Cobimetinib

COTELLIC ® is a kinase inhibitor indicated: For the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. ( 1.1 , 14.1 ) As a single agent for the treatment of adult patients with histiocytic neoplasms. ( 1.2 , 14.2 )

1.1 Unresectable or Metastatic Melanoma COTELLIC ® is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.

1.2 Histiocytic Neoplasms COTELLIC®, as a single agent, is indicated for the treatment of adult patients with histiocytic neoplasms.

Tablets: 20 mg, white, round, film-coated, debossed on one side with "COB". Tablets: 20 mg ( 3)

None. None. ( 4 )

Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib. New primary malignancies, cutaneous and non-cutaneous : Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of COTELLIC. ( 5.1 ) Hemorrhage : Major hemorrhagic events can occur with COTELLIC. Monitor for signs and symptoms of bleeding. ( 5.2 , 2.3 ) Cardiomyopathy : The risk of cardiomyopathy is increased in patients receiving COTELLIC with vemurafenib compared with vemurafenib as a single agent. The safety of COTELLIC has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with COTELLIC. ( 5.3 , 2.3 ) Severe Dermatologic Reactions : Monitor for severe skin rashes. Interrupt, reduce, or discontinue COTELLIC. ( 5.4 , 2.3 ) Serous Retinopathy and Retinal Vein Occlusion : Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. Permanently discontinue COTELLIC for retinal vein occlusion (RVO). ( 5.5 , 2.3 ) Hepatotoxicity : Monitor liver laboratory tests during treatment and as clinically indicated. ( 5.6 , 2.3 ) Rhabdomyolysis : Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. ( 5.7 , 2.3 ) Severe Photosensitivity : Advise patients to avoid sun exposure. ( 5.8 , 2.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 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 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 COTELLIC 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 COTELLIC [see Dosage and Administration (2.3) ] . Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC 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 COTELLIC with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies. Monitor patients receiving COTELLIC, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies.

5.2 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 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) ] .

5.3 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 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.

5.4 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 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) ].

5.5 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. […]

The following adverse reactions are discussed in greater detail in other sections of the label: New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1) ] Hemorrhage [see Warnings and Precautions (5.2) ] Cardiomyopathy [see Warnings and Precautions (5.3) ] Serious Dermatologic Reactions [see Warnings and Precautions (5.4) ] Serous Retinopathy and Retinal Vein Occlusion [see Warnings and Precautions (5.5) ] Hepatotoxicity [see Warnings and Precautions (5.6) ] Rhabdomyolysis [see Warnings and Precautions (5.7) ] Severe Photosensitivity [see Warnings and Precautions (5.8) ] Unresectable or Metastatic Melanoma: Most common adverse reactions for COTELLIC (≥20%) are 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, hyponatremia. ( 6.1 ) Histiocytic neoplasms: Most common adverse reactions (≥20%) are acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritus, dyspepsia, vomiting, dyspnea and urinary tract infections. The most common (≥5%) grade 3-4 lab abnormalities include: Hyponatremia, increased blood creatine phosphokinase, hypokalemia, increased blood creatinine, increased AST, hypocalcemia, lymphopenia, leukopenia, anemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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. Unresectable or Metastatic Melanoma The safety of COTELLIC 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 [see Clinical Studies (14) ] . All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either COTELLIC 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 COTELLIC 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 [see Clinical Studies (14) ]. In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. 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 COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC 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 COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Unresectable or Metastatic Melanoma Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib as a single agent than Patients Receiving Vemurafenib in Trial 1 Adverse reactions COTELLIC + Vemurafenib (n=247) Placebo + Vemurafenib (n=246) All Grades NCI CTCAE, v4.0. (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) GASTROINTESTINAL DISORDERS Diarrhea 60 6 31 1 Nausea 41 1 25 1 Vomiting 24 1 13 1 Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation 14 1 8 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction Includes solar dermatitis, sunburn, photosensitivity reaction 46 4 35 0 Acneiform dermatitis 16 2 11 1 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 28 2 23 0 Chills 10 0 5 0 VASCULAR DISORDERS Hypertension 15 4 8 2 Hemorrhage Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage 13 1 7 <1 EYE DISORDERS Vision impaired Includes vision blurred, visual acuity reduced, visual impairment 15 <1 4 0 Chorioretinopathy 13 <1 <1 0 Retinal detachment Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium 12 2 <1 0 The following clinically relevant adverse reactions (all grades) of COTELLIC 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 with Unresectable or Metastatic Melanoma in Trial 1 All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. The laboratory results are available for a total of 233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where indicated. Laboratory COTELLIC + Vemurafenib Placebo + Vemurafenib All Grades NCI CTCAE v4.0. Grades 3–4 All Grades Grades 3–4 % % % % AST – aspartate aminotransferase, ALT – alanine aminotransferase, GGT – gamma-glutamyltransferase Chemistry Increased creatinine 100 3.3 100

0.4 Increased AST 73 8 44

2.1 Increased ALT 68 11 55 5 Increased alkaline phosphatase 71 7 56

3.3 Increased creatine phosphokinase Increase creatine phosphokinase, n=213 for COTELLIC and 217 for vemurafenib. 79 14 16

0.5 Hypophosphatemia 68 12 38 6 Increased GGT 65 21 61 17 Hyponatremia 38 6 33

2.1 Hypoalbuminemia 42 0.8 20

0.4 Hypokalemia 25 4.5 17

3.3 Hyperkalemia 26 2.9 15

0.4 Hypocalcemia 24 0.4 10

1.7 Hematology Anemia 69 2.5 57

3.3 Lymphopenia Lymphopenia, n=185 for COTELLIC, and 181 for vemurafenib. 73 10 55 8 Thrombocytopenia 18 0 10 0 Histiocytic Neoplasms The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms [see Clinical Studies (14) ] . In Trial 2, 26 patients with histiocytic neoplasms received COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. The median treatment duration was 10.7 months. Table 5 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with COTELLIC. Table 6 presents laboratory abnormalities of grades ≥3 reported in patients with histiocytic neoplasms treated COTELLIC. In Trial 2, 4 patients (15%) receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. […]

Avoid concomitant administration of COTELLIC with strong or moderate CYP3A inducers or inhibitors. ( 2.3 , 7.1 , 7.2 )

7.1 Effect of Strong or Moderate CYP3A Inhibitors on COTELLIC Coadministration of COTELLIC with itraconazole (a strong CYP3A4 inhibitor) increased cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] .

7.2 Effect of Strong or Moderate CYP3A Inducers on COTELLIC Coadministration of COTELLIC with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John's Wort [see Clinical Pharmacology (12.3) ] .

Lactation: Do not breastfeed while taking COTELLIC. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, COTELLIC can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data on the use of COTELLIC 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 [see Data ] . 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.

8.2 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 COTELLIC and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential Contraception Females COTELLIC can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for 2 weeks after the final dose of COTELLIC. Infertility Females and Males Based on findings in animals, COTELLIC may reduce fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of COTELLIC have not been established in pediatric patients. The safety and effectiveness of COTELLIC were assessed, but not established, in a multi-center, open-label, dose-escalation study in 55 pediatric patients aged 2 to 17 years with solid tumors [NCT02639546]. No new safety events were observed in pediatric patients in this trial. Exposure in pediatric patients who received COTELLIC at the maximum tolerated dosage were lower than those previously observed in adults who received the approved recommended dosage. 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.

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

8.6 Hepatic Impairment Adjustment in the starting dose of COTELLIC is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3) ] .

8.7 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 [see Clinical Pharmacology (12.3) ].

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model.