Roche’s investigational combination of cobimetinib plus Zelboraf® (vemurafenib) provided significant benefit to people with advanced melanoma over Zelboraf alone

• Cobimetinib plus Zelboraf reduced the risk of disease worsening by half compared to Zelboraf alone
• Phase III coBRIM study results will be presented today during the Presidential Symposium at the European Society of Medical Oncology (ESMO) 2014 Congress and published in the New England Journal of Medicine
• Roche has submitted an EU marketing authorisation application for the combination for the treatment of BRAF V600 mutation-positive advanced melanoma

Basel, 29 September 2014 – Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced positive data from the coBRIM Phase III study. The results showed that people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf (vemurafenib) lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.¹

The combined therapy reduced the risk of disease worsening or death by half (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf alone. The safety profile was consistent with a previous study of the combination. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity, and lab abnormalities.¹

“We combined cobimetinib and Zelboraf in this study to better inhibit a major cancer growth pathway and hopefully improve clinical outcomes,” said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. “The coBRIM results are exciting because they support the potential of the combination as a new treatment option for people with BRAF mutation-positive advanced melanoma.”

The coBRIM results were statistically significant across multiple secondary endpoints. The median PFS by independent review committee (IRC) was 11.3 months for the combination arm compared to 6.0 months for the control arm (HR=0.60, 95 percent CI 0.45-0.79; p=0.0003). The objective response rate (ORR) was higher in the combination compared to the control arm (68 vs. 45 percent; p<0.0001). Overall survival (OS) data are not yet mature.¹

The late-breaking coBRIM data will be presented at ESMO 2014 today during the Presidential Symposium by Professor Grant McArthur, Peter MacCallum Cancer Centre, Australia (Abstract #LBA5_PR, Monday, September 29, 2014, 16:00-17:20 CEST) and are also part of the official press programme. Additionally, the study was published online today in the New England Journal of Medicine.¹

Roche has submitted the coBRIM data to the European Medicines Agency and plans to submit a new drug application to the U.S. Food and Drug Administration later this year.

About the coBRIM study

CoBRIM is an international, randomised, double-blind, placebo-controlled Phase III study evaluating the safety and efficacy of 60 mg once daily of cobimetinib in combination with 960 mg twice daily of Zelboraf, compared to 960 mg twice daily of Zelboraf alone. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas® 4800 BRAF Mutation Test) and previously untreated for advanced disease, were randomised to receive Zelboraf every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent.¹ Investigator-assessed PFS was the primary endpoint. In addition to PFS by IRC, ORR and OS, secondary endpoints included duration of response and other safety, pharmacokinetic and quality of life measures.

There was a higher overall frequency of Grade 3 or higher adverse events in the combination arm (65 vs. 59 percent), with close to half of these due to lab abnormalities. Common adverse events (occurring in more than 20 percent) observed at a higher frequency (all grades) in the combination arm compared to the Zelboraf arm included diarrhea (57 vs. 28 percent), nausea (39 vs. 24 percent), photosensitivity (28 vs. 16 percent), lab abnormalities (increased alanine aminotransferase [24 vs. 18 percent], increased aspartate aminotransferase [22 vs. 13 percent], increased creatine phosphokinase [an enzyme released by muscles, 30 vs. 3 percent]), and vomiting (21 vs. 12 percent). Common adverse events observed at a lower frequency in the combination arm included hair loss (14 vs. 29 percent), thickening of the outer layer of the skin (10 vs. 29 percent) and joint pain (33 vs. 40 percent). Most instances of each common adverse event were Grade 1 or 2 in severity.¹

Other select adverse events that were lower in the combination arm included cutaneous squamous cell carcinomas (3 vs. 11 percent; all grades) and keratoacanthomas (<1 vs. 8 percent; all grades). Serous retinopathy (collection of fluid under the retina) was observed at a higher frequency in the combination arm (20 vs. <1 percent) with most of these events either Grade 1 or 2 and temporary in nature. Specific adverse events leading to withdrawal from treatment were similar in both study arms, as was the overall discontinuation rate from treatment (13 vs. 12 percent).¹

About melanoma

Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer.^2,3 BRAF is mutated in approximately half of melanomas.⁴ When melanoma is diagnosed early, it is generally a curable disease,^5,6 but most people with advanced melanoma have a poor prognosis.³ More than 232,000 people worldwide are currently diagnosed with melanoma each year⁷ and more than 70,000 people worldwide die every year from melanoma and non-melanoma skin cancers.⁸ In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.⁹

About the cobimetinib and Zelboraf combination

Cobimetinib is designed to selectively block the activity of MEK,¹⁰ one of a series of proteins inside cells that make up a signalling pathway that helps regulate cell division and survival.¹¹ Cobimetinib binds to MEK while Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signalling that can cause tumours to grow.^12,13

About cobimetinib

Cobimetinib (GDC-0973, XL518) was discovered by Exelixis Inc. and is being developed in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumour types such as non-small cell lung cancer and colorectal cancer.

About Zelboraf

Zelboraf was the first prescription treatment for patients with unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche’s cobas® 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma.¹⁴ It is now approved in more than 80 countries and has been used to treat more than 11,000 patients worldwide. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and neuroscience. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostics that enable tangible improvements in the health, quality of life and survival of patients. Founded in 1896, Roche has been making important contributions to global health for more than a century. Twenty-four medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and chemotherapy.

In 2013 the Roche Group employed over 85,000 people worldwide, invested 8.7 billion Swiss francs in R&D and posted sales of 46.8 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com

All trademarks used or mentioned in this release are protected by law.

References
1. Larkin J, et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. N Engl J Med. 2014; [accepted for publication].
2. Algazi AP, et al. Treatment of cutaneous melanoma: current approaches and future prospects. Cancer Manag Res. 2010;2:197-211.
3. Finn L, et al. Therapy for metastatic melanoma: the past, present, and future. BMC Med. 2012;10:23.
4. Ascierto PA, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.
5. Leong SP. Future perspectives on malignant melanoma. Surg Clin North Am. 2003;83:453-6.
6. Creagan ET. Malignant melanoma: an emerging and preventable medical catastrophe. Mayo Clin Proc. 1997;72:570-4.
7. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx Last accessed March 2014
8. American Academy of Dermatology. Skin cancer. Availble at: http://www.aad.org/media-resources/stats-and-facts/conditions/skin-cancer Last accesed September 2014.
9. Bataille V. Risk factors for melanoma development. Expert Rev Dermatol. 2009;4:533-9.
10. Johnston S. XL518, a potent, selective, orally bioavailable MEK1 inhibitor, downregulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. Poster presented at: AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; October 22, 2007; San Francisco, CA. Abstract C209.
11. Khavari TA, et al. Ras/Erk MAPK signaling in epidermal homeostasis and neoplasia. Cell Cycle. 2007;6:2928-31.
12. Safaee Ardekani G, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7(10):e47054.
13. Haferkamp S, et al. Vemurafenib induces senescence features in melanoma cells. J Invest Dermatol. 2013;133:1601-9.
14. Zelboraf Summary of Product Characteristics, August 2014. Available at: http://www.ema.europa.eu Last accessed September 2014.

SOURCE: Roche