www.aasraw.com
ALK-Positive Lung Cancer Drug “Ceritinib(LDK378)”
ALK-Positive Lung Cancer Drug “Ceritinib(LDK378)”.............................................................................. 1 CeritinibWasApprovedForUsinginEU................................................................................................2 CeritinibDescription..........................................................................................................................2 HowDoesCeritinibWorkForTreatingNSCLC?.......................................................................................3 HowAboutCeritinibMedicalUses?.....................................................................................................3 HowToStorageCeritinib(LDK378)?......................................................................................................4 WhatIsSideEffectsOfCeritinib?.........................................................................................................4 WhatOtherBenefitsOfCeritinibHaveBeenShownInStudies?................................................................6 CeritinibGetsFirst-LineFDAApprovalforALK-PositiveLungCancer............................................................7 Reference............................................................................................................................... 8
1
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
Ceritinib Was Approved For Using in EU Ceritinib(CAS:1032900-25-6) has been shown to be effective at treating patients whose disease progressed during or shortly after treatment with crizotinib and who currently have very limited treatment options, as well as patients who have not been treated before. Regarding safety, the adverse effects with Ceritinib generally appeared manageable. The European Medicines Agency therefore decided that Ceritinib’s benefits are greater than its risks and recommended that it be approved for use in the EU. Ceritinib was originally given ‘conditional approval’ because there was more evidence to come about the medicine. As the company has supplied the additional information necessary, the authorisation has been switched from conditional to full approval. You must be curious about this product, Let us read more infromation about Ceritinib:
Ceritinib Description Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy. About 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Following treatment with crizotinib (a first-generation ALK inhibitor), most tumours develop drug resistance due to mutations in key “gatekeeper” residues of the enzyme. This occurrence led to development of novel second-generation ALK inhibitors such as ceritinib to overcome crizotinib resistance. The FDA approved ceritinib in April 2014 due to a surprisingly high response rate (56%) towards crizotinib-resistant tumours and has designated it with orphan drug status.
2
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
How Does Ceritinib Work For Treating NSCLC? Ceritinib is a selective and potent inhibitor of anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key step in the development and function of nervous system tissue. However, chromosomal translocation and fusion give rise to an oncogenic form of ALK that has been implicated in progression of NSCLC. Ceritinib thus acts to inhibit this mutated enzyme and stop cell proliferation, ultimately halting cancer progression.Because ceritinib is considered a targeted cancer therapy, an FDA-approved test is required to determine which patients are candidates for ceritinib. This test, developed by Roche, is the VENTANA ALK (D5F3) CDx Assay and is used to identify ALK-positive NSCLC patients who would benefit from ceritinib treatment.
How About Ceritinib Medical Uses? Ceritinib(LDK378) is a drug used to treat non-small cell lung cancer that has spread to other parts of the body and is anaplastic lymphoma kinase (ALK) positive. It is also being studied in the treatment of other types of cancer. Ceritinib blocks the protein made by the ALK gene. Blocking this protein may stop the growth and spread of cancer cells. Ceritinib is a type of tyrosine kinase inhibitor.
3
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
How To Storage Ceritinib(LDK378)? Keep Ceritinib(LDK378) in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom). Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush Ceritinib(LDK378) down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA’s Safe Disposal of Medicines website for more information if you do not have access to a take-back program. It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach.
What Is Side Effects Of Ceritinib? Important things to remember about the side effects of ceritinib: ▪ Most people do not experience all of the side effects listed. ▪ Side effects are often predictable in terms of their onset and duration. ▪ Side effects are almost always reversible and will go away after treatment is complete. ▪ There are many options to help minimize or prevent side effects. ▪ There is no relationship between the presence or severity of side effects and the effectiveness of the medication.
The following side effects are common (occurring in greater than 30%) for patients taking ceritinib: ▪ Diarrhea ▪ Hemoglobin decreased ▪ Increase in liver enzymes 4
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
▪ Nausea ▪ Vomiting ▪ Increase in creatinine ▪ Abdominal pain ▪ Fatigue ▪ Glucose increased ▪ Decrease in phosphate ▪ Decreased appetite
These side effects are less common side effects (occurring in about 10-29%) of patients receiving ceritinib: ▪ Constipation ▪ Lipase increased ▪ Esophageal disorder (Heart burn, dyspepsia, dysphagia) ▪ Rash ▪ Bilirubin (total) increased A serious, but very uncommon side effect of ceritinib is pneumonitis (swelling of the lungs). When this side effect occurred, it was often accompanied by breathing difficulty with cough or a low-grade fever requiring hospitalization. Symptoms may be similar to those symptoms from lung cancer. Contact your health care provider right away if you have any new or worsening symptoms. Another serious but very uncommon side effect of ceritinib is EKG changes. Not all side effects are listed above. Some that are rare (occurring in less than 10% of patients) are not listed here. However, you should always inform your health care provider if you experience any unusual symptoms.
5
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
What Other Benefits Of Ceritinib Have Been Shown In Studies? In two of these studies, involving 303 patients, the medicine was not compared with any other treatment. Response to treatment was assessed using body scans and standardised criteria used for solid tumours, with complete response being when the patient had no remaining signs of the cancer. In one study 56% of patients given ceritinib (92 of 163) were considered by the treating doctors to have shown a complete or partial response to the medicine. The average length of response was 8.3 months. In the second study, the overall response rate was 41% (57 of 140 patients) and the average length of response was 10.6 months. In the third study in 231 patients, ceritinib was compared with standard chemotherapy (medicines to treat cancer). Results showed that patients given ceritinib lived for an average of 5.4 months without their disease getting worse (progression-free survival) compared with 1.6 months in patients given standard chemotherapy. Ceritinib has also been shown to be effective at treating patients who had not been treated before in a study in 376 patients. Patients given ceritinib lived for an average of 16.6 months without their disease getting worse compared with 8.1 months in patients given standard chemotherapy.
6
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
Ceritinib Gets First-Line FDA Approval for ALK-Positive Lung Cancer The FDA has expanded the approval for ceritinib. The agent is now approved as a first-line treatment in patients with metastatic, ALK-positive, non-small-cell lung cancer. The US Food and Drug Administration (FDA) has expanded the approval for ceritinib. The agent is now approved as a first-line treatment in patients with metastatic, ALK-positive, non-small-cell lung cancer (NSCLC). Ceritinib(LDK378) was previously approved in 2014 for ALK-positive metastatic NSCLC in patients who had progressed or were intolerant to crizotinib. The agent is a selective oral ALK inhibitor, with a potency twenty times that of crizotinib. The new indication is based on results of the ASCEND-4 trial, results of which were published in January of this year in Lancet. The trial randomized 376 patients with metastatic NSCLC with ALK rearrangements to either ceritinib (189 patients) or to platinum-pemetrexed doublet therapy (187 patients). The primary endpoint was progression-free survival, and ceritinib was more effective. The median progression-free survival was 16.6 months with the study drug, compared with 8.1 months in the chemotherapy arm, for a hazard ratio of 0.55 (95% CI, 0.42–0.73; P < .0001). The overall response rate was also better, at 73% with ceritinib and 27% with chemotherapy. The median response duration was 23.9 months with ceritinib and 11.1 months with platinum/pemetrexed. At this point, overall survival data remain immature. Ceritinib was granted Breakthrough Therapy designation by the FDA, along with a priority review for first-line therapy in this patient population. The ASCEND-4 study also examined response rates in patients with measurable central nervous system lesions. The confirmed intracranial response rate was 57% with ceritinib, compared with 22% with chemotherapy. Serious adverse events (AEs) occurred in 38% of patients treated with ceritinib, and AEs leading to discontinuation of the drug occurred in 12%. Dose interruptions due to AEs were seen in 77% of ceritinib patients, and 66% required dose reductions. The most common AEs with the drug in ASCEND-4 included diarrhea, nausea, vomiting, fatigue, and abdominal pain. “Today’s approval represents the next step in the development of Zykadia as a treatment option for ALK-positive metastatic NSCLC, bringing this important medication to a patient population where a need still exists,” said Novartis Oncology’s CEO Bruno Strigini, in a press release.
7
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com
www.aasraw.com
Reference [1] Mano H: The EML4-ALK oncogene: targeting an essential growth driver in human cancer. Proc Jpn Acad Ser B Phys Biol Sci. 2015;91(5):193-201. doi: 10.2183/pjab.91.193. [PubMed:25971657]. [2] Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. (March 2017). “First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study”. Lancet. 389 (10072): 917–929. [3] Xuan C, Gunduz V. “NSCLC MARKET – Global Drug Forecast & Market Analysis to 2025”. Drug Development & Delivery. No. November–December 2016. [4] “FDA Approves Ceritinib for ALK-Positive Lung Cancer”. Medscape. April 29, 2014. [5] Au T.H., Cavalieri C.C., Stenehjem D.D. Ceritinib: A primer for pharmacists // Oncology pharmacy practice. — 2017. — Vol. 23(8). — P. 611 (doi: 10.1177/1078155216672315). [6] Nishio M, Murakami H, Horiike A, Takahashi T, Hirai F, Suenaga N, Tajima T, Tokushige K, Ishii M, Boral A, Robson M, Seto T: Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors. J Thorac Oncol. 2015 Jul;10(7):1058-66. doi: 10.1097/JTO.0000000000000566. [PubMed:26020125]. [7] Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M: Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21. [PubMed:17185414]. [8] Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. [PubMed:23742252].
8
AASraw Biochemical Technology Co.,Ltd aas14@aasraw.com