Novartis Phase III study demonstrates adjuvant Tafinlar® + Mekinist® reduced the risk of disease recurrence by 53% in patients with resected BRAF V600 mutation-positive melanoma

  • The three-year relapse-free survival (RFS) rate for patients treated with the combination was 58%, compared to 39% with placebo[1]
  • Consistent improvement in RFS observed across all pre-specified subgroups, including patients with stage III A, B and C melanoma[1]
  • Study demonstrated clinically meaningful improvements in secondary endpoints, including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR) [1]
  • First adjuvant targeted therapy combination to demonstrate a clinical benefit in patients with a BRAF V600 mutation[1]  
  • Results from COMBI-AD presented at the European Society for Medical Oncology annual congress and simultaneously published in the New England Journal of Medicine

BASEL, Switzerland I September 11, 2017 I Novartis today announced results from a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with the combination of Tafinlar® (dabrafenib) + Mekinist® (trametinib) [1] . 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 BRAF and MEK inhibitor combination therapy 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 [1]. 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 were simultaneously published in the New England Journal of Medicine[1],[2].

"The efficacy and tolerability of Tafinlar in combination with Mekinist seen in this study represent an important step forward in the treatment of stage III BRAF V600E/K mutation-positive melanoma," said lead investigator Axel Hauschild, MD, PhD, Professor of Dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany. "These unprecedented results confirm a targeted therapy combination has the potential to transform the standard of care in the melanoma adjuvant setting."

"While surgery is a curative option for most patients with localized melanoma, there is a need for improved standard of care therapies for patients - especially for stage III disease, which carries a higher risk of relapse and death following resection," said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. "The COMBI-AD data results address a significant unmet need in patients with stage III melanoma. We look forward to discussing the results with regulatory authorities worldwide."

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)[1]. 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 reached vs. 16.6 months, respectively; p<0.001) [1]. 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%) [1]. 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 DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and 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 [1]. 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) [1].

In a separate study, Novartis presented Phase II results from BRF113928, showing efficacy for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC) without prior systemic therapy for metastatic disease when treated with the combination of Tafinlar + Mekinist (Abstract #LBA51) [3]. Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 64% (95% CI: 46%-79%). After a median follow-up of 15.9 months, median duration of response (DoR) was 10.4 months (95% CI: 8.3-17.9 months), and median progression-free survival (PFS) was 10.9 months (95% CI: 7.0-16.6 months) [3]. Median OS was 24.6 months (95% CI: 12.3 months-not estimable), two-year OS rate was 51% (95% CI: 33-67%)[3]. These study results were simultaneously published in The Lancet Oncology [4].

Findings from the study demonstrated clinically meaningful antitumor activity in patients who had not received prior systemic therapy and in patients who had received at least one platinum-based chemotherapy for their metastatic NSCLC, supporting recent approvals by the European Commission (EC) and US Food and Drug Administration (FDA).

The most common AEs (incidence >20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough and dyspnea.

Additional poster and oral presentations related to the investigational use of Tafinlar and Mekinist in melanoma were also presented at the meeting, including:

  • Phase II Study of Neoadjuvant Dabrafenib + Trametinib (D+T) for Resectable Stage IIIB/C BRAF V600-Mutant Melanoma [Abstract #1220PD]
  • Five-year Efficacy and Safety Update From METRIC: Trametinib vs. Chemotherapy in Patients with BRAF V600E/K-Mutant Advanced or Metastatic Melanoma [Abstract #1226PD]
  • A Phase III Randomized, Double-Blind, Placebo-Controlled Study Comparing the Combination of PDR001 + Dabrafenib + Trametinib vs. Placebo + Dabrafenib + Trametinib in Treatment-Naïve Patients with Unresectable or  Metastatic BRAF V600-Mutant Melanoma (COMBI-i) [Abstract #1259TiP]
  • KEYNOTE-022 Update: Phase I Study of First-Line Pembrolizumab (pembro) Plus Dabrafenib (D) and Trametinib (T) for BRAF-Mutant Advanced Melanoma [Abstract # 1216O]
  • A Phase II, Randomized, Open Label Study of Neoadjuvant Pembrolizumab with/without Dabrafenib and Trametinib (D+T) in BRAF V600-Mutant Resectable Stage IIIB/C/D Melanoma (NeoTrio Trial) [Abstract #1256TiP]
  • Dabrafenib and Trametinib Combination in Real Life Patients Including Brain Metastases: French Experience within MelBase [Abstract #1255P]

About COMBI-AD

The COMBI-AD study is a randomized, 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 OS, DMFS, FFR, and safety.

About Melanoma

There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations. Gene tests can determine whether a tumor has a BRAF mutation [5],[6]. Patients who receive surgical treatment for melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery[7]. Adjuvant therapy may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning [7].

About Tafinlar + Mekinist Combination

Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, 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.

About Novartis

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 119,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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 References

[1] 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.

[2] 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.

[3] Planchard D, Smit EF, Groen HJM, et al. Phase 2 Trial (BRF113928) of Dabrafenib (D) Plus Trametinib (T) in Patients (pts) With Previously Untreated BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC). Abstract #LBA51. 2017 European Society of Medical Oncology (ESMO), September 8-12, 2017, Madrid, Spain.

[4] Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small cell lung cancer: an open-label, phase 2 trial. The Lancet Oncology. 2017.

[5] Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed May 31, 2017.

[6] Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. British Journal of Cancer. 2013.

[7] Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/. Accessed July 7, 2017.

SOURCE: Novartis

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