In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs
On November 10, 2015, the U.S. Food and Drug Administration approved cobimetinib (Cotellic) for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf).1,2 Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.
Supporting Efficacy Data
Approval was based on demonstration of improved progression-free survival and overall survival with the addition of cobimetinib to vemurafenib in a phase III double-blind trial.2,3 In the trial, 495 patients with previously untreated unresectable or metastatic melanoma with BRAF mutation detected by the cobas® 4800 BRAF V600 mutation test were randomized to receive vemurafenib at 960 mg twice daily with either cobimetinib at 60 mg (n = 247) or placebo (n = 248) once daily on days 1 to 21 in 28-day cycles until disease progression or unacceptable toxicity. Patients with abnormal liver function tests, a history of acute coronary syndrome within 6 months, evidence of class II or greater congestive heart failure, active central nervous system lesions, or evidence of retinal pathology were excluded from the trial.
Patients had a median age of 55 years (range, 23–88 years), 58% were male, 93% were white, 60% had stage M1c disease, 72% had an Eastern Cooperative Oncology Group performance status of 0, 45% had an elevated serum lactate dehydrogenase level, 10% had received prior adjuvant therapy, and < 1% had previously treated brain metastases.
Median progression-free survival was 12.3 months (95% confidence interval [CI] = 9.5–13.4 months) in the cobimetinib group vs 7.2 months (95% CI = 5.6–7.5 months) in the placebo group (hazard ratio [HR] = 0.56, P < .001). In interim analysis, median overall survival was not reached (95% CI = 20.7 months to not reached) vs 17 months (95% CI = 15.0 months to not reached; HR = 0.63, P = .0019). Confirmed objective response rate was 70% vs 50% (P < .001).
How It Works
Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2, components of the BRAF pathway. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and V600K mutations induce constitutive activation of the BRAF pathway. Cobimetinib inhibited tumor growth in xenografts expressing BRAF V600E.
Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in xenografts with BRAF V600E mutation. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF xenograft.
How It Is Used
The recommended dose of cobimetinib is 60 mg once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.
Recommended dose reductions are to 40 mg and then 20 mg, with permanent discontinuation of treatment if 20 mg cannot be tolerated. Recommended dose modifications follow. For asymptomatic and symptomatic cardiomyopathy, treatment should be interrupted for 2 and 4 weeks, and measurement of left ventricular ejection fraction should be repeated. Treatment can be resumed at the next lower dose if left ventricular ejection fraction is ≥ the lower limit of normal, absolute decrease in left ventricular ejection fraction from baseline is ≤ 10%, and, for symptomatic patients, symptoms resolve.
Treatment should be permanently discontinued if left ventricular ejection fraction is < lower limit of normal, absolute decrease from baseline in left ventricular ejection fraction is >10%, or, for symptomatic patients, symptoms persist. Treatment should be withheld for up to 4 weeks and resumed at a lower dose with improvement to grade 0 or 1 or improvement in signs/symptoms; treatment should be permanently discontinued for no improvement within 4 weeks at the lower dose for grade 3 hemorrhage, serous retinopathy, first occurrence of grade 4 liver function abnormality, grade 4 creatine phosphokinase elevation (treatment can be resumed at a lower dose with improvement to grade 3) or any creatine phosphokinase elevation and myalgia, intolerable grade 2 or any grade 3 or 4 photosensitivity, other intolerable grade 2 or any grade 3 adverse reactions, or first occurrence of any grade 4 adverse reaction (treatment may also be permanently discontinued for first occurrence). Treatment should be interrupted or reduced in dose for intolerable grade 2 or any grade 3 or 4 dermatologic reaction. Permanent discontinuation of treatment is recommended for grade 4 hemorrhage, retinal vein occlusion, recurrent grade 4 liver function abnormality, and recurrent grade 4 adverse reactions. No dose modification is required for new primary cutaneous or noncutaneous malignancies.
Coadministration of cobimetinib with strong (eg, itraconazole) or moderate CYP3A inhibitors should be avoided. If concurrent short-term use (≤ 14 days) of a moderate inhibitor (eg, erythromycin, ciprofloxacin) is unavoidable in patients receiving cobimetinib at 60 mg, the dose should be reduced to 20 mg; after discontinuation of the moderate CYP3A inhibitor, cobimetinib can be resumed at 60 mg. Concomitant use with strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s wort) should be avoided.
Safety Profile
In the phase III trial, the most common adverse events of any grade occurring more frequently in the combination group were diarrhea (60% vs 31%), photosensitivity reaction (46% vs 35%), nausea (41% vs 25%), pyrexia (28% vs 23%), and vomiting (24% vs 13%). Vascular disorders of any grade included hypertension in 15% vs 8% and hemorrhage in 13% vs 7%, and eye disorders of any grade included impaired vision in 15% vs 4%, chorioretinopathy in 13% vs < 1%, and retinal detachment in 12% vs < 1%. The most common grade 3 or 4 adverse events were diarrhea (6% vs 1%), photosensitivity reaction (4% vs 0%), and hypertension (4% vs 2%).
Cutaneous malignancies or premalignant conditions during treatment consisted of cutaneous squamous cell carcinoma or keratoacanthoma in 6% vs 20%, basal cell carcinoma in 4.5% vs 2.4%, and second primary melanoma in 0.8% vs 2.4%. Noncutaneous malignancies occurred in 0.8% vs 1.2%.
The most common grade 3 or 4 laboratory abnormalities with cobimetinib were increased gamma-glutamyltransferase levels (21% vs 17%), increased creatine phosphokinase levels (14% vs 0.5%), hypophosphatemia (12% vs 6%), and increased alanine transaminase levels (11% vs 5%).
Adverse events led to cobimetinib dose interruption or reduction in 55% of patients, with the most common reasons being rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase levels (5%), and to treatment discontinuation in 15%, with the most common reasons being liver laboratory abnormalities (8%) and retinal detachment (2%).
Cobimetinib carries warnings/precautions for new primary malignancies (cutaneous and noncutaneous), hemorrhage (including major events), cardiomyopathy (risk increased with combination therapy vs vemurafenib alone), severe dermatologic reactions, serous retinopathy and retinal vein occlusion, hepatotoxicity, rhabdomyolysis, severe photosensitivity, and embryofetal toxicity. Patients should be monitored for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of cobimetinib.
The safety of cobimetinib has not been established in patients with decreased left ventricular ejection fraction. Left ventricular ejection fraction should be assessed before treatment, after 1 month of treatment, and then every 3 months. Ophthalmologic evaluation should be performed at regular intervals and for any visual disturbances. Liver function tests should be performed during treatment and as clinically indicated. Creatine phosphokinase should be monitored periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. Patients should be monitored for signs/symptoms of bleeding and should be advised to avoid sun exposure. Women of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception. ■
References
1. U.S. Food and Drug Administration: Approved drugs. Cobimetinib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472193.htm. Accessed November 23, 2015.
2. Cotellic™ (cobimetinib) tablets prescribing information, Genentech, Inc, November 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf. Accessed November 23, 2015.
3. Larkin J, Ascierto PA, Dréno B, et al: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867-1876, 2014.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
