Long-term survival benefit shown for metastatic melanoma patients treated with Novartis Tafinlar® + Mekinist®

NovartisNovartis announced results from the landmark COMBI-d and COMBI-v clinical trials, concluding that first-line treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) offers both overall and progression-free long-term survival benefits to patients with unresectable or metastatic BRAF-mutation positive melanoma. Researchers reported that 34% (95% CI: 30-38%) of all patients in the pooled analysis who were treated with Tafinlar + Mekinist survived at five years[1]. Study authors also reported on prolongation in progression-free survival (PFS), with 19% (95% CI: 15-22%) of patients showing no sign of disease progression or death at five years. Five-year overall survival and PFS were similar in the pooled patient population[1],[4].

The results, from a pooled analysis of 563 patients from the COMBI-d and COMBI-v trials, represented the largest collection of data and longest follow-up among patients with advanced melanoma with BRAF V600-mutated unresectable or metastatic melanoma who were treated with Tafinlar + Mekinist. These data were presented at the 2019 ASCO Annual Meeting (Abstract #9507) and published simultaneously in The New England Journal of Medicine[1],[4].

"Our analysis demonstrates that first-line therapy with Tafinlar + Mekinist leads to five-year disease control in about one-fifth of the patients and five-year survival in about one-third of those treated," said Caroline Robert, MD, Ph.D., Head of the Dermatology Unit at the Institut Gustave Roussy in Paris. "While metastatic melanoma has historically had a very poor prognosis for patients, there are many reasons to be encouraged today. Our analysis demonstrates a clinically meaningful and positive impact on patient survival. These results show that targeted therapies may provide long-term survival and offer durable outcomes."

Of patients who achieved a complete response with Tafinlar + Mekinist, 19% (n=109) had five-year PFS and overall survival rates of 49% and 71%, respectively, compared with 19% and 34% in the overall population. Researchers also observed that the efficacy of subsequent treatment was preserved in patients who progressed on study treatment and subsequently received immune checkpoint inhibitor therapy.

Adverse events (regardless of causality) were reported in 548 of 559 patients (98%) with no new safety signals. Adverse events (AEs) led to permanent discontinuation of study treatment in 99 of 559 patients (18%); the most common events were pyrexia (4%), decreased ejection fraction (4%) and increased alanine aminotransferase (1%). No treatment-related deaths were reported in patients treated with dabrafenib plus trametinib.

"The five-year COMBI-d/v analysis is truly gratifying, as it shows us that many BRAF+ melanoma patients on Tafinlar + Mekinist are living much longer than what may have been expected when originally diagnosed," said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis. "Other Novartis-sponsored melanoma research at ASCO this week illustrates our drive to do even more in melanoma. Efficacy results from the study of the immunotherapy spartalizumab were encouraging as the oncology community learns more about how immunotherapies may be combined with established targeted therapies to provide an even greater benefit to patients."

About COMBI-d and COMBI-v

COMBI-d is a pivotal Phase III randomized, double-blinded study (NCT01584648) comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single-agent therapy with Tafinlar and placebo as first-line therapy in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 422 patients from 121 investigative sites.

COMBI-v is a two-arm, open-label, Phase III study comparing the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma (NCT01597908). The primary endpoint of this study was OS[1].

Efficacy Findings for Investigational Anti-PD-1 Antibody Spartalizumab (PDR001) Used in Combination With Tafinlar + Mekinist Also Reported

Also presented at ASCO were findings from the COMBI-i study evaluating Tafinlar + Mekinist in combination with spartalizumab in metastatic melanoma patients with known BRAF mutation (Abstract #9531). Results from the 36 patients enrolled in the safety run-in cohort (part 1) and biomarker cohort (part 2) showed a confirmed objective response rate by investigator assessment of 78% (n=28), with 42% (n=15) of patients exhibiting complete responses. All patients experienced at least one AE, 28 had grade >= 3 AEs and six had AEs leading to discontinuation of all three study drugs. The most common AEs (>/= 20%) included pyrexia, cough, arthralgia, rash, chills and fatigue. One patient died of cardiac arrest that was not considered related to study treatment. The clinical trial is ongoing[5].

About the COMBI-i Study

COMBI-i is a pivotal Phase III, double-blinded global study (NCT02967692) comparing the combination of Tafinlar + Mekinist to the same combination along with the investigational anti-PD1 therapy spartalizumab as first-line therapy in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study is being conducted in three parts. In the safety run-in (part 1), the primary endpoint was incidence of dose-limiting toxicities, and in the biomarker cohort (part 2), the primary endpoint was immune microenvironment and biomarker modulation. The randomized portion of the study (part 3) is ongoing, and the primary endpoint is investigator-assessed progression-free survival[5].

About Melanoma

There are about 280,000 new diagnoses of melanoma (Stages 0-IV) worldwide each year[6], approximately half of which have BRAF mutations[7]. Biomarker tests can determine whether a tumor has a BRAF mutation[8].

One way melanoma is staged is 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[9]. 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[10],[11]. Patients should ask their doctor if they are at risk for melanoma returning.

About Tafinlar + Mekinist Combination

Combination use of Tafinlar + Mekinist in patients with stage III resectable, unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Japan, Australia, Canada and other countries.

The combination of Tafinlar + Mekinist is also approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation in the US and advanced NSCLC with a BRAF V600 mutation in the EU.

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 NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 60 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Please see full Prescribing Information for Tafinlar and Mekinist.

About Novartis

Novartis is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis products reach more than 750 million people globally and we are finding innovative ways to expand access to our latest treatments. About 105,000 people of more than 140 nationalities work at Novartis around the world.

1. Paul D. Nathan, et al. Five-year analysis of dabrafenib plus trametinib (D+T) in patients with BRAF V600-mutant unresectable or metastatic melanoma confirms long-term benefit. Abstract #9507. 2019 American Society of Clinical Oncology Annual Meeting, May 31-June 4, Chicago, IL.
2. Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed May 31, 2016.
3. A Snapshot of Melanoma. National Cancer Institute. Available at: http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed May 31, 2016.
4. Robert C, et al. N Engl J Med. 2019 June 4. doi: 10.1056/NEJMoa1904059. [Epub ahead of print].
5. Georgina V. Long, et al. The anti-PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. Abstract #9531. 2019 American Society of Clinical Oncology Annual Meeting, May 31-June 4, Chicago, IL.
6. Globocan. World Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed October 10, 2018.
7. Schandendorf D, et al. Melanoma. Nature reviews Disease Primers. 2015.
8. Wilson MA, Molecular Testing in Melanoma. NCBI. 2012.
9. American Cancer Society. Melanoma Skin Cancer Stages. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html. Accessed October 10, 2018
10. 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.
11. Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/. Accessed October 10, 2018.

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