The FDA has granted accelerated approval to pralsetinib (GavretoTM, Blueprint Medicines Corporation), an oral selective RET kinase inhibitor, for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by the OncomineTM Dx Target (ODxT) Test (Life Technologies Corporation), which has also been approved as a companion diagnostic. RET alterations are implicated in 1% to 2% of NSCLC cases, as well as in a number of other cancer types.
The pralsetinib approval was based on data from the multicenter, open-label phase 1/2 ARROW trial (NCT03037385), a basket trial for patients with RET-altered solid tumors. The study's primary efficacy end points were overall response rate and duration of response, as determined by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Among 87 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy, pralsetinib produced an overall response rate of 57%, including a complete response rate of 5.7%; 80% of responses lasted six months or more, with a median duration of response that was not estimable. Among 27 patients naive to systemic treatment, pralsetinib produced an overall response rate of 70%, including a complete response rate of 11%; 58% of responses lasted at least six months, with a median duration of response of 9.0 months.
"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," commented study investigator 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, 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."
Adverse events of note included pneumonitis, occurring in 10% of patients, with 2.7% experiencing grade 3/4 reactions and 0.5% experiencing fatal reactions, and hypertension, occurring in 29% of patients, including grade 3 hypertension in 14% of patients. Hepatotoxicity was a significant concern, with increased aspartate aminotransferase (AST) occurring in 69% of patients, including grade 3/4 events in 5.4% of patients, and increased alanine aminotransferase (ALT) occurring in 46% of patients, including grade 3/4 events in 6% of patients; serious hepatic adverse reactions occurred in 2.1% of patients. Hemorrhagic events of grade 3 or higher occurred in 2.5% of patients, including one fatal hemorrhagic event. Pralsetinib has the potential to cause impaired wound healing, which can occur in patients who receive drugs inhibiting the vascular endothelial growth factor (VEGF) signaling pathway. It can also cause fetal harm when administered to a pregnant woman.
Any-grade adverse reactions occurring in at least 25% of patients included fatigue, constipation, and musculoskeletal pain, as well as hypertension. Grade 3/4 laboratory abnormalities occurring in at least 2% of patients included decreased lymphocytes, neutrophils, phosphate, hemoglobin, sodium, and calcium (corrected), as well as increased AST and ALT.
The recommended dosage of pralsetinib is 400 mg, administered orally once daily on an empty stomach.
Pralsetinib should not be coadministered with strong CYP3A inhibitors, combined P-gp and strong CYP3A inhibitors, or strong CYP3A inducers. If coadministration with combined P-gp and strong CYP3A inhibitors cannot be avoided, the pralsetinib dose should be reduced; if coadministration with strong CYP3A inducers cannot be avoided, the pralsetinib dose should be increased.
Because pralsetinib was granted accelerated approval, continued approval may be contingent upon verification of clinical benefit in one or more confirmatory trials.
For More Information
Clinicaltrials.gov (2020). 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). NLM identifier: NCT03037385.
US Food & Drug Administration (2020). FDA approves pralsetinib for lung cancer with RET gene fusions. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions
Blueprint Medicines Corporation (2020). Blueprint Medicines announces FDA approval of Gavreto™ (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. Available at: http://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-fda-approval-gavretotm-pralsetinibImage Credit: Scott Wilkinson and Adam Marcus. Courtesy of the National Cancer Institute / Winship Cancer Institute of Emory University