Pratinib is used to treat adult patients with advanced RET fusion-positive non-small cell lung cancer;

Pratinib instructions

Product Name: LuciPral    

Manufacturer: Lucius Pharmaceuticals

Chinese name: Pratinib

English Name: Pralsetinib

Drug approval number : 08 L 1007 / 23

 

【Summary】

Pratinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions ( CCDC6-RET ) and mutations ( RET V804L , RET V804M , and RET M918T ) with half-maximal inhibitory concentrations ( IC50s ) of less than 0.5 nM . In purified enzyme assays, Pratinib inhibited DDR1 , TRKC , FLT3 , JAK1-2 , TRKA , VEGFR2 , PDGFRb , and FGFR1 at higher concentrations, but still met clinical requirements at Cmax . In cell assays, Pratinib inhibited RET at concentrations approximately 14- fold, 40- fold, and 12- fold lower than VEGFR2 , FGFR2 , and JAK2 , respectively .

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through overactivation of downstream signaling pathways, leading to uncontrolled cell proliferation. Pratinib has anti-tumor activity in cultured cells and animal tumor implantation models containing cancerous RET fusions or mutations, including KIF5B-RET , CCDC6-RET , RET M918T , RET C634W , RET V804E , RET V804L , and RET V804M , and Pratinib can prolong the survival time of mouse intracranial implanted tumor models expressing KIF5B-RET or CCDC6-RET . 

 

【Indications】

(1) For the treatment of adult patients with advanced RET fusion-positive non-small cell lung cancer;

(2) For the treatment of adults and children aged 12 years and older with advanced or metastatic medullary thyroid cancer (MTC) with rearranged transfection (RET) mutation who are resistant to systemic therapy, and adults and children aged 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer (TC) who require systemic therapy and are refractory to radioiodine (if radioiodine is applicable).

 

【Specification】  

100mg/ pill, 120 pills / box.

 

【Storage】

 Store at 20 ° C to 25 ° C (68 ° C to 77 ° F) ; short-distance transportation is permitted within the temperature range of 15 to 30 ° C (59 – 86 ° F) .

 

【Usage and Dosage】

The recommended adult dose is 400 mg, taken orally once daily on an empty stomach (taking Pralsetinib Do not eat for at least 2 hours before taking it and do not eat for at least 1 hour after taking it)

 

【Adverse Reactions】

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

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

 

【Taboo】

none

 

【Notes】

Interstitial Lung Disease ( ILD ) / Pneumonitis: Withhold for Grade 1 or 2 reactions until resolution, then resume at low dose. Permanently discontinue for recurrent ILD/ Pneumonitis. Permanently discontinue for Grade 3 or 4 reactions.

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

Hepatotoxicity: Prior to initiating pralsetinib , monitor ALT and AST every 2 weeks for the first 3 months , monthly thereafter, and as clinically indicated. Based on severity, withhold, reduce dose, or permanently discontinue pralsetinib .

Hemorrhagic Events: Permanently discontinue pralsetinib in patients with severe or life-threatening hemorrhage .

Risk of Impaired Wound Healing: Do not use pralsetinib for at least 5 days before elective surgery . Do not use the drug for at least 2 weeks after major surgery and until the wound has healed. The safety of resuming pralsetinib after resolution of wound healing complications has not been established.

Embryo - Fetal Toxicity: Can cause fetal harm. Females of reproductive potential have a potential risk to the fetus and are advised to use effective non-hormonal contraception.

 

【Drug Interactions】

Strong CYP3A inhibitors: Avoid coadministration.

Concomitant P-gp and Strong CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the dose of pralsetinib .

Strong CYP3A inducers: Avoid coadministration. If coadministration 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-arm clinical trial ( ARROW , NCT03037385 ). The study enrolled patients with metastatic RET fusion-positive NSCLC who had received platinum-based chemotherapy and patients with treatment-naïve metastatic NSCLC in separate groups. RET gene fusions were determined by local laboratories using next-generation sequencing ( NGS ), fluorescence in situ hybridization ( FISH ), and other tests . Of the target population of 114 patients, 59 patients (using Dx technology) were retrospectively tested for efficacy. Patients with asymptomatic central nervous system ( CNS ) metastases were enrolled, including those whose steroid use was stable or reduced within 2 weeks prior to study enrollment . Patients received 400 mg orally once daily until disease progression or unacceptable toxicity.

The major efficacy outcome measures were overall response rate ( ORR ) and duration of response ( DOR ) according to RECIST v1.1 , assessed by a blinded independent central review ( BICR ).

Metastatic RET fusion-positive NSCLC previously treated with platinum-based chemotherapy

A total of 87 patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy were enrolled in the ARROW trial.

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 CNS metastases. Patients had received a median of 2 prior systemic therapies (range, 1-6 ); 45% had prior anti- PD-1/PD-L1 therapy, and 25% had prior kinase inhibitor therapy. A total of 52% of patients had received radiation therapy. RET fusions were detected in 77% of patients using NGS ( 45% tumor samples; 26% blood or plasma samples, and 6% unknown) , 21% using FISH , and 2% using other methods. The most common RET fusions drugged were KIF5B ( 75% ) and CCDC6 ( 17% ).

For 39 patients who received anti- PD-1 or anti- PD-L1 therapy, either sequentially or concurrently with platinum chemotherapy, an exploratory subgroup analysis of the ORR was 59% ( 95% CI: 42 , 74 ), while the median DOR was not reached ( 95% CI: 11.3 , NE ).

Among 87 RET fusion - positive NSCLC patients, 8 had significant CNS metastases at baseline BICR . No patient received brain radiotherapy within 2 months before entering the study. Four of the 8 patients had intracranial lesion responses, including 2 complete CNS responses; 75% of patients had a DOR ≥ 6 months.

Untreated RET fusion-positive NSCLC

Twenty-seven patients with previously untreated RET fusion-positive NSCLC and measurable disease were enrolled in ARROW .

Median age was 65 years (range, 30 to 87 ); 52% were female, 59% were white, 33% were Asian, and 4% were Hispanic or Latino. 96% of patients had an ECOG performance status of 0-1 , all patients ( 100% ) had metastatic disease, and 37% had a history of or current CNS metastases. RET fusions were detected in 67% of patients using NGS ( 41% tumor samples; 22% blood or plasma; 4% unknown) and 33% using FISH . The most common RET fusions detected were KIF5B ( 70% ) and CCD6 ( 11% ).