Novartis Phase III Study Demonstrates Adjuvant Tafinlar® + Mekinist® Reduces the Risk of Disease Recurrence by 53% in Patients With Resected BRAF V600 Mutation-positive Melanoma
CAMBERLEY, England, September 10, 2017 /PRNewswire/ --
- Over 15,000 new cases of melanoma are diagnosed in the UK each year
- First adjuvant study to demonstrate a clinical benefit in patients receiving targeted therapy for a BRAF V600 mutation
- The three-year relapse-free survival (RFS) rate for patients treated with the combination was 58%, compared to 39% with placebo
- Consistent improvement in RFS observed across all pre-specified subgroups, including stage III A, B and C melanoma
Novartis today announced results from a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma treated with the combination of Tafinlar® (dabrafenib) + Mekinist® (trametinib) after complete surgical resection. Findings from the COMBI-AD study, which met its primary endpoint, found a statistically significant 53% reduction in the risk of death or recurrence in patients treated with the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) versus placebo (HR [hazard ratio]: 0.47 [95% CI (confidence interval): 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001), with no new safety signals reported. Results of the study will be presented during the Presidential Symposium today at the European Society for Medical Oncology Congress (ESMO) in Madrid (Abstract #LBA6), and simultaneously published in the New England Journal of Medicine.,
Melanoma is the most serious form of skin cancer and the fifth most common cancer in the UK, with over 40 cases diagnosed every day. Rates of melanoma have increased by 45% in the last 10 years, and it's becoming increasingly prevalent in younger people. Approximately 40 - 50% of people with melanoma skin cancers have a mutation in the BRAF V600 gene.
"Today's findings provide important new insights for the treatment of stage III melanoma, a condition where many patients are at high risk of disease recurrence after surgery," said Professor Ruth Plummer, Consultant Medical Oncologist and study lead at Newcastle Hospitals NHS Foundation Trust. "The reduced risk of disease recurrence seen in the COMBI-AD study clearly demonstrates the value of combined dabrafenib and trametinib treatment in patients with stage III A, B and C BRAF V600E/K mutation-positive melanoma who have undergone surgical resection to help reduce the risk of melanoma returning."
The combination of Tafinlar + Mekinist is currently available in the UK for use in patients with unresectable or metastatic melanoma. Stage III melanoma is currently treated by surgical removal of the lymph nodes (lymphadenectomy), after which adjuvant radiotherapy is only recommended in specific cases.
"COMBI-AD is the first study to demonstrate a clinical benefit in stage III melanoma patients receiving targeted therapy in the adjuvant setting for a BRAF V600 mutation," said Barak Palatchi, Oncology General Manager, Novartis UK & Ireland. "We strive to improve the lives of people with melanoma and these findings demonstrate our ongoing commitment in scientific research, to help address significant unmet patient needs. We look forward to discussing the results with regulatory authorities, with the potential to make the treatment combination available to stage III patients in the UK."
The COMBI-AD study is a randomised, double-blind, placebo-controlled, Phase III study and included a total of 870 patients with stage III, BRAF V600E/K-mutant melanoma who had undergone prior complete surgical resection. Patients were treated for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC). The primary endpoint was RFS. Secondary endpoints included overall survival (OS), distant metastasis free survival (DMFS), freedom from relapse (FFR), and safety.
The COMBI-AD study evaluated Tafinlar + Mekinist in patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, randomised within 12 weeks of complete surgical resection. Patients received the Tafinlar (150 mg BID) and Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint was met, with the combination therapy shown to significantly reduce the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001). The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C. The combination treatment group also saw an improvement in the key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance)., Other endpoints, where the combination demonstrated a clinically meaningful benefit include DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and FFR (HR: 0.47 [95% CI: 0.39-0.57]).
Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported. Of patients treated with the combination, 97% experienced an AE; 41% had Grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo).
About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is licensed and NICE approved in the UK, as well as the US, EU, Australia, Canada and other countries.
Tafinlar and Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumour growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial programme across a range of tumour types conducted in study centres worldwide.
Tafinlar is also licensed in the UK and in over 60 countries worldwide, as a single agent to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.
In the UK, Novartis develops, manufactures and markets innovative medicines, devices and diagnostic tests which help improve patient outcomes. Based on four sites across the north and south of England, we employ approximately 1,500 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis by manufacturing the active pharmaceutical ingredients used worldwide in many medicines. In 2015 Novartis in the UK invested over £50million in R&D and is the largest commercial sponsor of clinical trials. For more information, please visit http://www.novartis.co.uk.
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1. Cancer Research UK. Skin cancer statistics. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/skin-cancer#heading-Zero. Accessed September 2017.
2. Hauschild A, Santinami M, Long GV, et al. COMBI-AD: Adjuvant Dabrafenib (D) Plus Trametinib (T) for Resected Stage III BRAF V600E/K-Mutant Melanoma. Abstract #LBA6. 2017 European Society of Medical Oncology (ESMO), September 8-12, 2017, Madrid, Spain.
3. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib Plus Trametinib for Stage III BRAF V600E/K-Mutant Melanoma. New England Journal of Medicine. 2017.
4. Cancer Research UK. Genetic tests on your melanoma cells. Available from: http://www.cancerresearchuk.org/about-cancer/melanoma/getting-diagnosed/tests-stage/genetic-tests-your-melanoma-cells. Accessed September 2017.
5. NICE. Trametinib in combination with dabrafenib for treating unresectable or metastatic melanoma: Technology Appraisal TA396. Available from: https://www.nice.org.uk/guidance/ta396/documents/final-appraisal-determination-document. Accessed September 2017.
6. NICE. Managing melanoma: Stage III. Available from: http://pathways.nice.org.uk/pathways/melanoma/managing-melanoma#content=view-node%3Anodes-stage-iii-melanoma. Accessed September 2017.
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