Home Forums Melanoma Diagnosis: Stage IV Braf/Mek combo results show good response duration

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    Catherine Poole

    Studies show drug combinations effective for melanoma

    Promising new trial data from trials aimed at delaying resistance to BRAF inhibitors

    VIENNA, date – Promising new data on drug combinations to treat metastatic melanoma were released today at a press briefing at the European Society for Medical Oncology’s ESMO2012 Congress in Vienna.

    The phase I and II trials focus on combining drugs to slow the development of resistance to drugs that inhibit BRAF, a gene that is mutated in a large proportion of melanomas. Earlier trials with drugs that target BRAF had generated excitement for their ability to quickly shrink melanoma tumours in suitable patients. But for many patients, the benefits proved short-lived as the cancer cells develop resistance to the drugs.

    “These studies exemplify an important characteristic of some tumors, which has emerged from recent laboratory research: the presence of specific mutations, such as the BRAF mutation in metastatic melanoma, which expose an Achilles’ heel—in this case, MEK,” commented Dr YosefYarden from the Weizmann Institute of Science in Israel. “In-depth understanding of cancers and their mutations is expected to highlight more deadly weaknesses of cancer, which we can exploit using new drugs and drug combinations.”

    • Randomised phase II study of the BRAF inhibitor dabrafenib alone vs combination with MEK1/2 inhibitor trametinib

    Dr Georgina Long from Westmead Hospital and the Melanoma Institute Australia and colleagues report that combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in progression-free survival, response rate and duration of response in 162 patients with melanoma that had BRAF V600 mutations.

    “We know that resistance emerges within 5-6 months of treating patients with single-agent selective BRAF inhibitor,” Dr Long said. “We also know that most of the resistance mechanisms identified so far result in re-activation of the pathway that the BRAF inhibitor initially blocked (MAP kinase pathway). This was the basis of the rationale to trial the addition of a MEK inhibitor. It blocks the same pathway, but lower down, and we hoped that by combining both drugs we would see a significant delay in the emergence resistance that would impact patients lives.”

    Patients in the study received either dabrafenib 150 mg twice daily; twice-daily dabrafenib plus once-daily 1 mg trametinib; or twice-daily dabrafenib plus once-daily 2mg trametinib. The combination prolonged progression-free survival over single-drug therapy from 5.8 months to 9.4 months, which represents a 60% improvement. Among patients who received both drugs at the higher dose, 41% had not progressed 12 months after treatment began, compared to 9% in the monotherapy arm of the study.

    “The combination therapy of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib prolongs the progression-free survival in patients with V600 BRAF mutation-positive metastatic melanoma compared with dabrafenib monotherapy,” Dr Long said. “Importantly, the combination also decreases the rate of the cutaneous toxicities compared with dabrafenib monotherapy, particularly the oncogenic cutaneous toxicity of squamous cell carcinoma.”


    So happy to hear the good news. My 35 year old son has now been on it for 7 months. He sees Dr. Infante in Nashville every month with a CT scan on alternating months. Although he has side effects of arthralgia, fevers, and fatigue, he says it is a small price to pay for the good reports.


    Catherine Poole

    Yes, this is great. We need promising therapies, now the wait until approval.


    Can you break this down for me? I’ve tried to research it online, but can’t find numbers. When they talk about the combo producing “prolonged survival” past the median 5/6 month mark for BRAF inhibitor alone, what are the studies showing? Sometimes there is so much enthusiasm behind things like this, but when you discover it’s only a couple months on average longer, it’s a bubble buster. So, how much longer on average does the combo therapy hold the melanoma at bay?


    Catherine Poole

    The best advice I have is to watch our webinar held last night by the doctor working with the dual therapy, Dr. Infante. It should be archived soon on our site. But for now, go to the webinar tab above in BLUE.

    With all of these new therapies we can only report what we know from a short time of clinical trial experience. I definitely think combinations of therapies will bring us the long term result we are looking for and starting these in stage 3 instead of 4 disease.


    catherine –

    i’m sorry i just dont’ have time to watch webinars now and try and read posts as often as i can. i’m working full time, we just moved into a new home and having to do a lot for my partner who is wiped out with treatment. i also don’t have high speed internet at my home so webinars are not really an option. so, in a nutshell, i’m hearing you say things look positive, but do they not look very positive for stage 4?


    Hi Zephyr-

    the study shows that on average patients get resistant to therapy after 9.4 months if they take the combination of BRAF + MEK inhibitors. On BRAF inhibitor alone, they get resistant after 5.8 months (on average as well).

    I wished we had had these extra 3.6 months of life.


    Catherine Poole

    I go along with the docs who say we have a few new tools now, immunotherapy and the braf/mek drugs. Somehow, these should be working together to create more of a chronic disease instead of it taking lives. But we’re just on the edge of new discoveries. I agree with Bettina that it does look like the dual therapy lasts longer in duration for remission than zelboraf alone. The longest so far is 2 years of remission in his trial. He basically said in the webinar it is best to work with your doctor to come up with the best combination and sequence. Sounds like you have a good doctor too. You might get an opinion at UCLA where they are doing a lot of amazing things!


    catherine & bettina,

    thanks so much!! that gives me a general idea. she has had first round of her IPI reinduction and if we don’t have good results, we’ll see what is available. she has VA insurance but they have really been on top of things and have the latest so we’re grateful.

    the ipi is REALLY fatiguing her this time but no other side effects so that’s good. 2nd infusion is monday.


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