ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

Okay.  One of the many zillion dollar questions in melanoma (for those who are BRAF positive) is:  "What treatment should I do first ~ BRAFi or immunotherapy?"  Right now [SPOILER ALERT!!!] we don't know, though the report below is trying to figure that out (at least for Stage III patients). And before I get to the report/ad for the study now enrolling:  Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma (NeoTrio)  ...here's a little review on adjuvant vs NEOadjuvant treatment.

In adjuvant trials or treatments, like the one I participated in, the melanoma patient must have all of their "measureable" melanoma removed.  (Would that we really could have ALL of our melanoma removed!!!) In real terms this means that all positive nodes or lesions that are visible on scans are surgically removed.  Additionally, though it depends on the study, if one has brain tumors, patients can have them zapped and if, over a certain period of time (this varies study to study) they do not recur, and the area fails to light up on subsequent scans, the patient may join the adjuvant trial/treatment, at which time they are given the treatment du jour.

In NEOadjuvant treatments/studies, patients keep the lesions they have and start the treatment du jour.  Sometimes after a certain amount of therapy the lesions are then removed, if they have not evaporated with the treatment, sometimes not.

Here is a March 2018 report I put up:  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.  Clearly you can read the entire report and abstract for yourself, but this was my take:

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.

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One more pertinent side note - Researchers have been working on seeing how things go for melanoma patients who are treated with immnotherapy (like anti-PD-1) COMBINED with targeted therapy (BRAF/MEK) for a while now.  Here are some reports:  ASCO 2017 (with links to the "whole she-bang") BRAFi and anti-PD1/PD-L1

Now, there's this:

Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: A phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial). Gonzalez, Menzies, Saw, ... Georgina V. Long. ASCO 2018. 

Background:  BRAF targeted and CTLA-4/PD-1 immunotherapies have high response rates and improve survival for patients (pts) with metastatic melanoma, however, most still die of this disease. It is hypothesised the activated cytotoxic T cell infiltrate that occurs early during treatment with BRAF/MEK inhibitors is potentiated by adding checkpoint inhibitors, resulting in improved response and survival. While trials combining BRAF/MEK inhibitors and anti-PD-1/L1 antibodies are underway in the metastatic setting, the neo-adjuvant (neo-adj) setting provides an opportunity to test different treatment schedules in small cohorts of pts. Tissue and blood biomarkers can be drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response, biomarkers of efficacy, and to select the best schedules to take forward to larger-scale trials.

Methods: Eligible pts with BRAF V600 mut, stage IIIB/C/D, resectable and measurable melanoma are evenly assigned to 3 cohorts (n = 60). All pts undergo complete macroscopic resection (RES) at wk 12 and receive neo-adj therapy for 12 wks preceding RES, followed by 40 wks of adjuvant (adj) therapy. Cohort 1 receive sequential therapy with D+T for 2 wks, then 4 pembrolizumab (pembro) doses until wk 12, and 3 wkly pembro after RES. Cohort 2 receive concurrent D+T and 3 wkly pembro before and after RES. Cohort 3 receive 3 wkly pembro for the entire treatment course. Pembro is given at a flat dose of 200mg. Ultrasound of known disease areas is undertaken during the neo-adj period. CT and FDG PET/CT are used to measure response and exclude progression in theneo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, wk 1, 4 and 12. The primary endpoint is the complete pathological response rate at RES following 12 wks of therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analysis. First patient enrolled 29Nov2017. Clinical trial information: NCT02858921

Best as I can tell they are going to take 60 Stage III patients with measureable disease, and put 20 into each of 3 groups.  The groups are treated as noted below, per ClinicalTrials.gov
Group 1 = 
  Sequential D + T, THEN Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 2 weeks, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 2, 4, 6, and 9, then once every 3 weeks from week 12 for 50 weeks
Group 2 = 
 Concurrent D + T AND Pembrolizumab

Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks

Group 3 = 
Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.

It seems to me that they should have offered immunotherapy followed by BRAF/MEK in a Group 4, so there could be a complete answer, but I guess that's just me.  CT's and PET/CT's along with blood and tumor sample testing will be used to follow patients and determine results.

Important stuff.  Good luck, ratties.  And...thanks. - c