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Dacomitinib Review: How To Treat NSCLC?
Dacomitinib Review: How ToTreat NSCLC?.......................................................................................... 1 FDAapproves dacomitinib for metastatic non-small cell lung cancer................................................2 What is Non-Small Cell Lung Cancer?........................................................................................... 2 Dacomitinib clinical application in non-small-cell lung cancer............................................................ 3 Dacomitinib Review.......................................................................................................................4 Dacomitinib Mechanism of action...................................................................................................4 Dacomitinib Uses.......................................................................................................................... 5 Dacomitinib Side Effects................................................................................................................ 5 Non-small Cell Lung Cancer Treatment: Dacomitinib VS Gefitinib................................................... 6 HowTo Buy Dacomitinib Powder online?....................................................................................... 8 Reference............................................................................................................................. 8
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FDA approves dacomitinib for metastatic non-small cell lung cancer On Sept. 27, 2018, the Food and Drug Administration approved dacomitinib tablets (VIZIMPRO, Pfizer Pharmaceutical Company) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Approval was based on a randomized, multicenter, open-label, active controlled trial (ARCHER 1050; NCT01774721) comparing the safety and efficacy of dacomitinib to gefitinib in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR TKI-containing therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomized (1:1) to receive either dacomitinib 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity. The trial demonstrated a significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated. The median progression-free survival, as determined by an independent review committee. was 14.7 and 9.2 months in the dacomitinib and gefitinib arms, respectively (hazard ratio 0.59; 95% CI: 0.47, 0.74; p<0.0001). The prescribing information contains warnings and precautions for interstitial lung disease (ILD), diarrhea, and dermatologic adverse reactions. Of 394 patients who received dacomitinib, serious adverse reactions occurred in 27%. The most common adverse reactions resulting in discontinuation in of dacomitinib were diarrhea and ILD. The most common (>20%) adverse reactions of dacomitinib were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus).
What is Non-Small Cell Lung Cancer? Lung cancer is the most common cancer worldwide, with more than two million new cases diagnosed globally in 2018. About 85 percent of all lung cancers are identified as non-small cell, and approximately 75 percent of these are metastatic, or advanced, at diagnosis. 2
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EGFR is a protein that helps cells grow and divide. When the EGFR gene is mutated it can cause the protein to be overactive resulting in cancer cells to form. EGFR mutations may occur in 10 to 35 percent of NSCLC tumors globally, and the most common activating mutations are deletions in exon 19 and exon 21 L858R substitution, which together account for more than 80 percent of known activating EGFR mutations. The disease is associated with low survival rates and disease progression remains a challenge.
Dacomitinib clinical application in non-small-cell lung cancer Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) that irreversibly binds to and inhibits EGFR/Her1, Her2 and Her4 subtypes with an efficacy comparable to other TKIs. In the ARCHER 1050 trial, progression-free survival was improved by dacomitinib compared with gefitinib, supporting dacomitinib as a first-line treatment option for advanced non-small-cell lung cancer with sensitive EGFR mutation. Regarding to the higher adverse events rate, dose reductions did not reduce the efficacy of dacomitinib and could effectively decreased the incidence and severity of adverse events. Considering the evolving landscape of EGFR-mutant non-small-cell lung cancer, future head to head comparison between dacomitinib and osimertinib could provide key information to determine the optimal TKI treatment schedule.
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The high incidence of Non-Small Cell Lung Cancer has forced us to think about treatment options, how to find effective methods?After many clinical studies, Dacomitinib treatment will be recommended to everyone. Next, let’s have a look at Dacomitinib:
Dacomitinib Review Dacomitinib, designed as (2E)-N-16-4-(piperidin-1-yl) but-2-enamide, is an oral highly selective quinazalone part of the second-generation tyrosine kinase inhibitors which are characterized by the irreversible binding at the ATP domain of the epidermal growth factor receptor family kinase domains. Dacomitinib is a medication for the treatment of non-small-cell lung carcinoma (NSCLC). It is a selective and irreversible inhibitor of EGFR. Dacomitinib was developed by Pfizer Inc and approved by the FDA on September 27, 2018. Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer model, although further investigations are needed. For now, Dacomitinib powder(CAS:1110813-31-4) can be provided by AASraw from China.
Dacomitinib Mechanism of action Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus.1 Around 40% of cases show amplification of EGFR gene and 50% of the cases present the EGFRvIII mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor.
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Dacomitinib Uses Dacomitinib is approved to treat: Non-small cell lung cancer (NSCLC) that has metastasized (spread to other parts of the body). It is used as first-line treatment in patients whose tumors have certain EGFR gene mutations. Dacomitinib is also being studied in the treatment of other types of cancer.
Dacomitinib Side Effects Important things to remember about the side effects of dacomitinib: ▪ Most people will not experience all of the dacomitinib side effects are listed here. ▪ Dacomitinib side effects are often predictable in terms of their onset, duration and severity. ▪ Dacomitinib side effects will improve after therapy is complete. ▪ Dacomitinib side effects may be quite manageable. There are many options to minimize or prevent the side effects of dacomitinib.
The following side effects are common (occurring in greater than 30%) for patients taking dacomitinib: ▪ Skin rash ▪ Bacterial or fungal nail infection (paronychia) ▪ Dry skin ▪ Low albumin ▪ Low calcium ▪ High blood glucose levels ▪ Diarrhea ▪ Mouth sores ▪ Decreased appetite ▪ Anemia (low hemoglobin) ▪ Low white blood cell count 5
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▪ Increased liver enzymes
These are less common side effects (occurring in 10-29%) for patients receiving dacomitinib: ▪ Chest pain ▪ Insomnia ▪ Hair loss ▪ Itching ▪ Redness, swelling, and pain on the palms of the hands and/or the soles of the feet ▪ Low potassium, magnesium and sodium levels ▪ Weight loss ▪ Nausea ▪ Constipation ▪ Limb pain ▪ Musculoskeletal pain ▪ Weakness/lack of energy ▪ Inflammation or infection of the eyes ▪ Increased serum creatinine ▪ Cough, nasal signs and symptoms, difficulty breathing and upper respiratory tract infection Not all side effects are listed above. Side effects that are very rare — occurring in less than about 10 percent of patients — are not listed here. But you should always inform your health care provider if you experience any unusual symptoms.
Non-small Cell Lung Cancer Treatment: Dacomitinib VS Gefitinib Among patients with EGFR-positive, non–brain metastatic non–small cell lung cancer (NSCLC), first-line dacomitinib improves progression-free survival (PFS) over gefitinib,
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according to a phase 3 study published in The Lancet
Oncology. First-generation EGFR–tyrosine kinase inhibitors (TKIs), including gefitinib, are used in the first line for patients with EGFR-position disease, which constitute between 10% and 44% of all lung adenocarcinomas. Previous study has not determined whether second-generation EGFR-TKIs are superior to the first-generation variety. For this open-label, randomized study (ARCHER 1050; ClinicalTrials.gov Identifier: NCT01774721), which the authors noted is the first phase 3 study to compare a second-generation EGFR-TKI with a first-generation EGFR-TKI in this setting, researchers enrolled 452 patients to receive dacomitinib (227 patients) or gefitinib (225 patients). Patients with brain metastases were not eligible. At a median follow-up of 22.1 months, median PFS was 14.7 months for dacomitinib vs 9.2 months for gefitinib; subgroup analyses also favored dacomitinib. Twelve complete responses were recorded in the dacomitinib group vs 4 in the gefitinib group. The objective response rates were, however, similar (75% for dacomitinib and 72% for gefitinib; P = .4234).
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Twenty-one patients receiving dacomitinib had a serious treatment-related adverse event (AE); this was true of 10 patients receiving gefitinib. Treatment-related deaths were reported for 2 patients receiving dacomitinib vs 1 for gefitinib. The authors concluded that “dacomitinib treatment was superior to gefitinib with respect to [PFS] and duration of response in the first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.”
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Reference [1] Kobayashi Y, Fujino T, Nishino M, et al. EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol. 2018;13(5):727–731. doi:10.1016/j.jtho.2018.01.009. [2] Kris MG, Camidge DR, Giaccone G, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015;26(7):1421–1427. doi:10.1093/annonc/mdv383. [3] Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–589. doi:10.1016/S1470-2045(16)30033-X. 8
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[4] Lacouture ME, Keefe DM, Sonis S, et al. A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer. Ann Oncol. 2016;27(9):1712–1718. doi:10.1093/annonc/mdw227. [5] Reckamp KL, Giaccone G, Camidge DR, et al. A phase 2 trial of dacomitinib (PF‐00299804), an oral, irreversible pan‐HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120(8):1145–1154. doi:10.1002/cncr.28561. [6] Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–1043. doi:10.1126/science.1141478. [7] Liu X, Wang P, Zhang C, et al. Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget. 2017;8(30):50209–50220. [8] Girard N. Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol 2018. [9] Inoue A, Kobayashi K, Maemondo M, et al. Final overall survival results of NEJ002, a phase III trial comparing gefitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. J Clin Oncol 2011;29:7519. [10] Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34. [11] Lin JJ, Cardarella S, Lydon CA, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 2016;11:556-65.
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