BRAF/MEK before surgery as well as after is MUCH better, than just AFTER surgery for melanoma!! Plus trial still recruiting resectable stage III/IV melanoma peeps.

We have long known that BRAF positive melanoma peeps can respond almost magically to BRAF inhibitors, and do even better, with fewer side effects and less tumor work-around, when those medications are combined with a MEK inhibitor.  However, we also know that far too often, despite the combo, tumors can still learn to rear their ugly heads after that initial response.  For that reason, BRAF/MEK inhibition is often used to lower tumor burden quickly, then start the patient on immunotherapy.  Lot's of studies are also looking at pairing this targeted therapy with immunotherapy and a host of other drugs that will boost the durability of these responses.  Here are a zillion BRAF inhibitor related posts:  More than you ever wanted to know about BRAF inhibitors/targeted therapy in melanoma

With all that being noted...the next great way to treat melanoma is through adjuvant care.  Meaning - after the patient is rendered "free of disease" (usually these are Stage III or IV patients whose tumors are removed surgically and/or treated with radiation, whose follow-up scans of the irradiated area show no viable tumor) they can then be treated with immunotherapy or targeted therapy to try to make sure that their melanoma does not come back.  This was the premise of the study arm I was in, taking nivo from 2010-2013.  We know adjuvant care, whether you use ipi, anti-PD-1, or BRAF/MEK, works for many in melanoma!!!  Here are a zillion posts on that:  Adjuvant treatments WORK in melanoma!!!

Now....with all that said...we are also learning about NEOadjuvant treatment.  This treatment is where you find out the patient has melanoma.  THEN you start them on their meds.  THEN you remove the tumor and continue the treatment.  Here are some reports on neoadjuvant studies looking at BRAFi as neoadjuvant, along with the the OpACIN trial which used ipi/nivo as neo-adjuvant for Stage III melanoma patients.  Note:  you will have to scroll through some of the posts as some of the NEO-adjuvants articles are interspersed. - Neoadjuvant studies in melanoma

Researcher Amaria (lead author of the article below), has figured largely in the published data for BRAF/MEK as neoadjuvant.  Now, there's this:

Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Amaria, Prieto, Tetzlaff, et al. Lancet Oncol. 2018 Jan 17.

Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation.

We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775.

Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months vs 2·9 months. Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]).

Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

In this study of only 21 stage III/IV patients who had never taken BRAF/MEK, whose tumors were BRAF positive, and could be removed surgically, were divided in 2 groups. Folks with "metastases to bone, brain, or other sites where complete surgical excision was in doubt" were excluded.  7 got standard of care:  complete excision of their tumor and "consideration" of adjuvant therapy.  21 got the BRAF/MEK combo (dabrafenib and trametinib) BEFORE surgical removal of their lesion as well as AFTER!  Ten of the 14 treated with BRAF/MEK before and after excision were alive without disease progression "vs none of seven in the standard of care group".  These results were deemed so good that this phase of the trial was stopped and only the neoadjuvant/adjuvant arm is continuing, and in fact, recruiting.

This is great news.  However, I do see several flies in this report.
1.  You researchers left out some folks in serious need of care...folks with brain, bone and other mets that you didn't see as a winning ticket.  I've been one of those peeps and was given adjuvant care.  Those folks need neo-adjuvant/adjuvant care as much (or more!!!!) than anybody!!  Here's a small tirade on their being left out of clinical trials:  A really good review of treatment data for Melanoma Brain Mets!!! (And this is from 2015!!!!!!!!)
2.  These are really small numbers...in both arms.
3.  The fact that the 7 in the standard care arm were eligible for "consideration" of adjuvant care is pretty lame.  That language tells me that some chose to forego adjuvant care!!!  So OF COURSE!!! ~ those who had no additional care did less well!!!!  To provide greater clarity and benefit, the authors should have clearly defined the standard of care group in regard to whether they actually utilized BRAF/MEK after resection or not.
4.  Finally, I really don't care for the major drama, yet lack of real information, posed in this categorization of the 7 peeps in the standard of care group:  "more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group".  At first blush it seems that all of the 7 are dead, along with the 4 out of the 14 in the neo/adjuvant group!!  Come on, Amaria!  You have better writing skills than this!  Some of these peeps may well have passed, but it is also possible that ALL these folks are alive, albeit with disease progression.  Clarification of that could easily have been included in this abstract and is hopefully made more clear in the actual published article.

Now...despite that critique...I am a huge fan of neoadjuvant treatment.  More and more, it is looking as though melanoma peeps treated in this way do better.  But, if nothing else, neoadjuvant treatment (treatment BEFORE surgical resection) provides decreased tumor bulk, therefore minimizing the invasiveness of the surgical resection.

You know me, Keep'n it💯!!!!!!!!!!  ~ les