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2015年11月17日，欧盟委员会批准罗氏Cotellic（cobimetinib）与威罗菲尼合并用于有BRAF V600突变的不可切除或转移性黑色素瘤成年患者治疗。
Dose modification advice for left ventricular dysfunction Permanent discontinuation of Cotellic treatment should be considered if cardiac symptoms are attributed to Cotellic and do not improve after temporary interruption. Table 2 Recommended dose modifications for Cotellic in patients with left ventricular ejection fraction (LVEF) decrease from baseline
Vemurafenib treatment can be continued when Cotellic treatment is modified, if clinically indicated. Dose modification advice for Cotellic when used with vemurafenib Liver laboratory abnormalities For Grade 1 and 2 liver laboratory abnormalities, Cotellic and vemurafenib should be continued at the prescribed dose. Grade 3: Cotellic should be continued at the prescribed dose. The dose of vemurafenib may be reduced as clinically appropriate. Please refer to the vemurafenib SmPC. Grade 4: Cotellic treatment and vemurafenib treatment should be interrupted. If liver laboratory abnormalities improve to Grade ≤1 within 4 weeks, Cotellic should be restarted at a dose reduced by 20 mg and vemurafenib at a clinically appropriate dose, per its SmPC. Cotellic treatment and vemurafenib treatment should be discontinued if liver laboratory abnormalities do not resolve to Grade ≤1 within 4 weeks or if Grade 4 liver laboratory abnormalities recur after initial improvement. Creatine phosphokinase (CPK) elevations Cotellic dosing does not need to be modified or interrupted to manage asymptomatic CPK elevations. Photosensitivity Grade ≤2 (tolerable) photosensitivity should be managed with supportive care. Grade 2 (intolerable) or Grade ≥3 photosensitivity: Cotellic and vemurafenib should be interrupted until resolution to Grade ≤1. Treatment can be restarted with no change in Cotellic dose. Vemurafenib dosing should be reduced as clinically appropriate, please refer to its SmPC for further information. Rash Rash events may occur with either Cotellic or vemurafenib treatment. The dose of Cotellic and/or vemurafenib may be either temporarily interrupted and/or reduced as clinically indicated. Additionally, for: Grade ≤2 (tolerable) rash should be managed with supportive care. Cotellic dosing can be continued without modification. Grade 2 (intolerable) or Grade ≥3 acneiform rash: General dose modification recommendations in Table 1 for Cotellic should be followed. Vemurafenib dosing can be continued when Cotellic treatment is modified (if clinically indicated). Grade 2 (intolerable) or Grade ≥3 non-acneiform or maculopapular rash: Cotellic dosing can be continued without modification if clinically indicated. Vemurafenib dosing may be either temporarily interrupted and/or reduced, please refer to its SmPC for further information. QT prolongation If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC (section 4.2) for dose modifications for vemurafenib. No dose modification of Cotellic is required when taken in combination with vemurafenib. Special populations Elderly patients No dose adjustment is required in patients aged ≥65 years old. Renal impairment No dose adjustment is recommended in patients with mild or moderate renal impairment based on population pharmacokinetic analysis (see section 5.2). There are minimal data for Cotellic in patients with severe renal impairment, therefore an effect cannot be excluded. Cotellic should be used with caution in patients with severe renal impairment. Hepatic impairment The safety and efficacy of Cotellic has not been established in patients with hepatic impairment (see section 5.2). There are no pharmacokinetic data in patients with moderate or severe hepatic impairment. Cotellic should be used with caution in patients with moderate to severe hepatic impairment. Non-Caucasian patients The safety and efficacy of Cotellic in non-Caucasian patients have not been established. Paediatric population The safety and efficacy of Cotellic in children and adolescents below 18 years of age have not been established. No data are available. Method of administration Cotellic is for oral use. The tablets should be swallowed whole with water. They can be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Before taking Cotellic in combination with vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. Cotellic in combination with vemurafenib in patients who have progressed on a BRAF inhibitor There are limited data in patients taking the combination of Cotellic with vemurafenib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1). Therefore other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established. Cotellic in combination with vemurafenib in patients with brain metastases The safety and efficacy of the combination of Cotellic and vemurafenib have not been evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain. The intracranial activity of cobimetinib is currently unknown (see sections 5.1 and 5.2). Serous retinopathy Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patients treated with MEK-inhibitors, including Cotellic (see section 4.8). The majority of events were reported as chorioretinopathy or retinal detachment. Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months). Most events observed in clinical trials were resolved, or improved to asymptomatic Grade 1, following dose interruption or reduction. Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If symptoms of new or worsening visual disturbances are identified, an ophthalmologic examination is recommended. If serous retinopathy is diagnosed, Cotellic treatment should be withheld until visual symptoms improve to Grade ≤1. Serous retinopathy can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2). Left ventricular dysfunction Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.8). Median time to initial onset of events was 4 months (1-7 months). LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see section 4.2). All patients restarting treatment with a dose reduction of Cotellic should have LVEF measurements taken after approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then as clinically indicated. Patients with a baseline LVEF either below institutional lower limit of normal (LLN) or below 50% have not been studied. Liver laboratory abnormalities Liver laboratory abnormalities can occur when Cotellic is used in combination with vemurafenib and with vemurafenib as a single agent (please refer to its SmPC). Liver laboratory abnormalities, specifically increases in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Alkaline Phosphatase (ALP), have been observed in patients treated with Cotellic plus vemurafenib (see section 4.8). Liver value abnormalities should be monitored by liver laboratory tests before initiation of combination treatment and monthly during treatment, or more frequently as clinically indicated (see section 4.2). Grade 3 liver laboratory abnormalities should be managed with vemurafenib treatment interruption or dose reduction. Manage Grade 4 liver laboratory abnormalities with treatment interruption, dose reduction or with treatment discontinuation of both Cotellic and vemurafenib (see section 4.2). Diarrhoea Cases of Grade ≥3 and serious diarrhoea have been reported in patients treated with Cotellic. Diarrhoea should be managed with anti-diarrhoeal agents and supportive care. For Grade ≥3 diarrhoea that occurs despite supportive care, Cotellic and vemurafenib should be withheld until diarrhoea has improved to Grade ≤1. If Grade ≥3 diarrhoea recurs, the dose of Cotellic and vemurafenib should be reduced (see section 4.2). Lactose intolerance This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption should consult with their physician and discuss whether the benefits outweigh the risks on an individual basis. Drug-drug interactions: CYP3A4 inhibitors Concurrent use of strong CYP3A inhibitors during treatment with Cotellic should be avoided. Caution should be exercised if a moderate CYP3A4 inhibitor is co-administered with Cotellic. If concomitant use with a strong or moderate CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety and dose modifications applied if clinically indicated (see Table 1 in section 4.2). QT prolongation If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC sections 4.2 and 4.4. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on cobimetinib CYP3A inhibitors Cobimetinib is metabolized by CYP3A and cobimetinib AUC increased approximately 7 fold in the presence of a strong CYP3A inhibitor (itraconazole) in healthy subjects. The magnitude of interaction could potentially be lower in patients. Strong CYP3A4 inhibitors (see section 4.4.): Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3A4 inhibitors include, but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interrupting cobimetinib therapy during the duration of inhibitor use. Moderate CYP3A4 inhibitors (see section 4.4.): Caution should be exercised if cobimetinib is co-administered with moderate CYP3A inhibitors. Moderate CYP3A4 inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. When cobimetinib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety. Mild CYP3A4 inhibitors: Cobimetinib can be co-administered with mild inhibitors of CYP3A without dose adjustment. CYP3A inducers Co-administration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study, however, a reduction in cobimetinib exposure is likely. Therefore, concomitant use of moderate and strong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, and St. John's Wort) should be avoided. Alternative agents with no or minimal CYP3A induction should be considered. Given that cobimetinib concentrations are likely to be significantly reduced when co-administered with moderate to strong CYP3A inducers, patient's efficacy may be compromised. P-glycoprotein inhibitors Cobimetinib is a substrate of P-glycoprotein (P-gp). Concomitant administration of P-gp inhibitors such as ciclosporin and verapamil may have the potential to increase plasma concentrations of cobimetinib. Effects of cobimetinib on other medicinal products CYP3A and CYP2D6 substrates A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) were not altered in the presence of cobimetinib. CYP1A2 substrates In vitro, cobimetinib is a potential inducer of CYP1A2 and may therefore reduce the exposure of substrates of this enzyme e.g., theophylline. No clinical DDI studies have been conducted to assess the clinical relevance of this finding. BCRP substrates In vitro, cobimetinib is a moderate inhibitor of BCRP (Breast Cancer Resistance Protein). No clinical DDI studies have been conducted to assess this finding, and clinically relevant inhibition of intestinal BCRP cannot be ruled out. Other anti-cancer agents Vemurafenib There is no evidence of any clinically significant drug-drug interaction between cobimetinib and vemurafenib in unresectable or metastatic melanoma patients and therefore no dose adjustments is recommended. Effects of cobimetinib on drug transport systems In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters OATP1B1, OATP1B3 and OCT1, however, it weakly inhibits these transporters. The clinical relevance of these findings has not been investigated. Padiatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should be advised to use two effective contraceptive methods, such as a condom or other barrier method (with spermicide, if available) during treatment with Cotellic and for at least three months following treatment discontinuation. Pregnancy There are no data from the use of Cotellic in pregnant women. Studies in animals have shown embryolethality and foetal malformations of the great vessels and skull (see section 5.3). Cotellic should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus. Breast-feeding It is not known whether cobimetinib is excreted in human breast milk. A risk to the newborns/infants cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue Cotellic therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data in humans for cobimetinib. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs (see section 5.3). The clinical relevance of this is unknown. 4.7 Effects on ability to drive and use machines Cotellic has minor influence on the ability to drive or use machines. Visual disturbances have been reported in some patients treated with cobimetinib during clinical trials (see sections 4.4 and 4.8). Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse effects that may affect their ability. 4.8 Undesirable effects Summary of the safety profile The safety of Cotellic in combination with vemurafenib has been evaluated in 254 patients with advanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset of first Grade ≥3 adverse events was 0.5 months in the Cotellic plus vemurafenib arm vs 0.8 months in the placebo plus vemurafenib arm. The safety of Cotellic in combination with vemurafenib has also been evaluated in 129 patients with advanced BRAF V600 mutated melanoma in Study NO25395. The safety profile of Study NO25395 was consistent with that observed in Study GO28141. In Study GO28141, the most common adverse reactions (>20%) observed with a higher frequency in the Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine phosphokinase, and vomiting. The most common adverse reactions (>20%) observed with a higher frequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis. Fatigue was observed at similar frequencies in both arms. Please refer to the vemurafenib SmPC for complete descriptions of all undesirable effects associated with vemurafenib treatment. Tabulated list of adverse reactions ADRs are based on results from a multi-centre, randomised, double-blind, placebo-controlled, Phase III Study (GO28141) that evaluated the safety and efficacy of Cotellic in combination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV). ADRs which were reported in melanoma patients are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for the classification of frequency: Very common ≥ 1/10 Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1,000 to < 1/100 Rare ≥ 1/10,000 to < 1/1,000 Very rare < 1/10,000 Table 3 lists adverse reactions considered associated with the use of Cotellic. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported according to NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141. Table 3 Adverse drug reactions in patients treated with Cotellic in combination with vemurafenib in Study GO28141
** Please refer to the paragraph Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis in the “Description of selected adverse reactions” section. a Includes both chorioretinopathy and retinal detachment events indicative of serous retinopathy (see section 4.4) b Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis Description of selected adverse reactions Haemorrhage Bleeding events have been reported more frequently in the Cotellic plus vemurafenib arm than in the placebo plus vemurafenib arm (all types and Grades: 10% vs 6%). Higher frequencies in the Cotellic plus vemurafenib arm were observed for cerebral haemorrhage (1% vs 0%), gastrointestinal tract haemorrhage (3% vs 1%), reproductive system haemorrhage (2% vs 1%) and haematuria (2% vs 1%). The majority of events were Grade 1 or 2 and non-serious (9% of patients in the Cotellic plus vemurafenib arm vs 5% patients in the placebo plus vemurafenib arm). Grade 3-5 events were experienced by 1% and 0.4% of patients, respectively. The median time to first onset was 2.8 months (range 0.0 to 12.7 months) in the Cotellic plus vemurafenib arm. Photosensitivity Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (41% vs 31%). The majority of events were Grades 1 or 2, with Grade ≥3 events occurring in 3% of patients in the Cotellic plus vemurafenib arm vs 0% in the placebo plus vemurafenib arm. There were no apparent trends in the time of onset of Grade ≥3 events. Grade ≥3 photosensitivity events in the Cotellic plus vemurafenib arm were treated with primary topical medicinal products in conjunction with dose interruptions of both cobimetinib and vemurafenib (see section 4.2). No evidence of phototoxicity was observed with Cotellic as a single agent. Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis Cutaneous squamous cell carcinoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 3% vs 11%). Keratoacanthoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 1% vs 8%). Hyperkeratosis has been reported with a lower frequency in the Cotellic plus vemurafenib vs placebo plus vemurafenib arm (all Grade: 10% vs 29%). Serous retinopathy Cases of serous retinopathy have been reported in patients treated with Cotellic (see section 4.4.) For patients reporting new or worsening visual disturbances, an ophthalmologic examination is recommended. Serous retinopathy can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2). Left ventricular dysfunction Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.4). LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see section 4.2). Laboratory abnormalities Liver laboratory abnormalities Liver laboratory abnormalities, specifically ALT, AST, and ALP have been observed in patients treated with Cotellic in combination with vemurafenib (see section 4.4). Liver laboratory tests should be monitored before initiation of combination treatment and monthly during treatment, or more frequently if clinically indicated (see section 4.2). Blood creatine phosphokinase increase Asymptomatic increases in blood CPK levels were observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm in Study GO28141 (see section 4.2). One event of rhabdomyolysis was observed in each treatment arm of the Study with concurrent increases in blood CPK. Table 4 provides the frequency of measured liver laboratory abnormalities and elevated creatine phosphokinase for all Grades and Grades 3-4. Table 4 Liver and other laboratory tests observed in the Phase III Study GO28141
Elderly patients In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or metastatic melanoma (n=254), 189 patients (74%) were <65 years of age, and 44 patients (17%) were 65-74 years of age, 17 (7%) were 75-84 years of age, and 4 patients (2%) were aged ≥85 years The proportion of patients experiencing adverse events (AE) was similar in the patients aged <65 years and those aged ≥65 years. Patients ≥65 years were more likely to experience serious adverse events (SAEs) and experience AEs leading to discontinuation of cobimetinib than those <65 years. Renal impairment No pharmacokinetic trial in subjects with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment based on the results of the population pharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renal impairment. Cotellic should be used with caution in patients with severe renal impairment. Hepatic impairment No pharmacokinetic data in subjects with hepatic impairment are available. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below). Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose There is no experience with overdose in human clinical trials. In case of suspected overdose, cobimetinib should be withheld and supportive care instituted. There is no specific antidote for overdosage with cobimetinib. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XE38 Mechanism of action Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node. In the preclinical models, the combination of cobimetinib and vemurafenib showed that by simultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the combination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a stronger inhibition of intracellular signalling and decreased tumour cell proliferation Clinical efficacy and safety There are no data on the safety or efficacy of Cotellic in combination with vemurafenib in patients with central nervous system metastasis or in patients with non-cutaneous malignant melanoma. Study GO28141 (coBRIM) Study GO28141 is a multi-centre, randomised, double-blind, placebo-controlled, Phase III study to evaluate the safety and efficacy of Cotellic in combination with vemurafenib as compared to vemurafenib plus placebo, in previously untreated patients with BRAF V600 mutation-positive unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV). Only patients with ECOG performance status 0 and 1 were enrolled in Study GO28141. Patients with ECOG performance status 2 or higher were excluded from the study. Following confirmation of a BRAF V600 mutation, using the cobas® 4800 BRAF V600 mutation test, 495 previously untreated patients with unresectable locally advanced or metastatic melanoma were randomised to receive either: • Placebo once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twice daily on Days 1-28, or • Cotellic 60 mg once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twice daily on Days 1-28 Progression-free survival (PFS) as assessed by the investigator (INV) was the primary endpoint. Secondary efficacy endpoints included overall survival (OS), objective response rate, duration of response (DoR) as assessed by INV and PFS as assessed by an independent review facility (IRF). Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23 to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated LDH was 46.3% in the cobimetinib plus vemurafenib arm and 43.0% in the placebo plus vemurafenib arm. In Study GO28141, there were 89 patients (18.1%) aged 65-74, 38 patients (7.7%) aged 75-84 and 5 patients (1.0%) aged 85 years and older. Efficacy results are summarized in Table 5. Table 5 Efficacy results from Study GO28141 (coBRIM) – Cut-off date 16 January 2015
a Assessed and confirmed by the investigator (INV) using RECIST v1.1 b Stratified analysis by geographic region and metastasis classification (disease stage) c Using Clopper-Pearson method d Using Hauck-Anderson method The primary analysis for Study GO28141 was conducted with a data cut-off date of 09 May 2014. Significant improvement in the primary endpoint, investigator-assessed PFS, was observed in patients assigned to the Cotellic plus vemurafenib arm compared to the placebo plus vemurafenib arm (HR 0.51 (0.39; 0.68); p-value < 0.0001). The median estimate for investigator-assessed PFS was 9.9 months for the Cotellic plus vemurafenib arm vs. 6.2 months for the placebo plus vemurafenib arm. The median estimate for independent review of PFS was 11.3 months for the Cotellic plus vemurafenib arm vs. 6.0 months for the placebo plus vemurafenib arm (HR 0.60 (0.45; 0.79); p-value = 0.0003). The objective response rate (ORR) in the Cotellic plus vemurafenib arm was 67.6% vs 44.8% in the placebo plus vemurafenib arm. The difference in ORR was 22.9 % (p-value<0.0001). Figure 1 Kaplan-Meier curves of progression-free survival (INV) – intent to treat population (cut-off date: 16 January 2015)
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考比替尼薄膜片|Cotellic（cobimetinib filmcoated tablets）简介：
2015年11月17日，欧盟委员会批准罗氏Cotellic（cobimetinib）与威罗菲尼合并用于有BRAF V600突变的不可切除或转移性黑色素瘤成年患者治疗。此次,欧盟的批准基于3期coBRIM研究数据，数据显示，在既往未治 ... 责任编辑：admin |
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