近日，诺华宣布，美国FDA已批准Tafinlar（dabrafenib）与Mekinist（trametinib）的组合，为BRAF V600E/K突变黑色素瘤患者的辅助新疗法。   全球每年约诊断出20万例黑色素瘤新病例，其中约有一半具有BRAF突变。基因测试可以确定肿瘤是否具有BRAF突变。接受手术治疗的黑色素瘤患者有较高的复发风险，因为黑色素瘤细胞可以在术后留在体内。对于这类患者，通常会建议使用辅助疗法，以降低黑色素瘤复发的风险。   Tafinlar加Mekinist组合疗法就是这样一款辅助疗法。Tafinlar和Mekinist分别针对RAS/RAF/MEK/ERK通路中的丝氨酸/苏氨酸激酶家族BRAF和MEK1/2中的不同激酶，它们通常存在于非小细胞肺癌（NSCLC）和黑色素瘤等癌症中。当Tafinlar与Mekinist一起使用时，其在减缓肿瘤生长方面的效果被证明比单药使用效果好。目前，这一组合疗法已在美国、欧盟、澳大利亚、加拿大等国获批，治疗具有BRAF V600突变的不可切除或转移性黑色素瘤患者。   此次该组合疗法的获批是基于临床试验COMBI-AD的结果。COMBI-AD是一项随机、双盲、安慰剂对照的3期研究，共包含870例具有BRAF V600E/K突变、先前接受过手术切除的III期黑色素瘤患者。这些患者根据BRAF突变类型（V600E vs. V600K）和阶段（IIIA vs. IIIB vs. IIIC）进行分层，并随机分配接受为期12个月的Tafinlar（150mg BID）加Mekinist（2mg QD）组合（n=438）疗法或匹配的安慰剂（n=432）治疗。研究的主要终点是无复发生存期（RFS），次要终点包括总生存期（OS）、无远处转移生存期（DMFS）、免于复发（FFR）和安全性。   在中位随访2.8年后，该研究抵达无复发生存期（RFS）的主要终点。与安慰剂相比，组合疗法显著降低疾病复发或死亡风险53％（HR: 0.47, 95％CI: 0.39-0.58, p<0.0001）。组合疗法的中位RFS未达到，安慰剂为16.6个月。在所有患者亚组和疾病亚期中，都观察到组合疗法在RFS上的疗效。该组合疗法还改善了患者的OS、DMFS和FFR等关键次要终点。组合疗法的不良事件与其他研究中的结果一致，没有发现新的安全问题。   “辅助疗法的目的是为了改善黑色素瘤患者的无复发和总生存期，辅助治疗方案在今天至关重要，因为超过一半的患者在手术后复发，”匹兹堡大学黑色素瘤和皮肤癌主任兼医学教授John M. Kirkwood博士说：“22年前我们开发了FDA批准的第一款辅助疗法，现在我们有了第一种有效的口服靶向组合疗法，可以防止扩散到淋巴结的具有BRAF突变的黑色素瘤患者复发。”    “预防和早期发现是黑色素瘤的重要保障措施，但这只是一部分。黑色素瘤是一种可以复发的侵袭性癌症，特别是当它显示某些警告迹象，如深度增加、溃疡或向淋巴结扩散时，”俄勒冈健康和科学大学（OHSU）医学院皮肤科主任Sancy Leachman博士说：“在这些患者有了经过验证的新疗法后，皮肤科医生需要确保合适的患者能够使用辅助疗法。‘观察和等待’的方法不再是护理标准。与外科医生、病理学家和肿瘤学家的多学科护理团队一道，根据患者的个人情况和突变状态确定正确的治疗方案，对我们的患者护理计划至关重要。”期待新组合疗法的获批可以为广大黑色素瘤患者带来生存希望。 TAFINLAR(dabrafenib) +MEKINIST(trametinib) INDICATION TAFINLAR®(dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF NSCLC. IMPORTANT SAFETY INFORMATION New Primary Malignancies. Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR with MEKINIST was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with MEKINIST who developed basal cell carcinoma, 2 experienced more than 1 occurrence (range: 1 to 3). In the NSCLC study, cutaneous squamous cell carcinoma (cuSCC) occurred in 3.2% of patients receiving TAFINLAR with MEKINIST. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy and for up to 6 months following discontinuation of TAFINLAR. No dose modifications are required in patients who develop new primary cutaneous malignancies. Noncutaneous Malignancies: In the NSCLC study, noncutaneous malignancies occurred in 1.1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies. Tumor Promotion in BRAF Wild-type NSCLC. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation status prior to initiation of therapy. Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the NSCLC study, fatal hemorrhagic events occurred in 2.2% of patients receiving TAFINLAR with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR and MEKINIST for grade 3 hemorrhagic events; if improved, resume at the next lower dose level. Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials with MEKINIST, colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively. Monitor patients closely for colitis and gastrointestinal perforations. Venous Thromboembolism. In the NSCLC study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 4.3% (4/93) of patients receiving TAFINLAR with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST and TAFINLAR for life-threatening PE. Withhold MEKINIST for uncomplicated DVT or PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose. Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the NSCLC clinical trial, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) below the institutional lower limit of normal (LLN) with an absolute decrease in LVEF >10% below baseline, occurred in 9% of patients receiving TAFINLAR with MEKINIST and resulted in dose interruption and permanent discontinuation of MEKINIST in 5% and 2.2% of patients, respectively. Dose interruption and permanent discontinuation of TAFINLAR occurred in 3.2% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving TAFINLAR with MEKINIST. Assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2- to 3-month intervals while on treatment. Withhold MEKINIST for up to 4 weeks, and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is <LLN. For symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction of >20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose on the recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared with baseline. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials including MEKINIST, the incidence of RVO was 0.2%. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently(within 24 hours) perform ophthalmologic evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. Retinal Pigment Epithelial Detachment (RPED): RPED can occur. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In the COMBI-d study, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown. Perform ophthalmologic evaluation periodically, and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks. Uveitis: Uveitis occurred in 2% of patients treated with the combination across metastatic melanoma trials. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, and eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification; for severe uveitis or iridocyclitis, interrupt TAFINLAR and treat as clinically indicated. Permanently discontinue TAFINLAR for persistent grade 2 or greater uveitis of >6 weeks duration. Interstitial Lung Disease (ILD). In clinical trials of MEKINIST as a single agent, ILD or pneumonitis occurred in 2% of patients. In the NSCLC study, 2.2% of patients receiving TAFINLAR with MEKINIST developed pneumonitis. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when the combination is used compared with TAFINLAR as a single agent. In patients treated with the combination in the metastatic melanoma studies, the incidence of fever was 54% and serious febrile reactions and fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. About half of the patients on combination therapy who experienced pyrexia had 3 or more discrete episodes. Fever was complicated by severe chills/rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% in patients receiving the combination. Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for fever higher than 104ºF. Withhold TAFINLAR and MEKINIST for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to the Prescribing Information for either agent for recommended dose modifications. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR and/or MEKINIST if the patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection. Serious Skin Toxicity. Across clinical trials of the combination in unresectable metastatic melanoma, serious skin toxicity occurred in 0.7% of patients. In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving the combination. No serious or severe cases of skin toxicity occurred in patients treated with the combination. Reductions in the dose of MEKINIST were required in 5% of patients receiving the combination, and no patient required permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Withhold TAFINLAR and MEKINIST for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower doses in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In the COMBI-d study, 27% of patients with a history of diabetes receiving the combination and 13% of patients receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. The incidence of grade 3 and grade 4 hyperglycemia based on laboratory values was 5% and 0.5% of patients treated with the combination, respectively. For patients receiving single-agent TAFINLAR, 4.3% of patients had grade 3 hyperglycemia based on laboratory values and no patients had grade 4 hyperglycemia. Monitor serum glucose levels upon initiation, and as clinically appropriate in patients with preexisting diabetes or hyperglycemia. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryo-fetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective nonhormonal contraception during treatment, and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their health care provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. In the NSCLC clinical trial, the most commonly occurring adverse reactions (≥20%) in patients receiving the combination were pyrexia (55%), fatigue (51%), nausea (45%), vomiting (33%), diarrhea (32%), dry skin (31%), decreased appetite (29%), edema (28%), rash (28%), chills (23%), hemorrhage (23%), cough (22%), and dyspnea (20%). The most common grade 3 or 4 adverse reactions (incidence ≥2%) were pyrexia (5%), fatigue (5%), dyspnea (5%), hemorrhage (3.2%), rash (3.2%), vomiting (3.2%), and diarrhea (2.2%). Other Clinically Important Adverse Reactions. The other clinically important adverse reactions observed in ≤10% of patients with NSCLC receiving the combination were pancreatitis and tubulointerstitial nephritis. Laboratory Abnormalities. In the NSCLC clinical trial, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were hyperglycemia (71%), increased blood alkaline phosphatase (64%), increased aspartate aminotransferase (61%), hyponatremia (57%), leukopenia (48%), anemia (46%), neutropenia (44%), lymphopenia (42%), hypophosphatemia (36%), increased alanine aminotransferase (32%), and creatinine (21%). The most common grade 3 or 4 laboratory abnormalities (incidence ≥10%) were hyponatremia (17%), lymphopenia (14%), and anemia (10%). 1）：https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf 2）：https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/mekinist.pdf