MedicalResearch.com Interview with:
Dr Alexander Menzies BSc(Med) MBBS (Hons) FRACP PhD
Medical Oncologist and Senior Research Fellow at Melanoma Institute Australia
The University of Sydney and Royal North Shore and Mater Hospital
MedicalResearch.com: What is the background for this study?
Response: For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis. However until now, Stage III melanoma patients (where the disease has spread to the lymph nodes) who have had their tumours surgically removed have simply had to play the waiting game to see if their melanoma would metastasise, with many ultimately dying of the disease.
Checkpoint inhibitor immunotherapies and drugs that target the mitogen-activated protein kinase (MAPK) pathway have improved the outcome of patients with metastatic melanoma, but their role as adjuvant therapy is still being actively investigated.
Prior Phase III trials (COMBI-D and COMBI-V) have shown improved overall survival in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. At Melanoma Institute Australia, we were keen to see if this improvement would be seen in the adjuvant setting also. This clinical trial was the first in the world to give targeted therapy to melanoma patients at an earlier stage of the disease to prevent spread and recurrence.
MedicalResearch.com: What are the main findings?
Response: In this trial, 870 patients with completely resected, high-risk, Stage III BRAF V600E/K–mutant melanoma were randomized 1:1 to receive dabrafenib 150 mg twice daily plus trametinib 2 mg once daily or two matching placebos for 12 months.
The trial found that with a median follow-up of 2.8 years, dabrafenib plus trametinib significantly prolonged relapse-free survival vs placebo with a risk reduction of 53%. The combination also improved overall survival (risk reduction 43%), distant metastasis-free survival and freedom from relapse. The safety profile of dabrafenib and trametinib was consistent with that observed in metastatic melanoma.
MedicalResearch.com: What should clinicians and patients take away from your report?
Response: Treatment with dabrafenib plus trametinib not only prevented resected Stage III melanoma from recurring, but it also increased overall survival.
Results from this clinical trial and the recently published CheckMate 238 trial of adjuvant nivolumab vs ipilimumab in the Stage III setting now suggest that we can stop melanoma in its tracks – effectively preventing it from spreading and saving lives.
These results will change the way we treat melanoma patients, and less patients will die from melanoma.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Results of this study have several ramifications. Firstly, it will improve the treatment of patients with resected (node positive) melanoma, but just as with metastatic melanoma, next we need to explore why some patients became resistant to treatment, in order to better improve outcomes further.
In what has been a fantastic period in melanoma research and treatment, the use of PD-1 immunotherapy (nivolumab), has also been shown to reduce the chance of recurrence in the high risk population (Stage III and Stage IV). Trials in the metastatic setting are now exploring new drugs and combinations, such as the combination of targeted and immunotherapy. Should they be successful, these treatments may also enter the adjuvant space.
We are running such trials at Melanoma Institute Australia. We are also trialling drugs in the neo-adjuvant setting in Phase II trials. The main aim is to find out if giving the combination treatment to Stage III patients (where their melanoma has spread to the lymph nodes) BEFORE they have surgery will result in improved clinical and pathological response of the melanoma tissue after 12 weeks treatment. It should also offer insight into how best to combine drugs for maximum benefit. Results of the first trial using dabrafenib and trametinib were presented at ESMO 2017, and we look forward to these results being published soon. A new trial combining BRAF/MEK and PD-1 immunotherapy has also commenced.
MedicalResearch.com: Is there anything else you would like to add?
Response: Results from this trial show that we now have ammunition to prevent melanoma spreading and progressing, which until now was a critical area of disease behaviour where we had no control. This research will change how melanoma is treated around the world, as we no longer have to passively wait to see if the melanoma spreads.
We can now actively and effectively attack the melanoma at an earlier stage, reducing the dreadful anxiety for patients about progressing to a potentially terminal illness and ensuring they have much better outcomes.
AMM – advisory board: MSD, Novartis, Pierre-Fabre. Honoraria BMS, Roche.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Georgina V. Long, M.B., B.S., Ph.D., Axel Hauschild, M.D., Ph.D., Mario Santinami, M.D., Victoria Atkinson, M.D., Mario Mandalà, M.D., Vanna Chiarion-Sileni, M.D., James Larkin, Ph.D., Marta Nyakas, M.D., Caroline Dutriaux, M.D., Andrew Haydon, M.B., B.S., Ph.D., Caroline Robert, M.D., Laurent Mortier, M.D., Ph.D., Jacob Schachter, M.D., Dirk Schadendorf, M.D., Ph.D., Thierry Lesimple, M.D., Ruth Plummer, M.D., Ran Ji, Ph.D., Pingkuan Zhang, M.D., Bijoyesh Mookerjee, M.D., Jeff Legos, Ph.D., Richard Kefford, M.B., B.S., Ph.D., Reinhard Dummer, M.D., and John M. Kirkwood, M.D.
September 10, 2017 DOI: 10.1056/NEJMoa1708539
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