Cotellic [cotellic + Zelboraf]
(Cobimetinib)Dosage & Administration
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Cotellic [Cotellic + Zelboraf] Prescribing Information
Indications and Usage, Histiocytic Neoplasms (COTELLIC®, as a single agent, is indicated for the treatment of adult patients with histiocytic neoplasms. | 10/2022 |
Dosage and Administration (Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with COTELLIC with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . The recommended dosage regimen of COTELLIC is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity [see Clinical Studies (14)] .Take COTELLIC with or without food [see Clinical Pharmacology (12.3)] .If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. | 10/2022 |
Warning and Precautions (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 vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with vemurafenib and in none of the patients receiving vemurafenib. 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 vemurafenib compared with patients receiving vemurafenib. In Trial 2, in patients with histiocytic neoplasms, 19% of patients experienced hemorrhage events (all were of grade 1 severity). 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 [see Dosage and Administration (2.3)] .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 or 3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with vemurafenib and 19% of patients receiving vemurafenib. 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). In Trial 2, in patients with histiocytic neoplasms, 8% of patients experienced grade 2 ejection fraction decreased and 12% experienced grade 3-4 events. The median time to first onset of LVEF decrease was 29 days (range 22 days to 114 days). Of the patients with decreased LVEF, all had dose interruption and/or reduction and none required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 60% of patients receiving COTELLIC with a median time to resolution of 31 days (range: 13 days to 126 days). 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 [see Dosage and Administration (2.3)] . 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 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 vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving COTELLIC with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with vemurafenib and 2.0% in patients receiving vemurafenib. 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). In Trial 2, in patients with histiocytic neoplasms, 81% of patients experienced rash events (all were of grade 1-2 severity). Interrupt, reduce the dose, or discontinue COTELLIC [see Dosage and Administration (2.3)]. 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 vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion. In Trial 2, in patients with histiocytic neoplasms, 4% experienced grade 2 retinopathy and 4% experienced grade 3 retinal vascular disorder. Perform an ophthalmological 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 [see Dosage and Administration (2.3)] .Hepatotoxicity can occur with COTELLIC . The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase [see Adverse Drug Reactions (6.1)] . Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant alkaline phosphatase >2 × ULN occurred in one patient (0.4%) receiving COTELLIC with vemurafenib and no patients receiving single-agent vemurafenib.In Trial 2, in patients with histiocytic neoplasms, 9% of the patients receiving COTELLIC experienced grade 3 or 4 aspartate aminotransferase increased and 5% of the patients experienced grade 3 or 4 alanine aminotransferase increased. Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC [see Dosage and Administration (2.3)] .Rhabdomyolysis can occur with COTELLIC. In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving COTELLIC with vemurafenib and 0.5% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving COTELLIC with vemurafenib and in 0.4% of patients receiving vemurafenib. 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 [see Dosage and Administration (2.3)] .In Trial 2, in patients with histiocytic neoplasms, 27% of patients experienced grade 2 CPK elevation and 27% of patients experienced grade 3-4 CPK elevation. | 10/2022 |
COTELLIC
- For the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. (,
1.1 Unresectable or Metastatic MelanomaCOTELLIC
®is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.)14.1 Unresectable or Metastatic MelanomaThe safety and efficacy of COTELLIC was established in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial conducted in 495 patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The presence of BRAF V600 mutation was detected using the cobas®4800 BRAF V600 mutation test. All patients received vemurafenib 960 mg orally twice daily on days 1–28 and were randomized to receive COTELLIC 60 mg or matching placebo orally once daily on days 1–21 of an every 28-day cycle. Randomization was stratified by geographic region (North America vs. Europe vs. Australia/New Zealand/others) and disease stage (unresectable Stage IIIc, M1a, or M1b vs. Stage M1c). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive placebo were not offered COTELLIC at the time of disease progression.
The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes were investigator-assessed confirmed objective response rate, overall survival, PFS as assessed by blinded independent central review, and duration of response.
The median age of the study population was 55 years (range 23 to 88 years), 58% of patients were male, 93% were White and 5% had no race reported, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had an elevated baseline serum lactate dehydrogenase (LDH), 10% had received prior adjuvant therapy, and <1% had previously treated brain metastases. Patients with available tumor samples were retrospectively tested using next generation sequencing to further classify mutations as V600E or V600K; test results were obtained on 81% of randomized patients. Of these, 86% were identified as having a V600E mutation and 14% as having a V600K mutation.
Efficacy results are summarized in Table 7and Figure 1.
Table 7 Efficacy Results from Trial 1 COTELLIC + Vemurafenib
(n=247)Placebo + Vemurafenib
(n=248)CI - Confidence Intervals; NE - not estimable Progression-Free Survival (Investigator-Assessed)Number of Events (%) 143 (58%) 180 (73%) Progression 131 169 Death 12 11 Median PFS, months (95% CI) 12.3 (9.5, 13.4) 7.2 (5.6, 7.5) Hazard Ratio (95% CI) 0.56 (0.45, 0.70) p-value (stratified log-rank test) <0.001 Overall SurvivalBased on the final overall survival analysis, conducted after 16 months from the PFS primary analysisNumber of Deaths (%) 114 (46.2%) 141 (56.9%) Median OS, months (95% CI) 22.3
(20.3, NE)17.4
(15.0, 19.8)Hazard Ratio (95% CI) 0.69 (0.54,0.88) p -value (stratified log-rank test) 0.0032 Objective Response RateObjective Response Rate 70% 50% (95% CI) (64%, 75%) (44%, 56%) Complete Response 16% 10% Partial Response 54% 40% p-value <0.001 Median Duration of Response, months (95% CI) 13.0 (11.1, 16.6) 9.2 (7.5, 12.8) Figure 1 Kaplan-Meier Curves of Overall SurvivalThe effect on PFS was also supported by analysis of PFS based on the assessment by blinded independent review. A trend favoring the COTELLIC with vemurafenib arm was observed in exploratory subgroup analyses of PFS, OS, and ORR in both BRAF V600 mutation subtypes (V600E or V600K) in the 81% of patients in this trial where BRAF V600 mutation type was determined.
Figure 1 - As a single agent for the treatment of adult patients with histiocytic neoplasms. (,
1.2 Histiocytic NeoplasmsCOTELLIC®, as a single agent, is indicated for the treatment of adult patients with histiocytic neoplasms.)14.2 Histiocytic NeoplasmsA single-center, single-arm trial (Trial 2) was conducted to evaluate the efficacy, safety, and tolerability of COTELLIC as a single agent in adult patients with histologically confirmed histiocytic neoplasms of any mutational status. Patients with documented BRAF V600E mutations were enrolled if they were unable to access a BRAF inhibitor or discontinued a BRAF inhibitor due to toxicity. Enrolled patients had multi-system disease, recurrent or refractory disease, or single-system disease that is unlikely to benefit from conventional therapies, based on best available evidence.
The trial included 26 patients with histiocytic neoplasms including Langerhans Cell Histiocytosis (n=4), Rosai-Dorfman Disease (n=4), Erdheim-Chester Disease (n=13), Xanthogranuloma (n=2) and Mixed Histiocytosis (n=3). Patients with BRAF V600 mutant positive (n=6) and BRAF V600 Wild type (n=20) received COTELLIC. Twenty-one patients (81%) had received prior systemic therapies. The median age was 50.5 years (range, 18 to 79 years). Sixty-five percent of patients were men (n=17) and 35% were women (n=9). The majority of patients were White (85%), 8% were Black or African American and 4% were Asian; 96% were neither Hispanic nor Latino.
Patients were treated with COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle (n=26). Eighteen patients required a dose reduction to 40 mg, and five patients required an additional dose reduction to 20 mg. The median duration of treatment following a dose reduction to 40 mg and 20 mg was 6.6 months and 3.9 months respectively.
The major efficacy outcome was best overall response rate (BORR), maintained on two occasions at least four weeks apart, as assessed by the investigator using the PET Response Criteria (PRC). Other clinical outcomes included PRC-based duration of response (DOR), and BORR maintained on two occasions at least four weeks apart, as assessed by investigator using RECIST v1.1.
The median duration of follow-up was 11.4 months (range, 0.2 to 36.8 months). The median time to PRC-based response was 2.0 (range, 0.2 to 17.3 months). The median PRC-based DOR was 31 months (range, 2 to 31 months). See Table 8below for efficacy results.
Table 8 Efficacy of COTELLIC in patients with Histiocytic neoplasms (Trial 2) Response PET Response,Complete Response by PRC was defined as a normalization of all lesions' (target and non-target) standardized uptake values (SUV) to background SUVliver (or SUVbrain for brain lesions only),Partial Response by PRC was defined as a ≥50% decrease from baseline in sum of SUV of all target lesions relative to SUVliver (or SUVbrain for brain lesions only)Enrolled Patients
(n=26)24 PET-evaluable patients out of 26 enrolled patients. 1 patient had missing baseline scan. 1 patient had short follow-up duration (not enrolled at least 16 weeks prior to the clinical cutoff date (CCOD)RECIST Response, Enrolled Patients
(n=26)19 RECIST-evaluable patients out of 26 enrolled patients. 6 patients had missing baseline scans; these patients had lesions that were not measurable by RECIST 1.1 definition. 1 patient had short follow-up duration (not enrolled at least 16 weeks prior to CCOD)Overall response rate, n (%) 20 (76.9%) 12 (46.2%) (95% Clopper-Pearson CI) (56.4, 91) (26.6, 66.6) Best Response, n (%) Complete Response 16 (61.5%) 3 (11.5%) Partial Response 4 (15.4%) 9 (34.6%)
- Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of COTELLIC with vemurafenib for patients with melanoma. ()
2.1 Patient Selection for Treatment of MelanomaConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with COTELLIC with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. - The recommended dose is 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take COTELLIC with or without food. ()
2.2 Recommended DosageThe recommended dosage regimen of COTELLIC is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity[see Clinical Studies (14)].Take COTELLIC with or without food
[see Clinical Pharmacology (12.3)].If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.
Tablets: 20 mg, white, round, film-coated, debossed on one side with "COB".
Lactation: Do not breastfeed while taking COTELLIC. (
There is no information regarding the presence of cobimetinib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman not to breastfeed during treatment with COTELLIC and for 2 weeks after the final dose.
None.