Investor Update

Basel, 07 May 2014

Roche presents final Phase 1b data on its investigational MEK-BRAF inhibitor combination therapy for metastatic melanoma at EADO 2014

  • BRIM7 study shows that cobimetinib and Zelboraf (vemurafenib) can be co-administered and provided a median progression-free survival of 13.7 months in BRAF inhibitor-naive patients
  • Confirmatory Phase 3 study, coBRIM, is ongoing and is expected to report later this year

Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that important new data have been presented for its investigational MEK inhibitor cobimetinib (GDC-0973) in combination with Zelboraf, a BRAF inhibitor, as a potential treatment option for patients with advanced BRAFV600 mutation-positive metastatic melanoma. These data were presented at the 10th European Association of Dermato Oncology (EADO) Congress in Vilnius, Lithuania.1

“These encouraging final data from the Phase 1b BRIM7 study are an important step in understanding the potential role of combining the MEK inhibitor cobimetinib and the BRAF inhibitor Zelboraf to treat metastatic melanoma,” said Sandra Horning, M.D., Head of Global Product Development and Chief Medical Officer at Roche. “In combining these molecules we aim to overcome resistance to BRAF inhibition and maximize potential patient benefit, and we look forward to the results of the ongoing Phase 3 coBRIM trial.”

The final results of BRIM7 (NO25395), an open label, dose-finding and dose expansion Phase 1b study evaluating the safety and tolerability of co-administered cobimetinib and Zelboraf showed promising anti-tumour activity for the combination. Among BRAF inhibitor-naive patients in the study (n=63) an 87% tumour response rate was achieved, including a complete response in 10% of the group. An additional 10% of patients achieved stable disease. The majority of tumour responses was observed within the first six weeks following initiation of treatment. The median progression-free survival (mPFS) in this group was 13.7 months and 83% were alive at one year.

For patients who had previously progressed on Zelboraf (n=66), the response and stable disease rates were 15% and 42%, respectively. The mPFS observed with the combination in this group was 2.8 months, and 32% were alive at one year.

The BRIM7 study showed that cobimetinib and Zelboraf could be administered concurrently at their respective single-agent maximum tolerated dose and schedule, allowing enrolled patients to receive the optimal combination regimen. Across all treated patients (n=129), the most common adverse events (regardless of attribution to the study drugs) included: diarrhoea (64%), non-acneiform rash (60%), fatigue (48%), nausea (45%), liver laboratory test abnormality (40%) and photosensitivity/sunburn (40%). The most frequently reported events that were Grade ≥3 were liver laboratory test abnormality (11%), cutaneous squamous cell carcinoma (9%), non-acneiform rash (8%), anaemia (7%), joint pain (6%), fatigue (5%) and diarrhoea (5%).

Roche is currently conducting a Phase 3 clinical study (coBRIM; GO28141) evaluating the efficacy and tolerability of the cobimetinib and Zelboraf combination, compared to Zelboraf alone, in patients with previously untreated BRAFV600 mutation-positive, unresectable locally advanced or metastatic melanoma.2 The primary results of coBRIM are expected later this year.

About the BRIM7 study

  • This large phase 1b study (n=129) enrolled patients who had BRAFV600 mutation-positive unresectable or metastatic melanoma, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and who were either BRAF inhibitor-naïve or had shown disease progression on Zelboraf.
  • The primary objectives of BRIM7 were to evaluate the safety and tolerability of the cobimetinib plus Zelboraf combination, and to identify the optimal dosing schedule for use in further clinical studies. The secondary objective was to assess anti-tumour activity.
  • Patients in the dose-escalation stage of the study received cobimetinib 60, 80 or 100 mg once daily (QD) given on a schedule of 14 days on/14 days off (14/14); 21 days on/7 days off (21/7); or continuously (28/0), and Zelboraf 720 or 960 mg twice daily (BID) continuously.
  • Following the dose-escalation stage, two dose levels were selected for further investigation: cobimetinib 60 mg QD 21/7 and Zelboraf (720 mg or 960 mg BID). A total of 39 patients received the 60/960 dose that was subsequently selected for use in the Phase 3 clinical programme.
  • Dose-limiting toxicities occurred in four out of 129 patients, two of which (mucositis, one patient and joint pain, one patient) were in the cobimetinib 60 mg QD 28/0 plus Zelboraf 960 mg BID group.
  • Adverse event frequency and severity were greater in BRAF inhibitor-naive patients compared with people who had previously received Zelboraf. This difference may be primarily explained by the study design, whereby patients who had progressed on Zelboraf were limited to doses in BRIM7 that were at or below their previously tolerated dose.

Presentation details for BRIM7 at EADO 2014

Ribas A. Vemurafenib plus cobimetinib. Oral presentation at the 10th EADO congress, Vilnius, Lithuania; 7 May 2014.

About cobimetinib

Cobimetinib (GDC-0973), discovered by Exelixis Inc. (Nasdaq: EXEL), is a novel and selective MEK inhibitor3 which, in combination with other medicines, may enhance anti-tumour activity and inhibit mechanisms of resistance. In the majority of patients, resistance to BRAF inhibitors will occur through re-activation of the MAPK pathway. Dual inhibition of this pathway with Zelboraf and cobimetinib may delay the onset of resistance and improve patient outcomes.

About Zelboraf

Zelboraf (vemurafenib) was the first BRAFV600-targeted therapy, indicated for the treatment of adult patients with BRAFV600 mutation-positive unresectable or metastatic melanoma.4 Zelboraf has been proven to extend overall survival compared with chemotherapy;5 it is now approved in more than 80 countries, and to date has been used to treat more than 11,000 patients worldwide.

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 Organisation 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.

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References
1. Ribas A, et al. BRIM7-Vemurafenib + cobimetinib Phase 1B study in BRAF mutant melanoma. Oral presentation to be presented at 10th European Association of Dermato-Oncology (EADO); Vilnius, Lithuania; 7-10 May 2014.
2. National Institutes of Health. A phase 3 study comparing GDC-0973, a MEK inhibitor, in combination with vemurafenib vs. vemurafenib alone in patients with metastatic melanoma. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01689519. Last accessed April 2014.
3. 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.
4. Zelboraf® Summary of Product Characteristics, February 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002409/WC500124317.pdf. Last accessed April 2014.
5. Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAFV600E mutation. N Engl J Med 2011;364(26):2507-16.