On September 4, 2020, pralsetinib (Gavreto) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for treatment of adults with metastatic RET fusion–positive non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.1,2 The FDA simultaneously approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for pralsetinib.
Supporting Efficacy Data
Approval was based on findings from the multicenter, open-label, multicohort ARROW trial (ClinicalTrials.gov identifier NCT03037385).2 The study enrolled in separate cohorts patients with metastatic RET fusion–positive NSCLC who experienced disease progression on platinum-based chemotherapy and treatment-naive patients with metastatic NSCLC. All patients received oral pralsetinib at 400 mg once daily until disease progression or unacceptable toxicity. The main efficacy outcome measures were overall response rate and response duration determined by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1.
Among the 87 patients with prior treatment with platinum chemotherapy, an objective response was observed in 50 (57%, 95% confidence interval [CI] = 46%–68%), with complete response in 5.7%. The median response duration was not reached (95% CI = 15.2 months to not estimable), with responses lasting at least 6 months in 80% of responders.
In an exploratory subgroup analysis among 39 patients who received anti–PD-1 or anti–PD-L1 therapy sequentially or concurrently with platinum-based chemotherapy, the objective response rate was 59% (95% CI = 42%–74%), and the median duration of response was not reached (95% CI = 11.3 months to not estimable). Among eight patients with measurable central nervous system metastases at baseline, an intracranial response was observed in four (complete response in two), and three responders had a response lasting at least 6 months.
Among the 27 patients with no prior systemic treatment, an objective response was observed in 19 (70%, 95% CI = 50%–86%), including a complete response in 11%. The median duration of response was 9.0 months (95% CI = 6.3 months to not estimable), with 58% of responders having responses lasting at least 6 months.
How It Works
Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M, and RET M918T). At higher but clinically achievable concentrations, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.
Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to uncontrolled cell proliferation. Pralsetinib exhibited antitumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L, and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.
How It Is Used
Patients must be selected for pralsetinib treatment based on the presence of a RET gene fusion as detected by an FDA-approved test.
The recommended dosage of pralsetinib is 400 mg once daily on an empty stomach, with treatment continuing until disease progression or unacceptable toxicity.
The recommended dose reductions for adverse reactions are sequentially to 300 mg, 200 mg, and 100 mg once daily. Treatment should be discontinued in patients unable to tolerate 100 mg once daily.
Prescribing information provides detailed instructions on dosage modification, including dose reduction and withholding of treatment, and treatment discontinuation, for adverse reactions including interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, and other grade 3 or 4 toxicity.
Concomitant use of pralsetinib with strong CYP3A inhibitors, combined P-gp and strong CYP3A inhibitors, and strong CYP3A inducers should be avoided. Prescribing information provides instructions on pralsetinib dose reduction if concomitant use with combined P-gp and strong CYP3A inhibitors cannot be avoided and pralsetinib dose increase if concomitant use with strong CYP3A inducers cannot be avoided.
Safety data are from a total of 220 patients with metastatic, rearranged-during-transfection (RET fusion–positive) NSCLC who received pralsetinib at 400 mg once daily in the ARROW trial. Among these patients, the median age was 60 years (range = 26–87 years), 52% were female, 50% were White, 41% were Asian, and 4% were Hispanic/Latinx.
The most common adverse events of any grade (≥ 25%), including laboratory abnormalities, were increased aspartate aminotransferase (AST; 69%), decreased hemoglobin (54%), decreased lymphocytes (52%), decreased neutrophils (52%), increased alanine aminotransferase (ALT; 46%), increased creatinine (42%), increased alkaline phosphatase (40%), fatigue (35%), constipation (35%), musculoskeletal pain (32%), decreased calcium (29%), hypertension (28%), decreased sodium (27%), decreased phosphate (27%), and decreased platelets (26%).
The most common grade 3 or 4 nonlaboratory adverse events were hypertension (14%), pneumonia (8%), and diarrhea (3.2%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (20%), decreased neutrophils (10%), and decreased phosphate (9%).
Serious adverse events occurred in 45% of patients, with those occurring in at least 2% consisting of pneumonia, pneumonitis, sepsis, urinary tract infection, and pyrexia. Adverse events led to dose interruption in 60%, with the most common causes (≥ 2%) including neutropenia, pneumonitis, anemia, hypertension, pneumonia, pyrexia, increased AST, increased creatine phosphokinase, fatigue, leukopenia, thrombocytopenia, vomiting, increased ALT, sepsis, and dyspnea. Dose reductions due to adverse events occurred in 36%, with the most common causes (≥ 2%) consisting of neutropenia, anemia, pneumonitis, decrease in neutrophil count, fatigue, hypertension, pneumonia, and leukopenia. Permanent discontinuation of treatment due to adverse events occurred in 15% of patients, with the most common causes being pneumonitis (1.8%), pneumonia (1.8%), and sepsis (1%). Fatal adverse events occurred in 5% of patients, with causes including pneumonia in three patients and sepsis in two.
Pralsetinib has warnings/precautions for interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, risk of impaired wound healing, and embryofetal toxicity.
Treatment should be permanently discontinued for recurrent interstitial lung disease/pneumonitis or grade 3 or 4 interstitial lung disease/pneumonitis. Treatment should not be started in patients with uncontrolled hypertension. Blood pressure should be optimized prior to initiation and monitored after 1 week, at least monthly thereafter, and as clinically indicated. ALT and AST levels should be monitored prior to initiating treatment, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Treatment should be permanently discontinued for severe or life-threatening hemorrhage. Treatment should be withheld for at least 5 days prior to elective surgery and for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pralsetinib after resolution of wound healing complications has not been
Patients should be advised not to breastfeed while receiving pralsetinib.
1. U.S. Food and Drug Administration: 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. Accessed September 18, 2020.
2. Gavreto (pralsetinib) capsules, for oral use, prescribing information, Blueprint Medicines, September 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213721s000lbl.pdf. Accessed September 18, 2020.