Cotellic (Cobimetinib) FDA Approved as Part of a Combination for Patients with Advanced Melanoma and a BRAF Mutation

March 2016, Vol 9, Seventh Annual Payers' Guide - Web Exclusive
Loretta Fala
Medical Writer

Melanoma, the sixth most common form of cancer and the most serious type of skin cancer, affects nearly 74,000 patients yearly in the United States.1,2 Melanoma is among the fastest growing cancers in the United States.3 The incidence of melanoma has increased dramatically in individuals aged <40 years, particularly in women.1 In men aged ≥50 years, melanoma is more prevalent than cancers of the colon, prostate, and lung.3

Ultraviolet radiation exposure from sunlight or tanning beds increases the risk for melanoma, which often affects the legs, arms, back, and face.1 Although melanoma usually develops in skin cells, it can also develop in other body parts, including the eyes, scalp, nails, feet, and mouth.1,3 In 2015, melanoma claimed the lives of nearly 10,000 Americans.2

Early-stage, localized melanoma may only require surgery to remove the cancer, and the 5-year survival rate is 90%.4 In later stages, the disease can spread to the liver, lungs, brain, and other areas.3 The 5-year survival for late-stage melanoma ranges from 20% to 70% at stage III (regional spread), and drops to <10% at stage IV (distant metastases) disease.4

Once melanoma spreads beyond the skin, treatment may include ≥1 of the following options—surgery to remove the affected lymph nodes, chemotherapy, radiation therapy, biologic therapy, oncolytic virus therapy, and targeted therapy.1,4-6

Biologic therapies and immunotherapies approved by the US Food and Drug Administration (FDA) include the programmed cell death receptor-1 inhibitors (nivolumab and pembrolizumab), a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), and the cytokines (interferon alfa, peginterferon-alfa 2b, and interleukin-2).4,5 A new oncolytic virus therapy (talimogene laherparepvec) is also FDA approved to treat melanoma.4,5 In addition, several targeted therapies are directed specifically at a certain genetic mutation. These include the BRAF inhibitors dabrafenib and vemurafenib, and the MEK inhibitor trametinib.4 The BRAF V600 mutation is present in an estimated 50% of metastatic melanomas.6 Evidence suggests that blocking MEK and mutated BRAF kinases, 2 proteins that operate within the different parts of the same signaling pathway, may achieve a greater, more durable tumor response than BRAF inhibition alone, and may help to prevent acquired resistance.6 A new MEK inhibitor was recently added for use in combination with a BRAF inhibitor to treat patients with advanced melanoma and specific mutations.7

Cobimetinib: A New Treatment Option for Advanced Melanoma

On November 10, 2015, cobimetinib (Cotellic; Genentech) received FDA approval for use in combination with vemurafenib (Zelboraf; Genentech) for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Cobimetinib is not indicated for the treatment of patients with wild-type BRAF mutations.7,8

Cobimetinib, a kinase inhibitor, blocks MEK proteins that regulate a signaling pathway involved in cellular proliferation.7 Vemurafenib, a BRAF inhibitor that affects a different part of the same pathway, received FDA approval in 2011 for patients with unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test.7,9

Cobimetinib was reviewed under the FDA’s priority review program with an expedited 6-month review.7 Cobimetinib also received an orphan drug designation, because it is approved for melanoma, which is a rare disease.7

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge. Today’s approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma.”7

The combination of cobimetinib plus vemurafenib was included as a preferred treatment option over single-agent therapy options for the first-line treatment, and for the second-line or subsequent treatment of metastatic or unresectable melanoma in the updated version of the National Comprehensive Cancer Network clinical guidelines for melanoma.4

Mechanism of Action

Cobimetinib, a reversible kinase inhibitor, prevents or slows the growth of cancer cells.7,8 Cobimetinib works by blocking the activity of the MAPK signaling pathway, specifically the MEK1 and MEK2 proteins. These MEK proteins regulate the extracellular signal-related kinase pathway, which plays a key role in cell proliferation.8 Defects in the signaling pathway can lead to uncontrolled cell growth and cancer. BRAF V600E and V600K mutations can activate the BRAF signaling cascade, which includes MEK1 and MEK2.8

Cobimetinib, a MEK inhibitor, and vemurafenib, a BRAF inhibitor, target 2 different kinases within the same signaling pathway. The use of these 2 inhibitors together increases cell death and reduces tumor growth in cells with BRAF V600E mutations compared with either inhibitor alone.8

Dosing and Administration

Before starting treatment with cobimetinib plus vem­urafenib, it is recommended that the presence of BRAF V600E or V600K mutation is confirmed in tumor specimens. A list of FDA-approved tests to detect BRAF V600 mutations in patients with melanoma is available at www.fda.gov/CompanionDiagnostics.8

The recommended dose of cobimetinib is 60 mg (three 20-mg tablets) orally once daily for the first 21 days of each 28-day cycle until disease progression or until unacceptable toxicity. Cobimetinib can be taken with or without food. Detailed dose-reduction instructions and dose-modification recommendations for adverse reactions are outlined in the full prescribing information.8

Cobimetinib is available as a 20-mg tablet for oral use.8

Clinical Study
CoBRIM Clinical Trial

The FDA approval of cobimetinib was based on the data from the CoBRIM clinical trial, a randomized, double-blind, placebo-controlled, phase 3 study that included 495 patients with previously untreated unresectable, locally advanced, or metastatic BRAF V600 mutation–positive melanoma.6,8

In this 12-month study, all patients received vemurafenib (960 mg twice daily on days 1-28), and were randomized to receive cobimetinib (60 mg once daily for 21 days of every 28-day cycle, followed by a 7-day rest period) or placebo. Treatment continued until disease progression or until unacceptable toxicity. Patients receiving placebo who experienced disease progression did not receive cobimetinib.8

The primary efficacy outcome was progression-free survival, based on the investigator assessment using the Response Evaluation Criteria in Solid Tumors, version 1.1.6,8 Other efficacy outcomes included overall survival, duration of response, investigator-assessed, confirmed objective response rate, and progression-free survival as assessed by a blinded independent central review. The patients’ median age was 55 years (range, 23-88 years); of the 81% of patients whose tumor samples were tested, 86% had a BRAF V600E mutation, and 14% had a BRAF V600K mutation.8

Patients who received cobimetinib plus vemurafenib showed a significant improvement in progression-free survival—an average delay of 12.3 months in disease worsening after starting treatment compared with 7.2 months for those receiving vemurafenib alone (Table).8

Figure

Complete or partial tumor shrinkage was shown in 70% of patients receiving the combination versus 50% of patients in the placebo arm.7,8

Approximately 65% of patients in the combination arm were alive 17 months after initial treatment compared with 50% of patients in the vemurafenib arm.7

After the FDA approval of cobimetinib, a final data analysis from the CoBRIM study was presented at the International Congress of the Society for Melanoma Research in November 2015. This analysis showed that 74.5% of patients with BRAF V600 mutation–positive advanced melanoma who received cobimetinb plus vemurafenib were alive at 1 year, and 48.3% were alive at 2 years.10,11

Safety

In the CoBRIM clinical trial, some of the adverse reactions occurring at an incidence of ≥10% (all grades) with cobimetinib plus vemurafenib compared with vemurafenib plus placebo included diarrhea, pyrexia, and hypertension.8

Grade 3 or 4 adverse events occurring in >2% of patients included diarrhea (6%), photosensitivity reactions (4%), and hypertension (4%).

Adverse reactions leading to the permanent discontinuation of cobimetinib in 15% of patients included liver abnormalities (2.4%), increased gamma glutamyltransferase (1.6%), increased alanine aminotransferase (1.6%), rash (1.6%), pyrexia (1.2%), and retinal detachment (2%).8
Cobimetinib has no contraindications.8

Drug Interactions

Cytochrome (CY) P3A inhibitors. The concomitant use of cobimetinib and strong or moderate CYP3A inhibitors should be avoided. The concurrent administration of cobimetinib with itraconazole, a strong CYP3A4 inhibitor, showed a 6.7-fold exposure to cobimetinib.8

CYP3A inducers. The concomitant use of cobimetinib with strong or moderate CYP3A inducers should be avoided, because coadministration may decrease cobimetinib exposure by >80% and reduce its efficacy.8

Warnings and Precautions

New primary malignancies. New primary malignancies (cutaneous and noncutaneous) have been associated with cobimetinib treatment, and the use of cobimetinib with vemurafenib may promote the development of noncutaneous malignancies. Patients should be monitored for new malignancies before starting therapy, during therapy, and for up to 6 months after the last dose of cobimetinib.8

Hemorrhage. Major hemorrhages can occur with cobimetinib. Patients should be monitored for the signs and symptoms of bleeding.8

Cardiomyopathy. There is an increased risk for cardiomyopathy with cobimetinib plus vemurafenib compared with vemurafinib alone. The safety of cobimetinib has not been established in patients with a decreased left-ventricular ejection fraction (LVEF). LVEF should be evaluated before starting treatment with cobimetinib, after 1 month, and every 3 months during subsequent treatment with cobimetinib.8

Severe dermatologic reactions. Patients receiving cobimetinib should be monitored for severe skin rashes or other skin reactions. If a skin rash or reaction occurs, cobimetinib treatment should be interrupted or the dose should be reduced or treatment discontinued.8

Serous retinopathy and retinal vein occlusion. Ocular toxicities have been reported with cobimetinib. An ophthalmologic evaluation should be conducted at regular intervals. Patients diagnosed with serous retinopathy should include treatment interruption, dose reduction, or the discontinuation of cobimetinib.8

Hepatotoxicity. Because hepatotoxicity can occur with cobimetinib, liver laboratory tests should be monitored during treatment and as clinically indicated.8

Rhabdomyolysis. Rhabdomyolysis has been reported with cobimetinib. Baseline serum creatine phosphokinase and creatinine levels should be obtained before starting treatment with cobimetinib, periodically during treatment, and as clinically necessary. Dose interruption or treatment discontinuation may be necessary.8

Severe photosensitivity. Because photosensitivity, even severe, can occur with cobimetinib, patients should be advised to avoid sun exposure, and to protect themselves with sunscreen, lip balm, and appropriate clothing.8

Embryo-fetal toxicity. Cobimetinib can cause fetal harm in pregnant women. Pregnant women should be advised of the potential risk to the fetus.8

Use in Specific Populations

Pregnancy. Cobimetinib can cause fetal harm when administered to a pregnant woman.9 Clinical data on the use of cobimetinib in pregnant women are not available. Pregnant women should be advised of the potential risk to the fetus.8

Lactation. Data are not available on the presence of cobimetinib in human milk, its effects on the breast-fed infant, or its effects on milk production. Nursing women should not breast-feed during cobimetinib treatment and for 2 weeks after the final dose.8

Females and males of reproductive potential. Cobimetinib can cause fetal harm in pregnant women, and may reduce fertility in females and males of reproductive potential. Women of reproductive potential should be advised to use effective contraception during treatment with cobimetinib.8

Pediatric and geriatric use. Data are insufficient to determine the efficacy and safety of cobimetinib in pediatric patients. Data on the use of cobimetinib in patients aged ≥65 years are insufficient to determine whether their treatment response differs from that of younger patients.8

Renal impairment. Studies have not been conducted in patients with renal impairment. For patients with mild-to-moderate renal impairment, no dose adjustment is necessary; for patients with severe renal impairment, no recommended dose has been determined.8

Conclusion

A new treatment option became available with the FDA approval of cobimetinib in combination with vemurafenib for patients with unresectable or metastatic melanoma and a BRAF V600E or V600K mutation. Patients receiving cobimetinib, a MEK inhibitor, plus vem­urafenib, a BRAF inhibitor, showed a significant improvement in progression-free survival and a greater complete or partial response rate compared with patients receiving vemurafenib alone. The combination of the MEK and BRAF inhibitors was also associated with improved overall survival compared with the BRAF inhibitor alone.

References

1. Mayo Clinic staff. Diseases and conditions: melanoma. June 16, 2015. www.mayo­clinic.org/diseases-conditions/melanoma/basics/definition/con-20026009. Accessed December 14, 2015.
2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. Bethesda, MD. http://seer.cancer.gov/statfacts/html/melan.html. Accessed December 14, 2015.
3. Melanoma Research Foundation. Melanoma fact sheet. www.melanoma.org/sites/default/files/u13882/It’s%20a%20Fact%20Sheet.pdf. Accessed December 14, 2015.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): melanoma. Version 2.2016. November 25, 2015. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed December 23, 2015.
5. American Cancer Society. Melanoma skin cancer: immunotherapy for melanoma skin cancer. Revised October 28, 2015. www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-treating-immunotherapy. Accessed December 23, 2015.
6. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-1876.
7. US Food and Drug Administration. FDA approves Cotellic as part of combination treatment for advanced melanoma. Press release. November 10, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471934.htm. Accessed December 14, 2015.
8. Cotellic (cobimetinib) tablets [prescribing information]. South San Francisco, CA: Genentech USA; November 2015.
9. Zelboraf (vemurafenib) tablet [prescribing information]. South San Francisco, CA: Genentech USA; August 2015.
10. Genentech. Updated data showed that Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib) helped people with a specific type of advanced melanoma live significantly longer than with Zelboraf alone. Press release. November 21, 2015. www.gene.com/media/press-releases/14612/2015-11-21/updated-data-showed- that-cotellic-cobime. Accessed December 21, 2015.
11. Atkinson V, Larkin J, McArthur G, et al. Improved overall survival (OS) with cobimetinib (COBI) + vemurafenib (V) in advanced BRAF-mutated melanoma and biomarker correlates of efficacy. Late-breaking abstract presented at the 2015 Society for Melanoma Research International Congress; November 18-21, 2015; San Francisco, CA.

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