2015年11月26日，欧盟委员会已批准Cotellic(cobimetinib)和Zelboraf (vemurafenib)联合使用治疗不能切除或伴有BRAF V600突变转移性黑色素瘤的成人患者。
欧盟批准基于Cotellic和Zelboraf联合使用对一年多病情没有好转的先前未经治疗BRAF V600突变阳性晚期黑色素瘤患者，能起到一定的疗效。
首席医疗官和全球产品开发主席Sandra Horning， M.D.指出，在治疗黑色素瘤方面，目前，已取得重大进展，在过去的五年中，有超过30种药品被批准，Cotellic和Zelboraf联合使用，比Zelboraf单独使用，能更强烈抑制肿瘤的生长。这就强调了组合药物在帮助的黑色素瘤患者活得更长，而且没有使他们疾病恶化起到了关键作用。
今天的欧盟批准主要基于coBRIM临床3期的研究结果，结果显示先前未经治疗 BRAF V600突变阳性黑色素瘤晚期患者联合使用MEK抑制剂Cotellic与Zelboraf接近一年(12.3个月) 没有使他们疾病恶化或死亡 (无进展生存期;PFS)。Zelboraf单独使用PFS只有7.2个月(危险比[HR]=0.58; 95%可信区间[CI] 0.46 0.72).
Cotellic与Zelboraf安全数据与单独使用Zelboraf的安全数据保持一致。在联用组中最常见的不良反应是腹泻、 皮疹、 恶心、 发热、 光敏、 肝室异常、 高含量肌酸磷酸激酶(CPK，肌肉释放的酶) 和呕吐。
in combination with ZELBORAF® (vemurafenib) for BRAF V600E or V600K(+) unresectable or metastatic melanoma
INDICATIONS AND USAGE
COTELLIC (cobimetinib) is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with ZELBORAF® (vemurafenib).
Limitation of Use: COTELLIC is not indicated for treatment of patients with wild-type BRAF melanoma.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Review the Full Prescribing Information for ZELBORAF for information on the serious risks of ZELBORAF.
New Primary Malignancies
New primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC.
Cutaneous Malignancies
•In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with ZELBORAF arm and the ZELBORAF arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with ZELBORAF, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the 2 patients with second primary melanoma was 9 months and 12 months
•Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with ZELBORAF
Non-cutaneous Malignancies
•Based on its mechanism of action, ZELBORAF may promote growth and development of malignancies. In Trial 1, 0.8% of patients in the COTELLIC with ZELBORAF arm and 1.2% of patients in the ZELBORAF arm developed non-cutaneous malignancies
•Monitor patients receiving COTELLIC, when administered with ZELBORAF, for signs or symptoms of non-cutaneous malignancies
Hemorrhage
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC
•In Trial 1, the incidence of grade 3-4 hemorrhages was 1.2% in patients receiving COTELLIC with ZELBORAF and 0.8% in patients receiving ZELBORAF. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with ZELBORAF and 7% in patients receiving ZELBORAF. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with ZELBORAF and in none of the patients receiving ZELBORAF. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with ZELBORAF compared with patients receiving ZELBORAF
•Withhold COTELLIC for grade 3 hemorrhagic events. If improved to grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for grade 4 hemorrhagic events and any grade 3 hemorrhagic events that do not improve
Cardiomyopathy
•Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%
•In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2-3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with ZELBORAF and 19% of patients receiving ZELBORAF. The median time to first onset of LVEF decrease was 4 months (range: 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months)
•Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated
Severe Dermatologic Reactions
Severe rash and other skin reactions can occur with COTELLIC.
•In Trial 1, grade 3 to 4 rash occurred in 16% of patients receiving COTELLIC with ZELBORAF and in 17% of patients receiving ZELBORAF, including grade 4 rash in 1.6% of patients receiving COTELLIC with ZELBORAF and 0.8% of the patients receiving ZELBORAF. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with ZELBORAF and 2.0% in patients receiving ZELBORAF. In patients receiving COTELLIC, the median time to onset of grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with grade 3 or 4 rash events, 95% experienced complete resolution, with the median time to resolution of 21 days (range: 4 days to 17 months)
•Interrupt, reduce the dose, or discontinue COTELLIC for severe dermatologic reactions
Serous Retinopathy and Retinal Vein Occlusion
Ocular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina).
•In Trial 1, ophthalmologic examinations, including retinal evaluation, were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with ZELBORAF. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged from 2 days to 9 months. The reported duration of serous retinopathy ranged from 1 day to 15 months. One patient in each arm developed retinal vein occlusion
•Perform an ophthalmologic evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation
Hepatotoxicity
Hepatotoxicity can occur with COTELLIC.
•The incidences of grade 3-4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with ZELBORAF compared with patients receiving ZELBORAF were 11% vs 6% for alanine aminotransferase, 7% vs 2.1% for aspartate aminotransferase, 1.6% vs 1.2% for total bilirubin, and 7% vs 3.3% for alkaline phosphatase. Concurrent elevation in ALT >3x the upper limit of normal (ULN) and bilirubin >2x ULN in the absence of significant alkaline phosphatase >2x ULN occurred in one patient (0.4%) receiving COTELLIC with ZELBORAF and no patients receiving single-agent ZELBORAF
•Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage grade 3-4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC
Rhabdomyolysis
Rhabdomyolysis can occur with COTELLIC.
•In Trial 1, grade 3-4 CPK elevations, including asymptomatic elevations over baseline, occurred in 12% of patients receiving COTELLIC with ZELBORAF and 0.4% of patients receiving ZELBORAF. The median time to first occurrence of grade 3-4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with ZELBORAF; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10x the baseline value with a concurrent increase in serum creatinine of 1.5x or greater compared with baseline occurred in 3.6% of patients receiving COTELLIC with ZELBORAF and in 0.4% of patients receiving ZELBORAF
•Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required
Severe Photosensitivity
Photosensitivity, including severe cases, can occur with COTELLIC.
•In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with ZELBORAF: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving COTELLIC with ZELBORAF, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on COTELLIC with ZELBORAF, 63% experienced resolution of photosensitivity reactions.
•Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable grade ≥2 photosensitivity with dose modifications
Embryo-Fetal Toxicity
•Based on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures (area under the curves [AUCs]) that were 0.9 to 1.4 × those observed in humans at the recommended human dose of 60 mg
•Advise pregnant women of the potential risk to a fetus.
— Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for 2 weeks following the final dose of COTELLIC
— Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF
Most Common Adverse Reactions for COTELLIC
•The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia and vomiting. The most common (≥5%) grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, and hyponatremia