GAVRETO LuciPral Pralsetinib Capsules

Product Name: LuciPral

English Name: Pralsetinib

Specification: 100 mg/capsule; 120 capsules/box.

[Summary]

Pralsetinib is a kinase inhibitor of wild-type RET, as well as oncogenic RET fusions (e.g., CCDC6-RET) and mutations (e.g., RET V804L, RET V804M, and RET M918T), with half-maximal inhibitory concentrations (IC50s) of less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRβ, and FGFR1 at higher concentrations; however, clinically relevant inhibition of these targets was still achieved at the Cmax (maximum plasma concentration). In cellular assays, the concentrations of pralsetinib required to inhibit RET were approximately 14-fold, 40-fold, and 12-fold lower than those required to inhibit VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive oncogenic potential through the hyperactivation of downstream signaling pathways, thereby leading to uncontrolled cellular proliferation. Pralsetinib demonstrated anti-tumor activity in cultured cells and animal tumor xenograft models harboring oncogenic RET fusions or mutations—including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L, and RET V804M. Furthermore, pralsetinib prolonged survival in mice bearing intracranial xenografts expressing KIF5B-RET or CCDC6-RET fusions.

[Indications]

Pralsetinib is an oral, once-daily, potent, and highly selective RET inhibitor indicated primarily for the treatment of the following cancers:

Non-Small Cell Lung Cancer (NSCLC)

Patients Post-Platinum-based Chemotherapy: Indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring *RET* gene fusions who have previously received platinum-based chemotherapy. Treatment-Naïve Patients: Indicated as first-line treatment for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a *RET* gene fusion.

Medullary Thyroid Carcinoma: Indicated for the treatment of adult and pediatric patients (aged 12 years and older) with advanced or metastatic *RET*-mutant medullary thyroid carcinoma (MTC) who require systemic therapy.

Thyroid Cancer: Indicated for the treatment of adult and pediatric patients (aged 12 years and older) with advanced or metastatic *RET*-fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate).

[Dosage and Administration]

The recommended dosage of pralsetinib varies depending on the specific circumstances of the patient. The following provides detailed information for different patient populations:

Adult Patients

Non-Small Cell Lung Cancer: For adult patients with locally advanced or metastatic NSCLC harboring a *RET* gene fusion, the recommended dosage is 400 mg orally once daily on an empty stomach (do not consume food for at least 2 hours before and at least 1 hour after taking the dose).

Medullary Thyroid Carcinoma: For adult patients with advanced or metastatic *RET*-mutant MTC who require systemic therapy, the recommended dosage is likewise 400 mg orally once daily on an empty stomach.

Thyroid Cancer: For adult patients with advanced or metastatic *RET*-fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate), the recommended dosage is also 400 mg orally once daily on an empty stomach.

Pediatric Patients (Aged 12 Years and Older)

Medullary Thyroid Carcinoma: Dosage is calculated based on body surface area (BSA) and administered orally once daily on an empty stomach. For a BSA ≥ 1.50 m², the dosage is 400 mg; for a BSA between 1.11 and 1.49 m², the dosage is 300 mg; and for a BSA between 0.91 and 1.10 m², the dosage is 200 mg.

Thyroid Cancer: The dosage and administration method are the same as for medullary thyroid carcinoma; the specific dosage is determined based on body surface area and administered on an empty stomach. However, in actual clinical practice, physicians will appropriately adjust the dosage based on the patient's individual circumstances—such as their hepatic and renal function status, or the occurrence of adverse reactions. Patients must strictly adhere to their physician's instructions regarding medication intake and must never alter the dosage on their own.

【Adverse Reactions】

The most common adverse reactions (≥25%) are fatigue, constipation, musculoskeletal pain, and hypertension.

The most common Grade 3 or 4 laboratory abnormalities (≥2%) are lymphopenia, neutropenia, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium, and elevated alanine aminotransferase (ALT).

【Contraindications】 None.

【Precautions】

Interstitial Lung Disease (ILD)/Pneumonitis: For Grade 1 or 2 reactions, withhold the drug until the reaction resolves, then resume at a reduced dose. Permanently discontinue the drug for recurrent ILD/pneumonitis. For Grade 3 or 4 reactions, permanently discontinue the drug.

Hypertension: Do not administer Pralsetinib to patients with uncontrolled hypertension. Optimize blood pressure control prior to initiating GAVRETO. Monitor blood pressure 1 week after initiation, at least monthly thereafter, and as clinically indicated. Based on severity, withhold, reduce the dose, or permanently discontinue Pralsetinib.

Hepatotoxicity: Monitor ALT and AST levels prior to initiating Pralsetinib, every 2 weeks during the first 3 months of treatment, monthly thereafter, and as clinically indicated. Based on severity, withhold, reduce the dose, or permanently discontinue Pralsetinib.

Hemorrhagic Events: Permanently discontinue Pralsetinib in patients experiencing severe or life-threatening hemorrhage.

Risk of Impaired Wound Healing: Withhold Pralsetinib for at least 5 days prior to elective surgery. Do not administer Pralsetinib for at least 2 weeks following major surgery, and until adequate wound healing has occurred. The safety of resuming Pralsetinib after the resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: May cause fetal harm. Women of reproductive potential should be advised of the potential risk to the fetus and are recommended to use effective non-hormonal contraception.

【Drug Interactions】

Strong CYP3A Inhibitors: Avoid concomitant use. Concomitant use with P-gp and strong CYP3A inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce the dose of Pralsetinib.

Strong CYP3A inducers: Avoid concomitant use. If concomitant use cannot be avoided, increase the dose of Pralsetinib.

[Safety and Efficacy]

The efficacy of Pralsetinib in patients with *RET* fusion-positive metastatic NSCLC was evaluated in a multicenter, non-randomized, open-label, multi-cohort clinical trial (ARROW, NCT03037385). This study enrolled patients with metastatic *RET* fusion-positive NSCLC across different cohorts, including those who had previously received platinum-based chemotherapy, as well as treatment-naïve patients with metastatic NSCLC. *RET* gene fusions were identified by local laboratories using next-generation sequencing (NGS), fluorescence *in situ* hybridization (FISH), and other assays. Among the target population of 114 patients, efficacy was retrospectively assessed in 59 patients for whom a companion diagnostic test (Dx) was utilized. Patients with asymptomatic central nervous system (CNS) metastases were eligible for enrollment, including those whose steroid use had been stable or decreasing within 2 weeks prior to study entry. Patients received Pralsetinib orally once daily at a dose of 400 mg until disease progression or unacceptable toxicity occurred.

Based on RECIST v1.1, the primary efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by a Blinded Independent Central Review (BICR).

Metastatic *RET* Fusion-Positive NSCLC Previously Treated with Platinum-Based Chemotherapy

Efficacy was evaluated in 87 patients with *RET* fusion-positive NSCLC who had previously received platinum-based chemotherapy and were enrolled in the ARROW trial cohorts.

The median age was 60 years (range: 28 to 85); 49% were female, 53% were White, 35% were Asian, and 6% were Hispanic/Latino. ECOG performance status was 0–1 (94%) or 2 (6%); 99% of patients had metastatic disease, and 43% had a history of or current central nervous system (CNS) metastases. Patients had received a median of 2 prior lines of systemic therapy (range: 1–6); 45% had received anti-PD-1/PD-L1 therapy, and 25% had received kinase inhibitor therapy. A total of 52% of patients had received radiotherapy. RET fusions were detected in 77% of patients using NGS (45% via tumor samples; 26% via blood or plasma samples; 6% unknown), in 21% using FISH, and in 2% using other methods. The most common RET fusion partners were KIF5B (75%) and CCDC6 (17%).

In an exploratory subgroup analysis of 39 patients who had received prior anti-PD-1 or anti-PD-L1 therapy—either sequentially or concurrently with platinum-based chemotherapy—the objective response rate (ORR) was 59% (95% CI: 42, 74), and the median duration of response (DOR) was not reached (95% CI: 11.3, NE).

Among the 87 patients with RET fusion-positive NSCLC, 8 had measurable CNS metastases at baseline per Blinded Independent Central Review (BICR). No patients had received brain radiotherapy within 2 months prior to study entry. Of these 8 patients, 4 demonstrated an intracranial lesion response, including 2 with a complete CNS response; 75% of these patients had a DOR of ≥6 months.

Treatment-Naïve RET Fusion-Positive NSCLC

Efficacy was evaluated in 27 treatment-naïve patients with RET fusion-positive NSCLC who were enrolled in the ARROW study with measurable disease.

The median age was 65 years (range: 30–87); 52% were female, 59% were White, 33% were Asian, and 4% were Hispanic or Latino. ECOG performance status was 0–1 in 96% of patients; all patients (100%) had metastatic disease, and 37% had a history of or current CNS metastases. RET fusions were detected in 67% of patients tested using NGS (41% tumor samples; 22% blood or plasma; 4% unknown) and 33% of patients tested using FISH. The most common RET fusion partners were KIF5B (70%) and CCDC6 (11%).

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).