F. Hoffmann-La Roche Ltd: FDA approves Roche's Tecentriq plus Cotellic and Zelboraf for people with advanced melanoma

Basel, 31 July 2020 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the U.S. Food and Drug Administration (FDA) approved Tecentriq (atezolizumab) plus Cotellic (cobimetinib) and Zelboraf (vemurafenib) for the treatment of BRAF V600 mutation-positive advanced melanoma patients. The safety profile observed in the Tecentriq combination was consistent with the known safety profiles of the individual medicines.

The supplemental Biologics License Application (sBLA) for Tecentriq was granted under priority review. The review was also conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology products among international partners.

"When receiving a cancer immunotherapy combined with targeted therapies, patients with BRAF V600 mutation-positive advanced melanoma were able to live for more than 15 months without their disease worsening," said Levi Garraway, M.D., Ph.D., Genentech's chief medical officer and head of Global Product Development. "Today's FDA approval of this Tecentriq combination represents an important step forward for many patients living with advanced melanoma."

The approval is based on results from the Phase III IMspire150 study, in which the addition of Tecentriq to Cotellic and Zelboraf helped people live longer without disease worsening or death compared to placebo plus Cotellic and Zelboraf (median PFS 15.1 months versus 10.6 months respectively; hazard ratio, HR=0.78; confidence interval: 0.63-0.97; P=0.025). The most common adverse reactions (rate =20%) in patients who received Tecentriq plus Cotellic and Zelboraf were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

Roche has an extensive development programme for Tecentriq, including multiple ongoing and planned Phase III studies across lung, genitourinary, skin, breast, gastrointestinal, gynecological and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines.

About the IMspire150 study
IMspire150 is a Phase III, multi-center, double-blind, placebo-controlled randomised study in people with previously untreated BRAF V600 mutation-positive metastatic or unresectable locally advanced melanoma. The study compared the efficacy and safety of Tecentriq plus Cotellic and Zelboraf to the combination of placebo plus Cotellic and Zelboraf. The primary endpoint of the study was investigator-assessed PFS. Key secondary endpoints include PFS by an independent review committee, overall survival, objective response rate, duration of response and other safety and pharmacokinetic measures.

Five hundred and fourteen adult patients took part in the study. Randomisation was stratified by lactate dehydrogenase (LDH) level and geographic region. Eligible patients were randomised 1:1 to one of two treatment groups, to receive 28-day cycles of either: Tecentriq plus Cotellic and Zelboraf (the Tecentriq group) or Placebo plus Cotellic and Zelboraf (the control group). In cycle 1, all patients received once-daily oral Cotellic 60 mg plus twice-daily oral Zelboraf 960 mg for 21 days followed by twice-daily Zelboraf 720 mg or 960 mg for 7 days in the Tecentriq group or control group, respectively. Patients in the Tecentriq group received Zelboraf 720 mg Days 1-28 of each subsequent cycle. The lower 720 mg dose of Zelboraf in the Tecentriq group was a safety measure to mitigate the risk of overlapping toxicities, while ensuring an efficacious dose of Zelboraf. Treatment was continued until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, whichever occurred first.

About advanced melanoma
Melanoma is a less common, but more aggressive and potentially deadly form of skin cancer.^1,2 When melanoma is diagnosed early, it is generally a curable disease,^3,4 but most people with advanced melanoma have a poor prognosis.² More than 287,000 people worldwide are currently diagnosed with melanoma each year.⁵ BRAF is mutated in approximately half of melanomas.⁶ In recent years, there have been significant advances in treatment for advanced melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high medical need and a steadily increasing incidence over the past 30 years.⁷

About Tecentriq (atezolizumab)
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

About Cotellic (cobimetinib)
Cotellic is designed to inhibit MEK1/2, proteins in a cell signaling pathway that helps control cell growth and survival. Cotellic, when used in combination with Zelboraf, is approved in the United States and Europe, as well as many countries around the world, for the treatment of people with melanoma that has spread to other parts of the body or cannot be removed by surgery and has a BRAF V600 mutation. Cotellic was discovered by Exelixis and is being developed by Genentech, a member of the Roche Group, in collaboration with Exelixis.

About Zelboraf (vemurafenib)
Zelboraf is a prescription medicine for the treatment of people with melanoma that has spread to other parts of the body or cannot be removed by surgery and has a BRAF V600 mutation. Zelboraf is designed to inhibit some mutated forms of BRAF, which cause abnormal signaling inside cancer cells leading to tumor growth. BRAF is a protein in a cell signaling pathway that helps control cell growth and survival. Zelboraf was the first approved product in its class. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon Inc., the small molecule structure-guided R&D center of the Daiichi Sankyo Group.

About Roche
Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people's lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare - a strategy that aims to fit the right treatment to each patient in the best way possible.

Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.

Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. More than thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the eleventh consecutive year, Roche has been recognised as one of the most sustainable companies in the Pharmaceuticals Industry by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2019 employed about 98,000 people worldwide. In 2019, Roche invested CHF 11.7 billion in R&D and posted sales of CHF 61.5 billion. 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] Algazi AP, et al. Treatment of cutaneous melanoma: current approaches and future prospects. Cancer Manag Res. 2010;2:197-211
[2] Finn L, et al. Therapy for metastatic melanoma: the past, present, and future. BMC Med. 2012;10:23.
[3] Leong SP. Future perspectives on malignant melanoma. Surg Clin North Am. 2003;83:453-6.
[4] Creagan ET. Malignant melanoma: an emerging and preventable medical catastrophe. Mayo Clin Proc. 1997;72:570-4.
[5] Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray FLast accessed: July 2020.
[6] Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.
[7] Bataille V. Risk factors for melanoma development. Expert Rev Dermatol. 2009;4:533-9

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