The approval was based on results from the phase 1/2 ARROW clinical trial, which demonstrated 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 FDA has granted accelerated approval to pralsetinib (Gavreto) for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test, according to Blueprint Medicines, the developer of the drug.1
Pralsetinib is a once-daily oral RET-targeted therapy designed to selectively and potently inhibit RET alterations that drive a number of cancer types, including approximately 1% to 2% of patients with NSCLC. Currently, RET is 1 of 7 NSCLC biomarkers that can be targeted with an FDA-approved therapy.
The approval of pralsetinib was based on results observed in the phase 1/2 ARROW clinical trial, which demonstrated 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. However, continued approval for this indication may be dependent upon verification and description of clinical benefit in a confirmatory trial.
"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, or Gavreto, marks another milestone in a paradigm shift toward precision medicine," Vivek Subbiah, MD, 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, as well as an investigator on the ARROW trial, said in a press release. "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,” Subbiah continued. “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."
The phase 1/2, open-label, first-in-human study was designed to evaluate the safety, tolerability, and efficacy of pralsetinib administered orally in individuals with RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancer, and other RET-altered solid tumors.2 The trial consists of 2 parts, including an already completed dose escalation portion and an expansion portion in patients treated with 400 mg of pralsetinib, once-daily. The study is being conducted at multiple sites across the US, EU, and Asia.
In 87 patients who were previously treated with platinum-based chemotherapy, the overall response rate (ORR) was 57% (95% CI, 46% to 68%) with a 5.7% complete response (CR) rate, and the median duration of response (DOR) was not estimable (95% CI, 15.2 months to not estimable). Moreover, among 27 treatment-naïve patients who were ineligible for platinum-based chemotherapy per the study protocol, the ORR was 70% (95% CI, 50% to 86%) with an 11% CR rate, and the median DOR was 9.0 months (95% CI, 6.3 months to not estimable).
Overall, the most common adverse events observed in the study were fatigue, constipation, musculoskeletal pain, and hypertension. Importantly, pralsetinib also has warnings and precautions of interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, risk of impaired wound healing and risk of embryo-fetal toxicity.
The drug will be co-commercialized in the US by Blueprint Medicines, Roche, and Genentech. Notably, pralsetinib should be available in the US within 1 week in a 100 mg dose strength. The recommended starting dose is 400 mg once daily.
The FDA also granted priority review to a new drug application (NDA) for pralsetinib for the treatment of patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer. A prescription drug user fee act date was set by the FDA for February 28, 2021.
1. Blueprint Medicines Announces FDA Approval of GAVRETO™ (pralsetinib) for the Treatment of Adults with Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer [news release]. Cambridge, Massachusetts. Published September 5, 2020. Accessed September 8, 2020. https://www.biospace.com/article/releases/blueprint-medicines-announces-fda-approval-of-gavreto-pralsetinib-for-the-treatment-of-adults-with-metastatic-ret-fusion-positive-non-small-cell-lung-cancer/
2. Genentech Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer [news release]. South San Francisco, California. Published September 4, 2020. Accessed September 8, 2020. https://www.gene.com/media/press-releases/14875/2020-09-04/genentech-announces-fda-approval-of-gavr