At present, the state has accelerated the accessibility of innovative overseas new drugs, but there is still a certain amount of time to wait for new drugs listed abroad to be listed in China, and overseas available drugs have always been a hot spot for the majority of cancer patients and their families. With reference to the official information of the FDA and CFDA, we have summarized the most comprehensive domestic unlisted tumor drug series for everyone, according to different cancer species, to provide reference for all oncologists and patients and their families!
Digestive tract system tumor series
First, Ripretinib treats gastrointestinal stromal tumors
Ripretinib is an oral KIT and PDGFRA kinase inhibitor that potently inhibits a wide range of different forms of c-KIT and PDGFRA mutations, including secondary resistance mutations and primary refractory mutations. Before The Approval of Ripretinib, patients with GASTROST had been facing a cure-free dilemma after third-line treatment resistance, and Ripretinib became the first fourth-line treatment in the history of GIST to be approved. Ripretinib is the only fourth-line treatment regimen recommended as a level I recommendation in the 2020 edition of the CSCO Guidelines for the Diagnosis and Treatment of Gastrointestinal Stromal Tumors, and at the same time the only recommended four-line regimen of GIST recommended in the 2020 edition of the NCCN Soft Tissue Sarcoma Clinical Practice Guidelines, bringing standard treatment options for the fourth-line treatment of patients with advanced GIST.
Product Name:Qinlock
Drug name (in English): Ripretinib
Chinese name: Riptinib/Rittinib, also known as DCC-2618
Target: KIT/PDGFRA
Manufacturers: Zaiding Pharmaceutical, Deciphera
U.S. Food and Drug Administration (FDA) Approval Date: May 15, 2020
Approved indications in the US: Adult patients with advanced gastrointestinal stromal tumors (GIST) who have previously received 3 or more tyrosine kinase inhibitors (fourth-line therapy).
Recommended dosage
150 mg orally once daily, may be taken with food or on an empty stomach.
Warnings and precautions
Palm Plan erythema syndrome: depending on the severity, QINLOCK is suspended and resumed at the same or reduced dose.
New primary cutaneous malignancies: routine dermatological evaluation at the initiation of QINLOCK and during treatment.
Hypertension: Patients with hypertension should not start QINLOCK and monitor blood pressure during treatment. Depending on the severity, QINLOCK is withheld and then continued at the same or reduced dose, or the drug is discontinued permanently.
Cardiac dysfunction: as clinical manifestations, ejection fraction is assessed by echocardiography or MUGA scan before starting QINLOCK and during treatment. For grade 3 or grade 4 left ventricular systolic insufficiency, QINLOCK is permanently discontinued.
Risk of poor wound healing: Discontinue QINLOCK at least 1 week before elective surgery. Do not take after major surgery until at least 2 weeks before the wound has fully healed. The safety of QINLOCK has not been restored after wound healing complications have been resolved.
Embryonic-fetal toxicity: can cause fetal injury. Female fetuses at risk of reproduction are recommended and effective contraception is taken.
Lactation: breastfeeding is recommended.
Clinical data
Phase I experimental data
The Repotinib Phase I Clinical Study (NCT02571036) is an ongoing multicenter, open-label dose-escalation (dose-escalation phase) and Phase II recommended dose (RP2D) extended (extended phase) study. The dose escalation phase is designed to give patients 20, 30, 50, 100, 150, 200 mgBID or 100, 150, 250 mg QD and other dose levels according to the pharmacologically guided 3+3 protocol to determine the drug RP2D, safety, tolerability, pharmacokinetic characteristics and initial anti-tumor efficacy; the extended phase is given to patients with KIT or PDGFRA gene mutations (including GIST patients) repertinib RP2D, that is, 150 mgQD therapy, Among them, patients with GIST can increase the amount to 150 mg OFBID after progression, mainly for the purpose of clarifying the efficacy and safety of repotinib in GIST and other tumors.
The Journal of Clinical Oncology published results of repotinib 150 mgQD for the treatment of GIST in August 2020. For patients with advanced GIST resistant to imatinib, the overall objective response rate (ORR) of repatinib was 11.3%, of which the ORR of the 2-line, 3-line, ≥-line, and 4-line ORR was 19.4%, 14.3%, and 7.2%, respectively, and the progression-free survival (PFS) was 10.7 months, 8.3 months, and 5.5 months, respectively.
As of May 8, 2020, 10, 17, and 40 patients treated with the original 2-line, 3-line, ≥4-line treatment had entered the reperitinib dose-escalating IPDE study, respectively. Cycle PFS (PFS1) of 11.0 months, 8.3 months and 5.5 months were obtained after receiving repettinib 150 mg QD, and cycle 2 PFS (PFS2) after disease progression received with reppritinib 150 mg BID was 5.6 months, 3.3 months and 4.6 months, respectively. The ratio of PFS benefit after dose increase to PFS benefit from pre-disease pro-disease proto-dose therapy was 51%, 40%, and 84%, respectively. It can be seen that patients receiving reperitinib 2-line, 3-line, or ≥4-line therapy can achieve meaningful PFS benefit from treatment with increased repettinib dose if the disease progresses;
Approved experimental data
INVICTUS (NCT03353753) was a randomized (2:1), double-blind, placebo-controlled, international multicenter Phase III study enrolling 129 patients with advanced GIST who had previously received multiple therapies (including at least imatinib, sunitinib, and rigofenib) and evaluated qinlock's efficacy and safety relative to placebo.
Results showed that the primary endpoint was met: progression-free survival was significantly increased (median PFS: 6.3 months vs 1.0 months) and an 85% reduction in the risk of disease progression or death (HR=0.15, p<0.0001) compared with placebo. In terms of secondary endpoint overall survival (OS), the Qinlock treatment group was significantly longer (median OS: 15.1 months vs 6.6 months) and the risk of death was 64% (HR= 0.36) compared with the placebo group; notably, the OS data in the placebo group included data on patients who switched to Qinlock after receiving placebo treatment. In another secondary endpoint, the overall response rate (ORR) was significantly improved in the Qinlock treatment group compared with the placebo group (ORR: 9.4% vs 0%, p=0.0504).
Common adverse reactions
The most common adverse reactions (>20%) were hair loss, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, loss of appetite, palmar erythrocyte paresthesia syndrome (PPES), and vomiting. Among patients treated with Qinlock, adverse reactions leading to permanent discontinuation occurred in 8% of patients, dose interruption due to adverse reactions occurred in 24% of patients, and dose reduction due to adverse reactions occurred in 7% of patients treated with Qinlock.
conclusion
As a new drug, ripretinib has many topics worth exploring in the future. For example, frontline treatment of patients is better, ripretinib is used to < whether 4-line treatment can bring greater benefits to patients, etc. In short, ripretinib, a new TKI drug, has given many patients with advanced GIST hope of survival, and it is expected that prepretinib will be listed on the mainland as soon as possible and benefit more patients with advanced GIST. A phase III study of Ripretinib versus sunitinib for second-line treatment with advanced GIST is also being conducted globally (NCT03673501).
Avapritinib (BLU-285)
Treatment of gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GIST) are rare mesophyllous tissue tumors, accounting for 0.1% to 3% of all gastrointestinal malignancies, with an incidence of 1 to 1.5 per 100,000. GIST can occur anywhere in the digestive tract, most commonly in the stomach and small intestine, and is primarily caused by mutations that encode the tyrosine kinase receptor protein gene KIT (CD117) or platelet-derived growth factor receptor A (PDGFRA) gene activation. According to statistics, more than 85% of GIST is activated by KIT gene mutations, and 80% of people without KIT mutations have PDGFRA gene mutations.
Avapritinib (BLU-285) is an oral, potent and selective inhibitor of KIT and PDGFRα. Avapritinib has shown extensive inhibitory effects in gastrointestinal stromal tumors (GIST) with KIT and PDGFRα mutations, including mutations in the PDGFRα gene D842V and other primary or secondary drug-resistant mutations.
Product Name:Ayvakit
Generic name: Avapritinib (Avatinib)
Manufacturer: Blueprint Medicines
Approved: January 2020 (US), March 2021 (China)
Specifications: 100 mg*30, 200 mg*30, 300 mg*30
Approved indications: PDGFRA exon 18 mutations, including adult patients with unresectable PDGFRA D842V mutations or metastatic gastrointestinal stromal tumors (GIST).
Recommended dose: 300 mg once daily, taken orally on an empty stomach (at least one hour before meals, at least two hours after meals)
Common side effects
Edema (swelling), nausea, fatigue / weakness (abnormal weakness or lack of energy in the body), cognitive impairment, vomiting, decreased appetite, diarrhea, changes in hair color, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.
Precautions
Avatriptinib may cause intracranial hemorrhage, in which case the dose should be reduced or the drug discontinued. Avapotriptynib can also cause central nervous system effects including cognitive impairment, dizziness, sleep disturbances, mood disorders, speech disorders, and hallucinations. If this happens, depending on the severity, alvatriptinib should be discontinued and then reused at the same or reduced dose when improving, or discontinued permanently.
The use of avatriptynib in pregnant women may cause harm to the developing fetus or newborn baby. In addition, healthcare workers should tell women with reproductive abilities, as well as men with reproductive abilities, to use effective contraceptive methods during treatment with avapotinib and within 6 weeks after the final dose.
1. Approved clinical data in the United States
Avapritinib conducted a NAVIGATOR Phase I clinical study in patients with advanced GIST, enrolling patients with metastatic GIST with PDGFRA or KIT mutations or who had previously received 22-line TKI. The results of its clinical trials were announced at the 2018 Annual Meeting. In patients with advanced GIST treated with fourth-line or higher treatment, Avapritinib had an ORR of 20% and a median duration of remission of 7.3 months; in patients with third-line/fourth-line treatment who had not previously received rigofenib, Avapritinib had an ORR of 26% and a median DOR of 10.2 months. It is worth noting that among GIST patients with PDGFRAD842V mutation, Avapritinib's ORR reached 84%, the DOR rate at 12 months was 76.3%, and the PFS rate at 12 months was 81.3%.
Data from the NAVIGATOR study updated at ASCO in 2019 showed that of the 43 PATIENTS with GIST with PDGFRA exon 18 mutation, Avapritinib's ORR was as high as 86%, of which 3 patients achieved complete remission (CR), the clinical benefit rate (CBR) reached 95.3%, and neither the median PFS nor the median DoR was achieved. The fact that this result is ineffective compared to the current standard treatment gives patients the dawn of life and hope of survival.
2. Approved clinical data in China
An open-label, multicenter Phase I/II clinical study to evaluate the safety, pharmacokinetic profile, and antineoplastic efficacy of avatinib in patients treated with unresectable or metastatic advanced gastrointestinal stromal tumors. At the 2020 China Association of Clinical Oncology (CSCO) Annual Meeting, CStone released the results of the Phase I/II study conducted in the Chinese group.
A total of 50 Chinese patients were assessed for the safety of avatinib, 8 patients with D842V mutations and 23 patients who had received at least 3-line prior treatment (4L+) were evaluated for efficacy, and the efficacy was evaluated by the investigators according to the Solid Tumor Efficacy Evaluation Criteria Version 1.1 (RECIST).
The study data showed that alvatinib showed initial anti-tumor activity in Patients with Chinese gastrointestinal stromal tumors carrying PDGFRα D842V mutations: at a dose of 300 mg once a day, all patients had a narrow target lesion in all patients, and 5 patients achieved investigator-assessed partial remission (PR) with a total objective response rate (ORR) of 62.5%, and the investigators evaluated disease stability (SD) in the other 3 patients.
In addition, avatinib has also shown some efficacy in patients with gastrointestinal stromal tumors who have received at least 3-line previous treatment, with the investigators assessing an ORR of 26.1%.
Avatinib has shown very good anti-tumor activity in patients with advanced gastrointestinal stromal tumors in China with PDGFRα exon 18 mutation, and has good safety and tolerability. This approval represents that the treatment of gastrointestinal stromal tumors has entered the era of precision targeting.
RAMUCIRUMAB
Treatment of gastric cancer / gastrophilic junction adenocarcinoma
Ramosumab is a fully human monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2), whose anti-cancer mechanism is similar to that of bevacizumab, which inhibits angiogenesis to prevent the proliferation and spread of cancer cells. It is the first FDA-approved drug for the treatment of stomach cancer after previous chemotherapy failures and has been validated from treatment guidelines around the world, including the NCCN, the Japan Gastric Cancer Society, and ESMO.
Product Name:Cyramza
Generic name: Ramucirumab
Manufacturer: Eli Lilly
Specifications: 100mg/10ml, 500mg/50ml
Listing time: USA (April 2014)
Recommended dose: monotherapy or in combination with paclitaxel for advanced gastric/gastroesophageal-conjugate adenocarcinoma with disease progression during or after fluorouracil- or platinum-containing chemotherapy, the usual dosage is 8 mg/kg once every 2 weeks, intravenous infusion time is more than 60 minutes.
Warnings and precautions
Bleeding: Ramolizumab increases the risk of bleeding as well as gastrointestinal bleeding, including severe and even life-threatening bleeding events. When the patient develops severe bleeding conditions, the administration is stopped permanently.
Arterial thrombosis: In clinical trials, 4 out of 236 patients had serious fatal arterial thrombotic events such as myocardial infarction, cardiac arrest, cerebrovascular accident, cerebral ischemia, etc. When the patient develops a severe thrombosis, the drug is stopped permanently.
Hypertension: Control hypertension before taking the drug. Blood pressure is monitored every two weeks or less during the medication. When severe hypertension occurs, the medication is discontinued until the blood pressure is controlled, and if the hypertension cannot be controlled with blood pressure lowering drugs, the medication is discontinued permanently.
Gastrointestinal perforation: When a perforation of the gastrointestinal tract occurs, the drug is stopped permanently.
Approved clinical data
(1) Ramolizumab VS placebo
Study 1 was a randomized, double-blind, multicenter clinical study of ramolimab plus BSC versus placebo +BSC, in which 355 patients with locally advanced or metastatic gastric cancer (including gastric cancer at the gastric floor esophageal junction) who had previously received platinum or halopyrimidine chemotherapy were randomly assigned to the ramoli monoclonal antibody group (8 mg/kg every 2 weeks, N=238) and placebo (N=117) in a 2:1 ratio. The experimental results showed that the OS of the two groups was 5.2 months VS 3.8 months, and the PFS of the two groups was 2.1 months vs 1.3 months, with obvious statistical differences.
(2) Ramoliumab + paclitaxel VS placebo + paclitaxel
Study 2 was a randomized, double-blind, multicenter clinical study of ramoliumab plus paclitaxel (a chemotherapy agent) versus placebo plus paclitaxel, in which 665 patients with locally advanced or metastatic gastric cancer (including gastric cancer at the gastric floor esophagus junction) previously underwent platinum or fluoropyrimidine chemotherapy were randomly assigned to the ramolimab group (8 mg/kg every 2 weeks, N=330) and placebo (N=335) on a 1:1 ratio. Both groups of patients received intravenous infusion of paclitaxel (80 mg/m2) on days 1, 8, and 15 of the 28-day cycle, respectively. The experimental results showed that the OS of the two groups was 9.6 months VS 7.4 months, the PFS of the two groups was 4.4 months VS 2.9 months, and the ORR (CR+PR) of the two groups was 28% VS 16%, with obvious statistical differences.
Clinical data in research (Asian data)
The RAINBOW-Asia study included a total of 440 patients with advanced gastric cancer or gastroesophageal-conjugate adenocarcinoma from the East Asia (China, Malaysia, Philippines and Thailand) region who had progressed after first-line chemotherapy, and were treated with ramosumab plus paclitaxel or placebo + paclitaxel on a 2:1 randomized basis, with The vast majority of patients in China. The common primary endpoints were progression-free survival (PFS) and overall survival (OS).
The results showed that the median PFS of patients in the ramosumab plus paclitaxel group was significantly longer than in the placebo group (4.14 months vs 3.15 months; HR=0.765; p=0.0184) and showed median OS benefit consistent with RAINBOW in the key globally registered clinical trials (8.71 months vs 7.92 months; HR=0.963; p=0.7426). Patients were well tolerated overall, consistent with known safety features of ramovizumab, and no new safety signals were observed.
To date, there is no standard protocol for second-line treatment of advanced gastric cancer in China, and the RAINBOW-Asia study is the first and only phase III study to confirm the clinical benefits of anti-angiogenesis therapy in the second-line population of advanced gastric cancer mainly in China.
Side effects and adverse reactions:
(1) The most common side effects of monotherapy (≥10%): hypertension, diarrhea;
(2) The most common side effects of combined paclitaxel (≥30%): fatigue, neutropenia, diarrhea, epistaxis;
Special populations
pregnant woman:
Animal trials have not been conducted to assess the effects of ramosumab on fertility and fetal development. The background risk of significant postnatal defects and inability to have children is unknown. Doctors should inform pregnant women that medications can cause potential harm to the fetus.
Lactating women:
Considering the potential risk that ramizumab may have serious adverse reactions to breastfed infants, women are advised not to breastfeed during treatment with ramosumab.
contraception:
Fertile women avoid pregnancy for at least 3 months after receiving remolizumab therapy and after receiving the last dose of ramosumab.
child:
The safety and efficacy of ramulimumab in pediatric patients has not been established.
senior citizen:
In clinical trials of ramosumab, no overall difference in safety or efficacy was observed between elderly patients over 65 years of age and younger patients.
Patients with renal insufficiency:
According to population pharmacokinetic analysis, patients with renal insufficiency are recommended without dose adjustment.
Patients with hepatic insufficiency:
According to population pharmacokinetic analysis, patients with mild hepatic insufficiency (total bilirubin is within the upper limit of normal values [ULN] and AST is greater than ULN or total bilirubin is greater than 1.0-1.5 times ULN, AST is any value) or moderate hepatic insufficiency (total bilirubin is greater than 1.5 to 3.0 times ULN, AST is any value) do not need to adjust the dose. Clinical deterioration has been reported in patients treated with CYRAMZA monotherapy and child-Pugh grade B or C cirrhosis.
Other cancerous series
A. Avelumab
Treatment of rare skin cancer Merck cell carcinoma
【Product Name】 Bavencio
【Manufacturer】Pfizer
【FDA approval date】 March 2017
【Indications】Treatment of rare skin cancer Merck cell carcinoma (MCC); for patients with locally advanced or metastatic urothelial carcinoma (UC) who have not progressed after receiving platinum-containing chemotherapy in the first line maintenance therapy; treatment of patients with locally advanced or metastatic transitional cell carcinoma who have progressed within 12 months of chemotherapy or neoadjuvant or adjuvant therapy with platinum-containing regimen; and combination with acytinib for advanced renal cancer.
【Adverse reactions】 The most common adverse reactions (≥ 20%) are fatigue, skeletal muscle pain, diarrhea, nausea, infusion-related reactions, rash, loss of appetite, peripheral edema.
【Usage and dosage】The recommended dose is intravenously every 2 weeks, 10mg / kg body weight, lasting 60 minutes.
About avilumab
Avelumab is a monoclonal antibody to human immunoglobulin G1 (IgG1) against programmed death ligand 1 (PD-L1). Avelumab binds to PD-L1 and blocks interactions between PD-L1 and programmed death 1 (PD-1) and B7.1 receptors. This eliminates the inhibitory effect of PD-L1 on cytotoxic CD8+ T cells, thereby restoring the anti-tumor T cell response.
Avelumab has also shown that natural killing (NK) cell-mediated direct tumor cell lysis can be induced through antibody-dependent cell-mediated cytotoxicity (ADCC).
Related tests:
The JAVELIN Bladder 100 study is a first-line, multicenter, randomized Phase III clinical trial to evaluate the efficacy and safety of Avelumab in first-line maintenance therapy in patients with locally advanced or metastatic urothelial carcinoma (UC).
The study included 700 patients with inoperable locally advanced or metastatic urothelial carcinoma who received platinum-based induction chemotherapy without disease progression and were randomly assigned 1:1 to receive Avelumab plus optimal supportive care or optimal supportive care alone. The primary endpoint of the study was overall survival (OS) and consisted of two main analysed populations: all patients who received randomization and those who were positive for PD-L1 expression (Ventana SP263 antibody). Secondary endpoints of the study included progression-free survival (PFS), objective response rate (ORR), and safety.
At data cut-off, the median follow-up time for the combined Avelumab group (n=350) and the optimal supportive group alone (n=350) was 19.6 and 19.2 months, respectively. Of the 700 patients included in the study, 358 (51%) had positive PD-L1 expression.
Avelumab in combination with optimal supportive care alone significantly improved osmosis and reduced the risk of death by 31% (HR=0.69, 95% CI: 0.56 to 0.86, unilateral P=0.0005) compared with optimal supportive care alone, with median OS of 21.4 months and 14.3 months in both groups.
In patients with positive PD-L1 expression, Avelumab combined with optimal supportive care also significantly improved OS (HR =0.56, 95% CI: 0.40 to 0.79, unilateral P=0.0003), the upper OS in the Avelumab plus optimal supportive group was not achieved, and the upper OS in the optimal supportive treatment group alone was 17.1 months. In addition, improvements in OS were observed in all pre-set subgroups.
Avelumab and optimal supportive care resulted in improvement in PFS (BIRC assessment) in both the overall population (HR=0.62, 95% CI: 0.52 to 0.75) or the PD-L1-positive population (HR=0.56, 95% CI: 0.43 to 0.73).
In terms of safety, the incidence of all grade adverse events in the Avelumab combined with the best supportive care group for any reason was 98.0%, the optimal supportive treatment group alone was 77.7%, and the incidence of ≥ grade 3 adverse events was 47.4% and 25.2%, respectively. The main ≥-grade 3 adverse events were urinary tract infections (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%).
2. The approval of bladder cancer is based on the results of an open, single-arm, multicenter JAVELIN solid tumor study that included 242 patients with locally advanced or metastatic transitional cell carcinoma with platinum-containing regimen treatment progression or as adjunctive treatment progression. Patients receive avelumab 10 mg/kg intravenously every 2 weeks until imaging or clinical progression or the appearance of unacceptable toxicity.
In 226 patients followed up for at least 13 weeks, the overall overall response rate (ORR) was 13.3% (n = 30) (95% CI: 9.1, 18.4). Among them, 4% of the patients had their tumors disappeared completely and achieved complete remission, and 9.3% of the patients achieved partial remission.
In 161 patients followed up for at least 6 months, the overall overall response rate was 16.1% (n = 26) (95% CI: 10.8, 22.8). Of these, 5.6% of patients achieved a complete response and 10.6% achieved a partial response.
The average corresponding time from self-medication to efficacy was 2.0 months (1.3 to -11.0). At present, the median duration of patient efficacy has not yet been achieved, with an average of 1.4 + -17.4 + months. Moreover, the results of the study between the efficacy of patients and the correlation between PDL1 expression showed no significant change between the different levels of PDL1 expression and efficacy.
3. The JAVELIN Renal 101 study was a randomized Phase III clinical study comparing avelumab combined with acytinib versus sunitinib for first-line treatment of advanced ccRCC. Results presented at the 2018 ESMO conference showed that the combined avelumab+acytinib regimen significantly improved patient median PFS (13.8 vs 8.4 months) compared to sunitinib. From the PERSPECTIVE OF ORR, the combined avelumab+acitinib protocol doubled the ORR (51.4% vs 25.7%) relative to the control group. Data from the 2021 ASCO GU update shows that the OS of avelumab and acytinib is similar to that of sunitinib in low/moderate-risk groups; in imDC high-risk populations, the OS of avelumab combined with acytinib is superior to sunitinib. In low-risk populations, PFS of immunocomposed therapy was superior to sunitinib, but there was no difference in OS.
Ii. Cabazitasel Cabazitaxel
Treatment of prostate cancer
Cabazitasel Cabazitaxel
【Product Name】 Jevtana®
【Manufacturer】Sanofi
【Applicable Diseases】: Carbaltazel Jevtana is suitable for prostate cancer. Such prostate patients have received prostate cancer patients with refractory metastases that have failed a regimen containing polyenylene paclitaxel.
【Dosage and mode of use】Recommended dose: administered once every 3 weeks, intravenous infusion of carbataxel 25 mg/m2 within 1 hour with oral prednisone 10 mg daily administration of carbabatazole treatment from beginning to end.
(1) Carbaltazel requires two dilutions before administration.
(2) Dilute the complete contents with the accompanying diluent to reach a concentration of 10 mg/mL cabatacele.
(3) Polyvinyl chloride (PVC) instruments should not be used.
(4) Pre-administration regimen: 30 minutes before each intravenous administration of cabazitaxel:
【FDA approval time】June 2010
【Adverse reactions】Neutropenia, hypersensitivity reactions, gastrointestinal reactions, renal failure.
About kabatazel
Cabataxacel is a second-line drug for prostate cancer developed by Sanofi-aventis, a chemical semi-synthetic taxane small molecule compound. Cabazitaxel's anticancer mechanism and characteristics are similar to those of docetaxel and belong to the antitubule class of drugs. By binding to tubulin, cabotazel promotes its assembly into microtubules, while preventing the disintegration of these assembled microtubules, stabilizing the microtubules, inhibiting cellular mitoticism and interphasecellular functions.
Related tests
1. On September 11, 2020, a study published online by The Lancet Oncology showed that cabotazel significantly improved the quality of life of patients with metastatic castration-resistant prostate cancer (mCPRC) compared with abiraterone or enzaluamine.
CARD (NCT02485691) is a randomized, multicenter, open-label phase IV clinical study involving 62 research centers in 13 European countries. Patients aged ≥ 18 years, with an ECOG PS score of≤ 2 and confirmed mCPRC were included, for a total of 225 patients. After a 1:1 randomization, there were 129 patients in the carbathazel group and 126 patients in the enzaluamine group. Previous studies have shown that carbaltazel significantly improves progression-free survival (PFS) and overall survival (OS) in patients compared with abiraterone or enzaluamine. This study focused on the outcome of quality of life in patients.
The median time of pain progression in the carbaltazel group was not estimated (NE; 95% CI NE–NE), compared with 8.5 months (4.9–NE) for patients using abiraterone or enzaluamine, with a risk ratio (HR) of 0.55;
The median time for symptomatic skeletal events in the cabatase group was NE (95% CI 20.0–NE), and in the abbitulone or enzaluamine group was 16.7 months (10.8–NE), HR=0.59;
The median time for the deterioration of the prostate-cancer therapeutic function score (FACT-P) in the carbathazel group was 14.8 months (95% CI 6.3–NE), compared with 8.9 months (6.3–NE) in the abbitaloxaline or enzaluamide group, hr=0.72;
EQ-5D-5L utility index score showed that patients in the carbaltazel group were more effective than those in the abiraterone or enzaluamine group;
There was no difference between the two groups in the EQ-5D-5L visual analog scale.
Studies have shown that carbaltazel improves patient quality of life compared to second-generation androgen signaling targeted inhibitor therapy.
2. The approval is based on a non-inferior, multicentric, randomized, open-label trial (PROSELICA) that studied 1200 patients with metastatic castration-resistant prostate cancer who had previously been treated with a docetaxel-containing regimen. The trial was conducted as a post-marketing requirement, comparing a lower dose of JEVTANA with an approved dose of 25 mg/m2. Patients receive a dose of JEVTANA 25 mg /m2 (n=602) or 20 mg/m2 (n=598).
The trial demonstrated that the overall survival of JEVTANA 20 mg/m2 was not significant compared to 25 mg/m2 in the population of intent to treat. The mean survival was estimated at 13.4 months for low-dose patients compared to 14.5 months for high-dose patients (hazard ratio = 1.024; 97.78% confidence interval: 0.886, 1.184). Estimated mean survivals of JEVTANA 20 mg/m2 and JEVTANA 25 mg/m2 were 15.1 months and 15.9 months, respectively, according to each protocol population (hazard ratio = 1.042; 97.78% confidence interval: 0.886, 1.224).
Bone marrow suppression, infection, and increased toxicity events were more frequent in the 25 mg/m2 dose group compared to lower doses. Deaths within 30 days (5.4% vs. 3.8%) within 30 days of the last study of drug doses, as well as early infection-related deaths within 30 days after the start of treatment (1.3% vs. 0.7%) were more common in the 25 mg/m2 group than in the 20 mg/m2 group. All early infection-related deaths occur in patients over the age of 60. For patients with high-risk clinical features, primary prophylaxis with G-CSF is recommended.
In clinical trials, more than 10% of patients treated with JEVTANA experienced adverse reactions and laboratory abnormalities, including neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, fatigue, abdominal pain, hematuria, back pain, and anorexia. Infections of grade 3-4 were reported in 20% of patients in the 25 mg / m2 group and 10% of patients at low doses. Febrile neutropenia developed in 9% of patients in the 25 mg/m2 group and 2% in the 20 mg/m2 group. The most common causes of dose interruption are fatigue and hematuria.
3. The FIRSTANA trial assessed whether Cabazitaxel 20 mg/m2 (C20 group) or 25 mg/m2 (C25 group) was superior to docetaxel 75 mg/m2 (D75 group) in terms of overall survival in patients with metastatic castration resistance prostate treated with chemotherapy. Patients with metastatic castration-resistant prostate cancer with an ECOG fitness score of 0-2 were randomly assigned to the C20, C25, and D75 groups on a 1:1:1 basis, with intravenous administration every 3 weeks and daily use of prednisone. Primary study endpoints were overall survival, with secondary endpoints including safety, progression-free survival, tumor status, PSA and pain relief, pharmacokinetics, and health-related quality of life.
From May 2011 to April 2013, 1168 patients were randomly grouped. The general situation when joining a group is similar between groups. The median survival in the C20, C25, and D75 groups was 24.May, 25.2, and 24.March, respectively, and the risk ratio in the C20 group versus the D75 group was 1.01 (95% CI, 0.85-1.20; P=0.997), and the risk ratio in the C25 group versus the D75 group was 0.97 (95% CI, 0.82-1.16; P=0.757). The median progression-free survival in the C20, C25, and D75 groups was 4.4 months, 5.1 months, and 5.3 months, respectively, and there were no significant differences between the treatment groups. The number of image response rates for tumors in the C25 group (41.6%) was higher than that in the D75 group (30.9%, nominal P=0.037 without multiplicity test correction). The incidence of treatment-related adverse events in the C20, C25, and D75 groups of grade 3-4 was 41.2%, 60.1%, and 46.0%, respectively, febrile neutropenia, diarrhea, and hematuria were more frequent in the C25 group, and peripheral neuropathy, limb edema, hair loss, and nail abnormalities were more frequent in the D75 group.
In patients with metastatic castration-resistant prostate cancer treated with chemotherapy, the C20 group and C25 group did not show overall survival dominance compared with the D75 group. The tumor remission rate was numerically higher in the C25 group than in the D75 group, and the progression-free survival of pain in the D75 group was numerically better than that in the C25 group. Cabazitaxel and docetaxel showed different toxic side effect characteristics, with fewer toxic side effects in the C20 group overall.
III. Smetinib (Koselugo)
Treatment of neurofibromatosis
Product name: Koselugo
Manufacturer: AstraZeneca
Listing time: April 10, 2020 (US)
Packing specification: 10mg/25mg*50
Indications: Symptomatic, inoperable plexiform fibromatosis (PN) of neurofibromatosis type 1 (NF1) in children 2 years of age and older
Application: Take on an empty stomach, 25 mg/m2 twice daily
Semetinib is an oral, selective, non-competitive ATP-active MEK1/2 inhibitor that exhibits antitumor activity in BRAF or RAS mutant cell lines and in various xenograft living models. The finished drug comes in capsules of 10 mg and 25 mg. The method of taking it is on an empty stomach, 25 mg/m2 twice a day.
Semetinib is the first targeted drug to receive FDA approval for the treatment of type 1 neurofibroma! This is based on the open-label, multicenter, one-arm study SPRINT trial (NCT01362803), in which NF1 pediatric patients carrying plexiform neurofibromas (PNs) that cannot be surgically treated. Trial results showed that treatment of Selumetinib resulted in an overall response rate (ORR) of 66% in patients, partial response in all patients, and sustained remission for at least 12 months in 82% of patients.
The latest findings of the study were published in N Engl J Med on April 9, 2020.
▲ Selumetinib treats patients with inoperable PN
The trial included a total of 50 children aged 2-18 years with a clinical diagnosis of neurofibroma type 1 (NF1) with inoperable plexiform neurofibroma (PN) and swallowing a complete capsule. Receiving the recommended dose (selumetinib 25 mg/m2 orally twice daily until disease progression or unacceptable adverse effects) and the overall response rate (ORR) assessed by NCI, the primary study endpoint, is defined as the percentage of patients whose tumor volume reduction ≥ 20% confirmed by MRI during follow-up MRI examinations of 3 to 6 months.
The results of the study showed that of the 50 children, a total of 37 (74%; 95% CI, 60 to 85) achieved partial remission, 35 (70%) achieved confirmed partial remission, and 28 (56%) achieved durable remission. This study did not reach median sustained remission time and median progression-free survival. Progression-free survival was 84% after 3 years of treatment start.
▲ 3 years of follow-up, Selumetinib and natural history, PFS is 84% and 15% respectively
The most common adverse reactions (more than 40% of patients) were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, stomatitis, headache, paronychia, and pruritus. In terms of serious adverse reactions, Selumetinib can cause cardiomyopathy, leading to heart failure, manifested by a decrease in ejection fraction and elevated creatinine phosphokinase; it can also lead to ophthalmic toxicity, manifested by retinal vein obstruction, retinal pigment epithelial detachment, visual impairment, etc.
AstraZeneca signed a strategic cooperation agreement with the Hainan Boao Lecheng International Medical Tourism Pilot Zone Administration on "Innovative Oncology Drugs to Be Tried First in Boao".
The two sides will cooperate through the "Oncology Drug Trial First and Tumor Diagnosis and Treatment Center" to accelerate the introduction of global innovative oncology drugs into China, and provide innovative diagnosis and treatment solutions for Chinese patients as soon as possible, including the treatment of neurofibromatosis type 1 (NF1) small molecule drug simetinib.
In October 2020, China's first application for "Selumetinib Imported Urgently Needed Clinical Drugs" submitted by Boao Super Hospital was approved by the Hainan Food and Drug Administration.
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