Novartis combination Tafinlar® + Mekinist® receives positive CHMP opinion for adjuvant treatment of BRAF V600 mutation-positive melanoma

• Phase III trial showed a 53% reduction in risk of recurrence or death with the combination of a BRAF and MEK inhibitor as adjuvant therapy versus placebo[1]
• Relapse-free survival benefit with Tafinlar + Mekinist combination was observed across all patient subgroups, including stage III A, B and C
• If approved, expected to be the first targeted combination therapy in the EU for adjuvant treatment of melanoma

Basel, July 27, 2018 - Novartis today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Tafinlar^® (dabrafenib) in combination with Mekinist^® (trametinib) for the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation, following complete resection. The CHMP recommendation is based on findings from the COMBI-AD study, which was published in The New England Journal of Medicine (NEJM).

Patients who have been diagnosed with stage III melanoma are at a higher risk of recurrence after surgical resection. The COMBI-AD study found a statistically significant 53% reduction in the risk of recurrence or death in patients treated with the BRAF and MEK inhibitor combination therapy after surgical resection versus placebo[1].

With an estimated 6,000 stage III BRAF mutant melanoma skin cancers diagnosed across Europe each year[2], this potential approval may provide patients in the EU the opportunity for a targeted combination therapy that doubles relapsed-free survival versus a placebo.

"Melanoma is an aggressive, highly recurrent and often fatal disease. In advanced melanoma, we've demonstrated the ability to reduce the risk of death or recurrence by more than half," said Liz Barrett, CEO, Novartis Oncology. "Today's CHMP opinion brings us another step closer to reimagining earlier stage therapy for patients throughout Europe and making strides to bring improved outcomes for people living with melanoma."

"These relapse-free survival results are unprecedented," said lead investigator Axel Hauschild, MD, PhD, Professor of Dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany. "The overall survival improvements also demonstrated by Tafinlar in combination with Mekinist, among other key secondary endpoints, are encouraging in the treatment of stage III BRAF V600E/K mutation-positive melanoma. Adjuvant treatment options are critical for this patient community at risk for recurrence."

About COMBI-AD Study
The COMBI-AD study evaluated Tafinlar + Mekinist among patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, randomized 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 in that combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not yet 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 estimated one-year, two-year, and three-year RFS were consistently higher than placebo (one year: 88% vs. 56%; two year: 67% vs. 44%; three year: 58% vs. 39%). The combination treatment group also saw an improvement in a 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 secondary endpoints where the combination demonstrated a clinically meaningful benefit include distant metastasis-free survival (DMFS) (HR: 0.51 [95% CI: 0.40-0.65]), and freedom from relapse (FFR) (HR: 0.47 [95% CI: 0.39-0.57])[1].

Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported. Of patients treated with the combination, the most frequently reported AE's were pyrexia, fatigue, nausea, headache, chills, diarrhea, vomiting, arthralgia and rash[1].

About Melanoma
There are nearly 200,000 new diagnoses of melanoma (stages 0-IV) worldwide each year, approximately half of which have BRAF mutations. Biomarker tests can determine whether a tumor has a BRAF mutation[3],[4].

Melanoma is staged by how far it has metastasized. In stage III melanoma, tumors have spread to the regional lymph nodes, presenting a higher risk of recurrence or metastases[4]⁴. Patients who receive surgical treatment for stage III melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery; almost half (44%) of patients receiving placebo per the COMBI-AD study had a recurrence of disease within the first year[1],[5]. Adjuvant therapy is additional treatment given after surgical resection, and may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning[5].

References
[1] 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.
[2] KANTAR Health. Downloaded November 2017.
[3] Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed 2018.
[4] Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF Mutations in Melanoma Patients: Implications for Molecular Testing in Clinical Practice. British Journal of Cancer. 2013.
[5] Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/ Accessed 2018.