2013年7月12日美国食品和药品监督管理局(FDA)批准Gilotrif(afatinib)为有晚期(转移)非小细胞肺癌(NSCLC)患者，当用一种被FDA-批准的测试检验时其肿瘤表达特殊类型的表皮生长因子受体(EGFR)基因突变。.
肺癌是男性和女性中癌相关死亡首要原因。按照美国国家癌症研究所，估计今年228,190美国人将被诊断有肺癌，而159,480将死于该病。约85%肺癌是NSCLC，使之为肺癌最常见类型。约10%的NSCLC中存在EGFR基因突变，这些基因突变的多数表达EGFR外显子19缺失或外显子21 L858R取代。
Gilotrif是一个酪氨酸激酶抑制剂阻断促进癌细胞发展的蛋白。意向为肿瘤表达EGFR外显子19缺失或外显子21 L858R取代基因突变患者。Gilotrif正在被批准与therascreen EGFR RGQ PCR Kit同时，一种协同诊断有助于确定 患者的肺癌细胞是否表达EGFR突变。
美国FDA药物评价和研究中心血液学和肿瘤学室主任Richard Pazdur，M.D.说：“今天的批准进一步示范更多了解所患疾病的分子通路可能导致靶向治疗的发展，”“Gilotrif是今年被批准对有其肿瘤有EGFR外显子19缺失或外显子21 L858R取代突变未治疗的转移NSCLC患者第二个药物。”
在5月，FDA批准Tarceva(厄洛替尼[erlotinib])对有NSCLC患者的一线治疗。在Tarceva的新适应证批准同时批准与cobas EGFR突变测试，一种协同诊断确定患者有EGFR基因突变肿瘤。
美国FDA装置和放射卫生中心在体外诊断和放射卫生室主任Alberto Gutierrez，Ph.D.说：“协同诊断测试和药物的批准在肿瘤学是重要发展，因为它们帮助我们对需要它们患者的安全和有效治疗。”
FDA批准therascreen EGFR RGQ PCR药盒是根据来自使用支持Gilotrif的批准的临床研究数据。在临床试验中来自NSCLC参加者肿瘤样品帮助确证测试的使用为检测在这个患者群中EGFR突变。
在一项345例有转移NSCLC参加者其肿瘤有EGFR突变的临床研究确定Gilotrif的安全性和有效性。参加者被随机赋予接受Gilotrif或直至6个疗程的化疗药物培美曲塞[pemetrexed]和顺铂[cisplatin]。
参加者接受Gilotrif有延迟肿瘤生长(无进展生存)是4.2个月晚于接受化疗患者。总生存无统计意义差别。
Gilotrif的常见副作用包括腹泻，皮疹相似于痤疮，干皮肤，瘙痒，口腔炎症，甲沟炎，食欲减低，体重减轻，膀胱炎，鼻出血，流鼻涕，发热，眼炎和低钾血症。严重副作用包括腹泻可能导致肾衰和严重脱水，严重皮疹，肺炎和肝脏毒性。
FDA在优先审评计划下审评Gilotrif，它提供一种加快评审可能提供安全和有效治疗药物当没有另外已有满意治疗时，或比已上市产品提供显著改进时。
Gilotrif由总部里奇菲尔德，康恩Boehringer Ingelheim Pharmaceuticals，Inc上市。Therascreen EGFR RGQ PCR药盒由总部在英国的QIAGEN Manchester Ltd制造Cobas EGFR突变测试由加州普莱森Roche Molecular Systems制造，而Tarceva由集团Roche成员总部加州的Genentech 和总部纽约Farmingdale的OSI Pharmaceuticals共同上市。
FDA approves GILOTRIF™ (afatinib) as first-line treatment for metastatic non-small cell lung cancer with common EGFR mutations
 |
Ridgefield, CT, July 12, 2013 /PRNewswire/ — Boehringer Ingelheim Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved GILOTRIF™ (afatinib) tablets for oral use, as a new first-line (initial) treatment for patients with metastatic non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.1 Discovered and developed by Boehringer Ingelheim, GILOTRIF is the first FDA-approved oncology product from the company.
In some people, genetic mutations lead to the constant activation of the EGFR protein, which is associated with uncontrolled cell division and the development and progression of NSCLC.2 Among patients diagnosed with NSCLC (the most common form of lung cancer3), it is estimated that between 10 and 15 percent of Caucasians and approximately 40 percent of Asians have EGFR mutations4 – which in 90 percent of cases are one of the two most common EGFR mutations (Del19 or L858R).5
“The approval of GILOTRIF offers a new treatment option and provides a personalized treatment approach for patients with EGFR mutation-positive metastatic non-small cell lung cancer,” said Berthold Greifenberg, M.D., vice president, Clinical Development and Medical Affairs, Oncology. “Over the past decade, great progress has been made in understanding the biology of lung cancer and GILOTRIF is an example of how, at BI, we are translating this knowledge into a new treatment option for patients.”
To determine if a patient is eligible for GILOTRIF, physicians must conduct a test for genetic mutations – also known as biomarker testing – to determine if a common EGFR mutation is present. For this reason, and in line with FDA’s current guidance, BI collaborated with QIAGEN, a leading global provider of sample and assay technologies, on the development of a companion diagnostic for GILOTRIF. QIAGEN’s therascreen® EGFR RGQ PCR Kit was reviewed and approved by the FDA in parallel to GILOTRIF and will be used to identify patients who may be eligible for treatment.
“We are truly excited to be able to offer GILOTRIF as a new treatment option for these patients. This approval is an achievement for Boehringer Ingelheim Oncology and the many teams and individuals who committed themselves to developing this therapy based on its potential identified in the clinical trial program,” said Kevin Lokay, vice president and business unit head, Oncology, Boehringer Ingelheim Pharmaceuticals, Inc. “GILOTRIF marks the first, of what we expect will be many, oncology products to emerge from our research and development program.”
For more information about the FDA-approved therascreen® EGFR RGQ PCR Kit, please contact QIAGEN at +49 2103 29 11826.
About the LUX-Lung 3 Clinical Trial
The approval of GILOTRIF was supported in part by the LUX-Lung 3 trial – one of the largest Phase III trials conducted to date in the first-line EGFR mutation-positive, locally advanced or metastatic NSCLC treatment setting.
Results showed that within the general study population, in the GILOTRIF arm, median progression-free survival (PFS) was 11.1 months versus 6.9 months for the chemotherapy arm (pemetrexed/cisplatin) (p<0.001).1 Approximately 90 percent of patients in the study had the most common EGFR mutations (Del19 and L858R).1 In these patients, the median PFS in the GILOTRIF arm was 13.6 months versus 6.9 months in the chemotherapy arm.1
In the LUX-Lung 3 trial, the most common drug-related adverse events (AEs) observed with GILOTRIF were diarrhea (96%), rash/dermatitis acneiform (90%), stomatitis (71%), paronychia (58%), dry skin (31%), decreased appetite (29%) and pruritus (21%).1 Serious adverse events (SAEs) were reported in 29 percent of patients treated with GILOTRIF; the most frequent SAEs were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each).1
About GILOTRIF (afatinib)
GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1
Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.1
GILOTRIF is an oral, once-daily kinase inhibitor that is designed to bind and irreversibly inhibit the following receptors: EGFR (ErbB1), HER2 (ErbB2) and ErbB4.1
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Diarrhea
•Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.
•For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.
Bullous and Exfoliative Skin Disorders
•Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.
Interstitial Lung Disease (ILD)
•ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.
•Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
•In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.
•Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.
Keratitis
•Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryofetal Toxicity
•GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
•Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF.
ADVERSE REACTIONS
•The most common adverse reactions (≥20%) in the GILOTRIF-treated patients (n=229) in the pivotal study were diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.
•Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
•More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
•Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
•Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Nursing Mothers
•It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Renal Impairment
•GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated.
Hepatic Impairment
•GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.
Full GILOTRIF prescribing information is available here or by contacting Boehringer Ingelheim’s Medical and Technical Information (MTI) Unit at 1-800-542-6257.