FDA Approves GAVRETO (Pralsetinib) For Adult Patients with Metastatic Rearranged During Transfection Fusion-Positive Non-Small Cell Lung Cancer

FDA Approves GAVRETO (Pralsetinib) For Adult Patients with Metastatic Rearranged During Transfection Fusion-Positive Non-Small Cell Lung Cancer

On September 4, 2020, the U.S. Food and Drug Administration (FDA) approved GAVRETO (pralsetinib) 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 test. Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The approved recommended dosage of GAVRETO (pralsetinib) is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO). Continue treatment until disease progression or until unacceptable toxicity.

Additional information regarding dosage and administration as well as warnings and precautions about interstitial lung disease (ILD)/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, risk of impaired wound healing, and embryo-fetal toxicity can be found in the full prescribing information linked below. GAVRETO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T).
• General PK: At 400 mg once daily under fasting conditions, the steady state geometric mean (CV%) of C_max and AUC_0-24h of pralsetinib is 2830 (52.5%) ng/mL and 43900 (60.2%) h•ng/mL, respectively. Pralsetinib C_max and AUC increases inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose). Pralsetinib plasma concentrations reaches steady state by 3 to 5 days. The mean accumulation ratio is < 2-fold after once-daily repeated oral administration.
• Absorption: T_max ranges from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg (0.15 to 1.5 times the recommended dose).
• Food Effect: The mean (90% CI) C_max of pralsetinib increases by 104% (65%,153%), the mean (90% CI) AUC_0-INF increases by 122% (96%,152%), and the median T_max is delayed from 4 to 8.5 hours, following administration of a single dose of GAVRETO with a high-fat meal compared to the fasted state.
• Distribution: The mean (CV%) apparent volume of distribution of pralsetinib is 228 L (75%). Protein binding of pralsetinib is 97.1% and is independent of concentration.
• Elimination: The mean (± SD) plasma elimination half-life of pralsetinib is 22.2 hours (13.5) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance of pralsetinib is 9.1 L/h (60%) at steady state.
• Metabolism: Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro.
• Excretion: Approximately 73% (66% as unchanged) of the total administered radiolabeled pralsetinib was recovered in feces and 6% (4.8% as unchanged) in urine.

Drug Interactions

• Strong CYP3A Inhibitors: Avoid coadministration. Coadministration of GAVRETO with a strong CYP3A inhibitor increases pralsetinib exposure, which may increase the incidence and severity of adverse reactions of GAVRETO.
• Combined P-gp and Strong CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the current dose of GAVRETO as recommended below. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the combined P-gp and strong CYP3A inhibitor.

o Reduce 400 mg once daily to 200 mg once daily
o Reduce 300 mg once daily to 200 mg once daily
o Reduce 200 mg once daily to 100 mg once daily

• Strong CYP3A Inducers: Avoid coadministration. If coadministration cannot be avoided, increase the starting dose of GAVRETO to double the current GAVRETO dosage starting on Day 7 of coadministration of GAVRETO with the strong CYP3A inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the strong CYP3A inducer. Coadministration of GAVRETO with a strong CYP3A inducer decreases pralsetinib exposure, which may decrease efficacy of GAVRETO.

Use in Specific Populations

• No clinically significant differences in the PK of pralsetinib were observed based on age (18 to 87 years), sex, race (White, Black, Asian), body weight (29.5 to 149 kg), or mild and moderate renal impairment (CLcr 30-89 mL/min). Pralsetinib has not been studied in patients with severe renal impairment (CLcr < 15 mL/min).
• Hepatic Impairment: No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). GAVRETO has not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).

Efficacy and Safety

Efficacy of GAVRETO was evaluated in patients with RET fusion-positive metastatic NSCLC in a multicenter, non-randomized, open-label, multi-cohort clinical trial. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review according to RECIST v1.1. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 25%) were fatigue, constipation, musculoskeletal pain, and hypertension. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected), and increased ALT.

Full prescribing information is available at https://go.usa.gov/xGWz4.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.