ESMO 2017 Press Release: Combination Targeted Adjuvant Therapy Doubles Relapse-free Survival in Stage III Melanoma

LUGANO-MADRID – Combination targeted adjuvant therapy with dabrafenib and trametinib doubles relapse-free survival in patients with stage III BRAF-mutant melanoma, according to late-breaking results from the COMBI-AD trial presented today at the ESMO 2017 Congress in Madrid (1) and published in the New England Journal of Medicine. (2)

“There is no standard of care for the adjuvant treatment of stage III melanoma,” said the COMBI-AD presenter Axel Hauschild, Professor of Dermatology, University of Kiel, Kiel, Germany. “Interferon is approved for this situation but improves relative relapse-free survival by just 20% compared to placebo.”

Previous phase III trials have shown that the combination of dabrafenib and trametinib improved overall survival and progression-free survival, and was well tolerated, in patients with advanced, unresectable metastatic BRAF-mutant melanoma. (3,4)

COMBI-AD is the first clinical trial of targeted therapies for adjuvant treatment of stage III melanoma. All patients had a BRAF mutation – 91% harboured a V600E mutation and 9% had a V600K mutation, which is the typical distribution in clinical practice. Patients had lymph node metastases which had been completely excised. The primary endpoint of the trial was to prolong relapse-free survival.

This double-blind trial randomised 870 patients 1:1 to combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib versus matching placebos. Patients were treated for 12 months.

The trial met its primary endpoint. At a median follow-up of 2.8 years, the combination therapy had significantly reduced the risk of disease recurrence or death by 53% compared to placebo (hazard ratio [HR], 0.47; 95% confidence interval, 0.39–0.58). The relapse-free survival benefit with the combination therapy was observed across all patient subgroups.

The combination treatment also showed a benefit in secondary endpoints including overall survival (HR, 0.57), distant metastases-free survival (HR, 0.51) and freedom from relapse (HR, 0.47).

“These are the best results ever shown for an adjuvant treatment in stage III melanomas,” said Hauschild. “Combination treatment with dabrafenib and trametinib more than doubled the relapse-free survival time compared to placebo and the improvement in overall survival was impressive, too.”

Some 97% of patients on the combination had an adverse event of any kind and 41% had serious (grade 3/4) adverse events, compared to 88% and 14% with placebo, respectively. Around one-quarter (26%) of patients on the combination had to stop treatment due to adverse events versus 3% on placebo.

“The number of treatment discontinuations was a little higher than in trials on stage IV melanoma patients,” said Hauschild. “This could be because 90% of patients had no progressive disease and were treated for the scheduled full year. The longer patients receive treatment, the more likely they are to have adverse events. But there were no new toxicities compared to those already seen in stage IV disease and overall we can say the treatment was well tolerated.”

He concluded: “These are practice changing results. The combination of dabrafenib and trametinib is a new and very effective adjuvant treatment option in high-risk melanoma patients.”

Commenting on the results, Dr Olivier Michielin, head of Personalised Analytical Oncology, Lausanne, Switzerland, ESMO Melanoma Faculty Coordinator, said: “We have been trying to develop adjuvant therapies for melanoma for many years. Interferon led to minimal benefit and high toxicity and has not been widely adopted. The first revolution was ipilimumab, which improved progression-free survival and overall survival compared to placebo. Presented at the ESMO 2016 Congress, this was the first big breakthrough in the adjuvant setting. The ipilimumab regimen used in that study is, however, fairly toxic.”

“Interferon and ipilimumab are both immunotherapies but COMBI-AD is the first trial reporting on the use of targeted therapies in the adjuvant setting for melanoma,” continued Michielin. “The improvements in progression-free survival and overall survival are both very significant, making this new treatment an attractive option for patients with BRAF mutations, who constitute around half of the melanoma population. The different toxicity profiles between immunotherapy and the targeted therapies will factor into decisions on which to use.”

He concluded: “Both ipilimumab and the combination of dabrafenib plus trametinib have improved overall survival compared to placebo. We now need to determine which adjuvant strategy is best suited for which patient, factoring in also the upcoming results of PD-1 blockade in that setting.”

In the same ESMO session, late-breaking results will be presented from the randomised BRIM8 trial of adjuvant vemurafenib in patients with resected BRAF-mutant melanoma at high risk for recurrence. (5) The drug had previously shown robust clinical activity in BRAF-mutant advanced/metastatic melanoma.

Adjuvant vemurafenib did not improve the primary endpoint of disease-free survival in patients with stage IIIC disease but appeared to be effective and well tolerated in patients with resected stage IIC–IIIB BRAF-mutant melanoma.

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

  1. Abstract LBA6_PR ‘COMBI-AD: Adjuvant Dabrafenib (D) Plus Trametinib (T) for Resected Stage III BRAF V600E/K–Mutant Melanoma‘ will be presented by Dr Axel Hauschild during Presidential Symposium III on Monday, 11 September 2017, 16:30 to 17:45 (CEST) in Madrid Auditorium.
  2. Long G.V., Hauschild A., Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. DOI: 10.1056/NEJMoa1708539
  3. Robert C, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–39. doi: 10.1056/NEJMoa1412690
  4. Long GV, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–1888. doi: 10.1056/NEJMoa1406037. 
  5. Abstract LBA7_PR ‘BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence’ will be presented by Dr Karl Lewis during Presidential Symposium III on Monday, 11 September 2017, 16:30 to 17:45 (CEST) in the Madrid Auditorium.

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Abstract LBA6_PR

COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma

A. Hauschild1, M. Santinami2, G.V. Long3, V. Atkinson4, M. Mandala5, V. Chiarion Sileni6, M.S. Nyakas7, C. Dutriaux8, A. Haydon9, C. Robert10, L. Mortier11, J. Schachter12, R. Ji13, P. Zhang13, B. Mookerjee13, J. Legos13, R. Kefford14, R. Dummer15, J. Kirkwood16 
1Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany, 2Oncology, Fondazione Istituto Nazionale Tumori, Milan, Italy, 3Melanoma Medical Oncology, Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, Australia, 4Medical Oncology, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Queensland, Australia, 5Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy, 6Melanoma Oncology Unit, Veneto Oncology Institute, Padua, Italy, 7Department of Oncology, Rikshospitalet-Radiumhospitalet HF, Oslo, Norway, 8Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France, 9Medical Oncology, The Alfred Hospital, Melbourne, Australia, 10Dermatology, Institute Gustave Roussy, Paris, France, 11Dermatology, Université de Lille, Lille, France, 12Oncology, Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel, 13Medical Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 14Medical Oncology, Macquarie University, Melanoma Institute Australia, Westmead Hospital, and the University of Sydney, Sydney, Australia, 15Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland, 16Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

Background: Surgery is curative for most patients (pts) with localized melanoma; however, those with regional nodal involvement (stage III disease) are at a higher risk for relapse and death after resection. In phase 3 trials of advanced or metastatic BRAF V600–mutant melanoma, D+T combination therapy improved clinical outcomes and was well tolerated.

Methods: In this randomized, double-blind, placebo-controlled, phase 3 study (COMBI-AD [NCT01682083]), pts with high-risk, stage III, BRAF V600E/K–mutant melanoma without prior anticancer therapy were randomized 1:1 within 12 weeks of complete surgical resection to receive D 150 mg twice daily plus T 2 mg once daily or matching placebos. Pts were treated for 12 months and stratified based on BRAFmutation (V600E vs V600K) and stage (IIIA vs IIIB vs IIIC). The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.

Results: A total of 870 pts (stage IIIA, 18%; IIIB, 41%; IIIC, 40%; unknown, 1%) were randomized (D+T, n = 438; placebo, n = 432). The primary endpoint was met. At the time of the data cutoff for the primary analysis (June 30, 2017; median follow-up, 2.8 years), D+T 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). RFS benefit with D+T was observed across all patient subgroups. D+T also improved secondary endpoints of OS (HR, 0.57 [95% CI, 0.42-0.79]), DMFS (HR, 0.51 [95% CI, 0.40-0.65]), and FFR (HR, 0.47 [95% CI, 0.39-0.57]). With D+T, 97% of pts had an adverse event (AE), 41% had grade 3/4 AEs, and 26% had AEs leading to treatment discontinuation (vs 88%, 14%, and 3%, respectively, with placebo).

Conclusions: Combination D+T adjuvant therapy was associated with improvements in RFS, OS, DMFS, and FFR, and manageable safety in pts with high-risk, resected, stage III, BRAF V600E/K–mutant melanoma. This regimen represents a new adjuvant treatment option in this setting.

Clinical trial identification: ClinicalTrials.gov number: NCT01682083 EudraCT number: 2012-001266-15 Release date: May 31, 2017

Legal entity responsible for the study: GlaxoSmithKline

Funding: GlaxoSmithKline

Disclosure: A. Hauschild: Clinical trial support or speaker´s honoraria or consultancy fees from Amgen, BMS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche during the conduct of the study.
G.V. Long: Personal fees as a consultant advisor to BMS, Novartis, Roche, Amgen, Merck MSD, Pierre Fabre, and Array outside the submitted work.
V. Atkinson: Travel reimbursement and advisory board speaker's fees from MSD, BMS, and Novartis, speaker's fees from Roche, and advisory board fees from Pierre Fabre outside the submitted work.
M. Mandala: Advisory board, lectures, and research activity fees from Roche; and advisory board and lecture fees from Novartis, MSD, and BMS outside the submitted work.
V. Chiarion Sileni: Assistance with manuscript preparation from ArticulateScience, LLC, and advisory board fees from BMS, MSD, Roche, Novartis, and Merck Serono during the conduct of the study.
M.S. Nyakas, C. Dutriaux: Assistance with manuscript preparation from ArticulateScience, LLC, during the conduct of this study. 
A. Haydon: Lecture fees from Novartis during the conduct of the study.
C. Robert: Advisory board fees from BMS, MSD, Novartis, and Roche during the conduct of the study.
L. Mortier: Assistance with manuscript preparation from ArticulateScience, LLC, and medical board fees from Novartis during the conduct of this study; and medical board fees from Roche outside the submitted work. 
R. Ji, P. Zhang: Employment by Novartis during the conduct of the study.
B. Mookerjee: Employment and stock options from Novartis and stock options from GlaxoSmithKline during the conduct of the study; employment and stock options from Novartis and GlaxoSmithKline outside the submitted work.
J. Legos: Employment by and shareholder of Novartis and non-financial support from ArticulateScience, LLC, during the conduct of the study. 
R. Kefford: Institutional reimbursement advisory boards fees from Novartis during the conduct of the study and institutional reimbursement advisory boards fees from BMS, Merck, Amgen, and Teva outside the submitted work.
R. Dummer: Intermittent, project-focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, and Pierre Fabre outside the submitted work. 
J. Kirkwood: Grants from Merck and Prometheus and personal fees from Prometheus, BMS, Novartis, Roche, Genentech, EMD Serono, and ArrAY Biopharma outside the submitted work.
All other authors have declared no conflicts of interest.

Keywords: adjuvant, dabrafenib, trametinib, BRAF V600–mutant melanoma

Abstract LBA7_PR

BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence

K. Lewis1, M. Maio2, L. Demidov3, M. Mandala4, P.A. Ascierto5, C. Herbert6, A. Mackiewicz7, P. Rutkowski8, A. Guminski9, G. Goodman10, B. Simmons10, C. Ye10, Y. Yan10, D. Schadendorf11
1Division of Medical Oncology, University of Colorado Denver School of Medicine, Aurora, CO, USA, 2Division of Medical Oncology and Immunology, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy, 3Dermatology, N. N. Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russian Federation, 4Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy, 5Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy, 6Oncology, Bristol Haematology and Oncology Centre, Bristol, UK, 7Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland, 8Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland, 9Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia, 10Product Development, Genentech, Inc., South San Francisco, USA, 11Department of Dermatology, University Hospital Essen, Essen, Germany

Background: Vemurafenib has previously demonstrated robust clinical activity in BRAFV600+ advanced/metastatic melanoma. We evaluated adjuvant vemurafenib in pts with BRAFV600+ melanoma with high recurrence risk.

Methods: This 2-cohort (C) study randomized 498 adult pts with fully resected stage IIC, IIIA, or IIIB (C1) melanoma or Stage IIIC melanoma (C2) 1:1 to vemurafenib 960 mg twice daily or placebo for 52 weeks. Stratification was by geographic region and additionally by disease stage in C1. The primary endpoint was disease-free survival (DFS). Hierarchical analysis of C2 before C1 was prespecified. Secondary objectives included safety, distant metastasis–free survival (DMFS), and overall survival (OS).

Results: Median study followup was 34 months in C2 and 31 months in C1. In C2, median DFS was greater, though not statistically significant, with adjuvant vemurafenib vs placebo (Table). Adjuvant vemurafenib substantially improved DFS vs placebo in C1. Subgroup analyses by common disease and demographic covariates were consistent with the overall analysis. Results for DMFS were similar to that of DFS; OS data are immature. Median exposure to study drug was similar in both cohorts (median duration = 364.0 days; median dose intensity of ≈80% in both). Vemurafenib-treated pts in C1 and C2 had similar incidences of serious adverse events (AEs) (16.2% and 16.1% respectively); the rate of treatment discontinuation because of AEs was slightly higher in C1 (22.7%) than C2 (15.1%). Overall, the safety profile of adjuvant vemurafenib was consistent with previous data and no new safety signals were observed.

Summary of efficacy

DFS, disease-free survival; DMFS, distant metastasis–free survival; HR, hazard ratio; NE, not evaluable; VEM, vemurafenib. aStratification was by region and disease stage for Cohort 1 and by region for Cohort 2.

Conclusions: Although the study did not meet the primary DFS endpoint in pts with stage IIIC disease (C2), adjuvant vemurafenib appears to be effective and well tolerated in pts with resected stage IIC–IIIB BRAFV600+ melanoma (C1). Further followup is needed to assess OS benefit.

Clinical trial identification: Trial protocol number: GO27826 v9 (14 March 2017). Data available from 12 July 2017.

Legal entity responsible for the study: F. Hoffmann-LaRoche Ltd.

Funding: F. Hoffmann-LaRoche Ltd.

Disclosure: K. Lewis: Dr. Lewis reports grants from Roche/Genentech, Amgen, Incyte, and EMD Serono, and personal fees from Roche/Genentech, Incyte, and SunPharma, grants from Amgen, grants from EMD Serono.
L. Demidov: Dr. Demidov received honoraria with MSD, Novartis (GSK), Roche, BMS; participated in a consulting or advisory role with BMS, MSD; received research funding with MSD, GSK, Roche, BMS, Novartis; and provided expert testimony for Amgen.
M. Mandala: Dr. Mandala reports grants and personal fees from Roche, and personal fees from Novartis, BMS, and MSD.
P.A. Ascierto: Dr. Ascierto reports grants and personal fees from Roche-Genentech, BMS, and Array, and personal fees from MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte.
P. Rutkowski: Dr. Rutkowski reports grants and personal fees from Novartis, and personal fees from Roche, MSD, BMS, Amgen, Pfizer, and Blueprint.
A. Guminski: Dr. Guminski reports personal fees and other from BMS, personal fees from MSD, Merck, and Eisai, and travel support from Astellas.
G. Goodman: Dr. Goodman is an employee of and owns stock options in Roche/Genentech.
B. Simmons: Dr. Simmons is an employee of and owns stock in Roche/Genentech.
C. Ye: Dr. Ye is an employee of and owns stock and stock options in Roche/Genentech.
Y. Yan: Dr. Yan is an employee of and owns stock in Roche/Genentech.
D. Schadendorf: Dr. Schadendorf reports patients' fees from Novartis, Roche, Merck/MSD, GSK, and BMS, and personal fees from Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Merck/MSD, and BMS.
All other authors have declared no conflicts of interest.

Keywords: vemurafenib, adjuvant, melanoma