Serpatinib is indicated for: 1. Metastatic RET fusion-positive non-small cell lung cancer 2. Ret mutation medullary thyroid cancer 3. RET-positive thyroid cancer

Serpatinib instructions

Product Name: LuciSel

Manufacturer: Lucius Pharmaceuticals

Chinese name: Serpatinib

English name: Selpercatinib

Drug approval number: 09 L 1008/23 

 

【Summary】

Selperctinib is a kinase inhibitor. Selperctinib inhibits wild-type RET and multiple mutant RET isoforms, and inhibits VEGFR1 and VEGFR3 with IC50 values ​​ranging from 0.92 nM to 67.8 nM. In other enzyme assays, Selperctinib also inhibits FGFR1, 2, and 3 at higher concentrations that are still clinically achievable. In cell-based assays, Selperctinib inhibits RET at approximately 60-fold lower concentrations than FGFR1 and 2, and approximately 8-fold lower than VEGFR3.

Certain point mutations or chromosomal rearrangements in RET involving RET in-frame fusions can result in constitutively activated chimeric RET fusion proteins that exert oncogenic effects by promoting cellular proliferation in tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated antitumor activity in cells containing constitutively activated RET proteins caused by gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib demonstrated antitumor activity in mice implanted with patient-derived RET fusion-positive tumors.

 

【Indications】

1. Metastatic RET fusion-positive non-small cell lung cancer

2. Ret mutation medullary thyroid cancer

3. RET-positive thyroid cancer

 

【Specification】 

40mg/pill, 120 pills/box.

 

【Storage】

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

 

【Usage and Dosage】

Patients were selected for treatment with selpercatinib based on the presence of RET gene fusions (NSCLC or thyroid) or specific RET gene mutations (MTC).

The dosage for adults and children over 12 years old is based on body weight.

Less than 50 kg: 120 mg orally 2 times a day

50 kg and above: 160 mg orally, twice a day

The selpercatinib dose should be reduced accordingly in patients with severe hepatic impairment.

 

【Adverse Reactions】

The most common adverse reactions, including laboratory abnormalities, were (≥25%) increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, thrombocytopenia, increased total cholesterol, rash, decreased sodium, and constipation.

 

【Taboo】

none

 

【Notes】

Hepatotoxicity: Monitor ALT and AST before starting selpercatinib, every 2 weeks for the first 3 months, and monthly thereafter. Based on severity, withhold, reduce dose, or permanently discontinue selpercatinib.

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

QT Interval Prolongation: Monitor patients at risk for significant QTc prolongation. Assess QT interval, electrolytes, and TSH at baseline and during periodic treatment. Monitor QT interval more frequently when selpercatinib is used concomitantly with strong and moderate CYP3A inhibitors or drugs known to prolong the QTc interval. Based on severity, withhold and reduce dose or permanently discontinue selpercatinib.

Bleeding Events: Permanently discontinue selpercatinib in patients with severe or life-threatening hemorrhage.

Hypersensitivity Reactions: Discontinue selpercatinib and initiate corticosteroids. Upon resolution, continue dose reduction by 1 dose level per week until the dose prior to the onset of hypersensitivity is reached. Continue steroids until the patient reaches target dose, then taper.

Risk of Impaired Wound Healing: Do not use selpercatinib for at least 7 days prior to elective surgery. Do not administer selpercatinib for at least 2 weeks after major surgery and until the wound has healed. The safety of continued use of selpercatinib after resolution of wound healing complications has not been established.

Embryo-fetal toxicity: Can cause fatal damage. Potential reproductive risk to female fetuses, effective contraceptive measures are recommended.

 

Safety and efficacy

1. RET fusion-positive metastatic non-small cell lung cancer

In a multicenter, open-label, multi-group clinical trial (LIBRETTO-001, nct0357128), the efficacy of Selpercatinib in patients with advanced RET fusion-positive NSCLC was evaluated. This study divided patients with advanced or metastatic RET fusion-positive NSCLC who received platinum-based chemotherapy and those with advanced or metastatic NSCLC who did not receive systemic treatment into two groups. Local laboratories prospectively determined RETgene alterations using next-generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescence in situ hybridization (FISH). Adult patients took 160 mg of Selpercatinib orally twice daily until unacceptable toxicity or disease progression occurred. The primary efficacy outcome measures, determined by a blinded independent review committee (BIRC) according to RECIST v1.1, were overall response rate (ORR) and duration of response (DOR).

 

Platinum-based chemotherapy for metastatic RET fusion-positive NSCLC

A total of 105 patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy were enrolled in the LIBRETTO-001 cohort to evaluate their efficacy.

Median age was 61 years (range, 23 to 81 years); 59% were female; 52% were white, 38% were Asian, 4.8% were black, and 3.8% were Hispanic/Latino. ECOG performance status was 0-1 (98%) or 2 (2%), and 98% of patients had metastatic disease. Patients had received 3 prior systemic therapies (range, 1-15); 55% had received prior anti-PD-1/PD-L1 therapy. RET fusions were detected in 90% of patients using NGS (81.9% of tumor samples; 7.6% of blood or plasma samples), 8.6% using FISH, and 1.9% using PCR.

In the 58 patients who received anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum chemotherapy, an exploratory subgroup analysis showed an ORR of 66% (95% CI: 52%, 78%) and a median DOR of 12.5 months (95% CI: 8.3, NE).

Among 105 patients with RET fusion-positive NSCLC, 11 had significant CNS metastases at baseline, as assessed by a blinded independent review committee. No patient received brain radiation therapy within 2 months before study entry. Ten of the 11 patients had a response in intracranial lesions, and all patients had a DOR of ≥6 months.

 

Treatment-naïve RET fusion-positive NSCLC

Efficacy was evaluated in 39 patients with previously untreated RET fusion-positive NSCLC who were enrolled in the LIBRETTO-001 group.

Median age was 61 years (range, 23-86 years); 56% were female; 72% were white, 18% were Asian, and 8% were black. All patients had an ECOG performance status of 0-1 (100%), and all patients (100%) had metastatic disease. RET fusions were detected in 92% of patients using NGS (69% of tumor samples; 23% of blood samples) and in 8% of patients using FISH.

 

2. RET mutant medullary thyroid cancer

Selpercatinib was evaluated in a multicenter, open-label, multigroup clinical trial (LIBRETTO-001, NCT0357128) that divided patients with advanced or metastatic RET-mutant MTC who had previously received cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were refractory to cabozantinib and vandetanib into two groups.

RET-mutant MTC previously treated with cabozantinib or vandetanib

Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had been treated with cabozantinib or vandetanib and were included in the LIBRETTO-001 arm.

Median age was 57 years (range, 17 to 84 years); 66% were male; 89% were white, 7% were Hispanic/Latino, and 1.8% were black. ECOG performance status was 0-1 (95%) or 2 (5%), and 98% of patients had metastatic disease. Patients had received 2 prior systemic therapies (range, 1-8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR testing, and 2% using unknown testing.

 

RET mutant MTC refractory to cabozantinib and vandetanib

Efficacy was evaluated in 88 patients with RET-mutant MTC who were treated with cabozantinib and vandetanib and were enrolled in the LIBRETTO-001 arm.

The median age was 58 years (range, 15 to 82 years), with 2 patients (2.3%) aged 12 to 16 years; 66% were male; 86% were white, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease, and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioiodine). RET mutation status was detected in 78.4% of patients using NGS (76.1% tumor samples; 2.3% blood samples), 18.2% using PCR testing, and 3.4% using unknown testing.

 

3. RET fusion-positive thyroid cancer

In a multicenter, open-label, multi-group clinical trial (LIBRETTO-001, NCT0357128), the efficacy of selpercatinib in patients with advanced RET fusion-positive thyroid cancer was evaluated. Twenty-seven patients with RET fusion-positive thyroid cancer who were refractory to radioactive iodine (RAI) (if RAI was an appropriate treatment option) and patients with RET fusion-positive thyroid cancer who were refractory to RAI and received sorafenib, lenvatinib, or both were evaluated in two groups.

The median age was 54 years (range, 20 to 88); 52% were male; 74% were white, 11% were Hispanic/Latino, 7.4% were Asian, and 3.7% were black. ECOG performance status was 0-1 (89%) or 2 (11%). All patients (100%) had metastatic disease from primary tumor histology, including papillary thyroid cancer (78%), poorly differentiated thyroid cancer (11%), anaplastic thyroid cancer (7%), and Hurthle cell carcinoma (4%). Patients had received 3 prior lines of therapy (range, 1-7). RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% of patients using blood samples.