Cobimetinib Roche

Cobimetinib Roche® is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.

Patient Selection

Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Cobimetinib Roche with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dose

The recommended dosage regimen of Cobimetinib Roche 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.

Take Cobimetinib Roche with or without food.

If a dose of Cobimetinib Roche is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.

Dose Modifications

Concurrent CYP3A Inhibitors

Do not take strong or moderate CYP3A inhibitors while taking Cobimetinib Roche.

If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking Cobimetinib Roche 60 mg, reduce Cobimetinib Roche dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of Cobimetinib Roche 60 mg.

Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Cobimetinib Roche (40 or 20 mg daily).

Adverse Reactions

Review the Full Prescribing Information for vemurafenib for recommended dose modifications.

Table 1: Recommended Dose Reductions for Cobimetinib Roche

Table 2: Recommended Dose Modifications for Cobimetinib Roche for Adverse Reactions

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib.

New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur with Cobimetinib Roche.

Cutaneous Malignancies

In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the Cobimetinib Roche with vemurafenib arm and the vemurafenib 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 Cobimetinib Roche with vemurafenib, 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 two 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 Cobimetinib Roche. Conduct dermatologic monitoring for 6 months following discontinuation of Cobimetinib Roche when administered with vemurafenib.

Non-Cutaneous Malignancies

Based on its mechanism of action, vemurafenib may promote growth and development of malignancies [refer to the Full Prescribing Information for vemurafenib]. In Trial 1, 0.8% of patients in the Cobimetinib Roche with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies.

Monitor patients receiving Cobimetinib Roche, when administered with vemurafenib, 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 Cobimetinib Roche.

In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving Cobimetinib Roche with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving Cobimetinib Roche with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving Cobimetinib Roche 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 Cobimetinib Roche with vemurafenib compared with patients receiving vemurafenib.

Withhold Cobimetinib Roche for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume Cobimetinib Roche at a lower dose level. Discontinue Cobimetinib Roche 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 Cobimetinib Roche. The safety of Cobimetinib Roche 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 Cobimetinib Roche 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 Cobimetinib Roche 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 Cobimetinib Roche. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting Cobimetinib Roche 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 Cobimetinib Roche.

In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving Cobimetinib Roche with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving Cobimetinib Roche with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving Cobimetinib Roche with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving Cobimetinib Roche, 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 Cobimetinib Roche.

Serous Retinopathy And Retinal Vein Occlusion

Ocular toxicities can occur with Cobimetinib Roche, 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 Cobimetinib Roche 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.

Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt Cobimetinib Roche until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation.

Hepatotoxicity

Hepatotoxicity can occur with Cobimetinib Roche.

The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving Cobimetinib Roche 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. Concurrent elevation in ALT > 3 times the upper limit of normal (ULN) and bilirubin > 2 X ULN in the absence of significant alkaline phosphatase > 2 X ULN occurred in one patient (0.4%) receiving Cobimetinib Roche with vemurafenib and no patients receiving single-agent vemurafenib.

Monitor liver laboratory tests before initiation of Cobimetinib Roche 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 Cobimetinib Roche.

Rhabdomyolysis

Rhabdomyolysis can occur with Cobimetinib Roche.

In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving Cobimetinib Roche 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 Cobimetinib Roche 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 Cobimetinib Roche with vemurafenib and in 0.4% of patients receiving vemurafenib.

Obtain baseline serum CPK and creatinine levels prior to initiating Cobimetinib Roche, 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 Cobimetinib Roche may be required.

Severe Photosensitivity

Photosensitivity, including severe cases, can occur with Cobimetinib Roche.

In Trial 1, photosensitivity was reported in 47% of patients receiving Cobimetinib Roche with vemurafenib: 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 Cobimetinib Roche with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on Cobimetinib Roche with vemurafenib, 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 or greater photosensitivity with dose modifications.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, Cobimetinib Roche 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-times 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 Cobimetinib Roche, and for 2 weeks following the final dose of Cobimetinib Roche.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Inform patients of the following:

New Primary Cutaneous Malignancies

Advise patients to contact their health care provider immediately for change in or development of new skin lesions.

Hemorrhage

Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage.

Cardiomyopathy

Advise patients to report any history of cardiac disease and of the requirement for cardiac monitoring prior to and during Cobimetinib Roche administration. Instruct patients to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider.

Serious Dermatologic Reactions

Instruct patients to contact their healthcare provider to immediately report severe skin changes.

Serious Retinopathy And Retinal Vein Occlusion

Instruct patients to immediately contact their healthcare provider if they experience any changes in their vision.

Hepatotoxicity

Advise patients that treatment with Cobimetinib Roche requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction.

Rhabdomyolysis

Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider.

Severe Photosensitivity

Advise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.

Embryo-fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Cobimetinib Roche.

Females of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib Roche and for at least 2 weeks after the final dose of Cobimetinib Roche.

Lactation

Advise females not to breastfeed during treatment with Cobimetinib Roche and for 2 weeks after the final dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with cobimetinib have not been conducted. Cobimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in bone marrow of rats.

No dedicated fertility studies have been performed with cobimetinib in animals; however, effects on reproductive tissues observed in general toxicology studies conducted in animals suggest that there is potential for cobimetinib to impair fertility. In female rats, degenerative changes included increased apoptosis/necrosis of corpora lutea and vaginal epithelial cells at cobimetinib doses approximately twice those in humans at the clinically recommended dose of 60 mg based on body surface area. In male dogs, testicular degeneration occurred at exposures as low as approximately 0.1 times the exposure in humans at the clinically recommended dose of 60 mg.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action, Cobimetinib Roche can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Cobimetinib Roche during pregnancy. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal Data

Administration of cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.

Lactation

Risk Summary

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 Cobimetinib Roche and for 2 weeks after the final dose.

Females And Males Of Reproductive Potential

Contraception

Females

Cobimetinib Roche can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Cobimetinib Roche and for 2 weeks after the final dose of Cobimetinib Roche.

Infertility

Females and Males

Based on findings in animals, Cobimetinib Roche may reduce fertility in females and males of reproductive potential.

Pediatric Use

The safety and effectiveness of Cobimetinib Roche have not been established in pediatric patients.

Juvenile Animal Data

In a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined.

Geriatric Use

Clinical studies of cobimetinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Hepatic Impairment

Adjustment in the starting dose of Cobimetinib Roche is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Renal Impairment

No dedicated pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment (CLcr 30 to 89 mL/min) based on the results of the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment.

The following adverse reactions are discussed in greater detail in other sections of the label:

• New Primary Cutaneous Malignancies
• Hemorrhage
• Cardiomyopathy
• Serious Dermatologic Reactions
• Serous Retinopathy and Retinal Vein Occlusion
• Hepatotoxicity
• Rhabdomyolysis
• Severe Photosensitivity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Cobimetinib Roche was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 960 mg twice daily on Days 1-28 and received either Cobimetinib Roche 60 mg once daily (n=247) or placebo (n=246) on Days 1-21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the Cobimetinib Roche plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies.

In Trial 1, 15% of patients receiving Cobimetinib Roche experienced an adverse reaction that resulted in permanent discontinuation of Cobimetinib Roche. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving Cobimetinib Roche, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of Cobimetinib Roche were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common ( ≥ 20%) adverse reactions with Cobimetinib Roche were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.

Table 3: Incidence of Adverse Drug Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving Cobimetinib Roche with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1

Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving Cobimetinib Roche plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%).

The following adverse reactions (all grades) of Cobimetinib Roche were reported with < 10% incidence in Trial 1:

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Table 4: Incidence of Laboratory Abnormalities Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3–4) of Patients in Trial 1*

There is no information on overdosage of Cobimetinib Roche.

Cardiac Electrophysiology

Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with cobimetinib, when administered with vemurafenib. Review the Full Prescribing Information for vemurafenib for details.

The pharmacokinetics of cobimetinib was studied in healthy subjects and cancer patients. Cobimetinib exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the recommended dosage). Following oral administration of Cobimetinib Roche 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV).

Absorption

Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC0-24h was 4340 ng·h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of Cobimetinib Roche was 46% (90% CI: 40%, 53%) in healthy subjects. A high-fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg Cobimetinib Roche was administered to healthy subjects.

Distribution

Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. No preferential binding to human red blood cells was observed (blood to plasma ratio of 0.93). The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis.

Elimination

Following oral administration of Cobimetinib Roche 60 mg once daily in cancer patients, the mean elimination half-life (t½) was 44 (range: 23–70) hours and the mean apparent clearance (CL/F) was 13.8 L/h (61% CV).

Metabolism

CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of cobimetinib metabolism in vitro. Following oral administration of a single 20 mg radiolabeled cobimetinib dose, no oxidative metabolites > 10% of total circulating radioactivity were observed.

Excretion

Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug).