin and paclitaxel, and indicated for the first‑line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer, and erlotinib (Tarceva™), which is prescribed for patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen.

Companion diagnostic
The FDA has also approved the Oncomine™ Dx Target (ODxT) Test , a companion diagnostic for pralsetinib developed by Life Technologies, a subsidiarey of Thermo Fisher Scientific).

Improved care
The efficacy of pralsetinib was investigated in patients whose tumors had RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next-generation sequencing, fluorescence in situ hybridization, or other tests. The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST v1.1.

Efficacy for RET fusion-positive NSCLC was evaluated in 87 patients previously treated with platinum chemotherapy. The ORR was 57% (95% confidence interval [CI] 46%, 68%); 80% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 27 patients who never received systemic treatment. The ORR for these patients was 70% (95% CI 50%, 86%); 58% of responding patients had responses lasting 6 months or longer.

“Targeted therapies have dramatically improved care for patients with non-small cell lung cancer driven by oncogenes, including EGFR and ALK, and the approval of the selective RET inhibitor pralsetinib marks another milestone in a paradigm shift toward precision medicine,” said Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics and center medical director of the Clinical Center for Targeted Therapy at The University of Texas MD Anderson Cancer Center, and an investigator on the ARROW trial.

“Patients treated with pralsetinib had durable clinical responses, with a subset achieving complete responses characterized by the resolution of all target lesions, an uncommon outcome in metastatic lung cancer. We observed this activity with or without prior therapy and regardless of RET fusion partner or the presence of brain metastases. This approval represents an important advance with the potential to change standards of care for patients with RET fusion-positive non-small cell lung cancer, who have historically had limited treatment options,” Subbiah added.

Adverse events
The most common adverse reactions, including laboratory abnormalities, (≥25%) were increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase, increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.

Breakthrough therapy
“Pralsetinib is the second breakthrough therapy discovered by Blueprint Medicines that has received FDA approval in 2020, less than 10 years since the company started operations. This progress reflects the power of our scientific platform, our focus on delivering transformative outcomes to patients and our urgency to address important medical needs,” said Jeff Albers, Chief Executive Officer of Blueprint Medicines.

“We are working with our partner Genentech to rapidly bring pralsetinib to healthcare providers and patients in the U.S., applying our complementary capabilities to support patient identification and access to treatment. Ultimately, we aim to accelerate the identification of patients with RET fusion-positive non-small cell lung cancer and enable them to rapidly access treatment with pralsetinib,” Albers concluded.

Thyroid Cancer
The FDA has also granted Priority Review to pralsetinib for the treatment of people with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer, and is expected to make a decision on approval by 28 February 2021. This New Drug Application (NDA) was accepted for review under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.

Prescribing information
The recommended pralsetinib dose is 400 mg orally once daily. Pralsetinib is taken on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib).

Click here for the full prescribing information for pralsetinib.

Clinical trials
Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW) – NCT03037385

[1] Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes [published correction appears in Nat Rev Clin Oncol. 2017 Nov 28;:]. Nat Rev Clin Oncol. 2018;15(3):151-167. doi:10.1038/nrclinonc.2017.175

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