Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

Here's a link to the nice little ad (I mean announcement!!!):  ARRAY pharma gains FDA approval for the Encorafenib/Binimetinib

Here are prior posts on the combo: 
This from May 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 

My review: 
PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.

This from March 2018:  Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!

Here are some snippets from that post:
I report this again only because "they" are!  Institutions, Big Pharma, and researchers like to have their name in lights.  So, I will shine my spotlight once again!  I reported on and evaluated the results of the COLUMBUS study here, back in May of 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 
Now that title statement, is absolutely true and good!!!  In that report, I went to the trouble to look up these stats:

From The coBRIM trial - August 2016 we learned - that when cobinmetinib and vemurafinib were combined, the median overall survival (OS) was 22.3 months and the median progression free survival (PFS) was 12.3 months.

From this discussion of BRAF/MEK and immunotherapy (Nov 2016)  we learned = that generally treatment that was a combination of a BRAF inhibitor and a MEK inhibitor could illicit a response rate of 48-59%, even as much as 70% with some combo's and PFS of 11-12 months.

So, yes...the encorafenib with vemurafenib combo has a better PFS than the combo's noted above ~ at least in this study of the 192 BRAF positive unresectable/metastatic Stage IIIB/C or Stage IV peeps  who were given it below.....

[The abstract followed (you can see it for yourself via the link above).] My synopsis:

But...  Here are some comments I made (in red) in the prior post which provides more info about the trial and trial results than this re-run abstract just posted in the Lancet:

Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial. [Why the hell not???? You could put them in their own separate group, so as not to sully your results Array CEO person!!! And still give them access to the drug!]

In Part 1 of the study, the median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for vemurafenib alone. The improvement in PFS represented a 46% reduction in the risk of progression or death. [That's good, but of course we have learned never to give vemurafenib, a BRAF inhibitor without a MEK inhibitor!!! So that's a bit of a false comparison!]

The objective response rate (ORR) with the combination was 63%versus 40% with vemurafenib. [Again...not comparing apples to apples...we KNOW that response rates are better with a BRAF/MEK combo!!!] With single-agent encorafenib, the ORR was 51%. [This fact can at least be compared to single agent vemurafenib response rate of 40%.]

Grade 3/4 AEs were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. [As previously demonstrated, side effects were DECREASED with a BRAF/MEK combo.]

Okay.  My synopsis is this:  Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS.  This combo showed a PFS of 14.9 months.  Objective response rate was 63% with the comb0.  There was an ORR of 51% to encorafenib alone.  Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending.  OS data for encorafenib/binimetinib has not yet been reported.  OS in most other BRAF/MEK combo's is around 2 years.  The combo discussed here demonstrated fewer side effects than when the BRAFi component was used alone....which is consistent with other reports using a BRAF/MEK combo vs BRAFi alone.

PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.  Hang tough ratties.  You will save us all. - c

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So....yep.  Pretty good sum up, I'd say.  STILL have no OS data.  Which is possibly good...in that they are having to watch it a long time, because these ratties are still trucking!  Or, possibly not good...and Array and the researchers just haven't wanted to put it out there yet!  (Oh, yeah...I'm definitely in the pocket of Big Pharma, right?  Just a little inside MPIP humor there!!!)  Hopefully, those numbers will be good and the Encorafenib/Binimetinib BRAF/MEK combo will be an improvement over current BRAF/MEK combo's for BRAF positive melanoma peeps.  However, the problem with this trial is just as it so often is with others: 
1.  We don't compare apples to apples. 
2.  We leave out folks (brain mets, LMD, ocular, and mucosal melanoma patients) in serious need....cause WHY????  (Yeah, I actually know.  Those folks do not respond as well to most current therapies and make your products look bad don't they Array, BMS, Merck...and all the rest of you???) 
3.  We don't base trial questions on what we already KNOW!!!
4.  Results are slow in coming.
5.  We saw the same logs over and over.

_______________________________________________
Now, BACK TO TODAY ~ I don't think this approval is necessarily a bad thing at all!!!  But....I do believe in truth in advertising.

Here are a few more deets from the package insert:  OOOOOPS!  Is Array inept or not providing full disclosure???!!!  Cause.....no matter how I look it up, I have not succeeded in finding a working link to the prescribing info for BRAFTOVI, only the one for MEKTOVI seems to be working.  So, I'll suffice it to say that these are basically new BRAF/MEK inhibitors that should be given together for folks with BRAF positive (V600E or V600K) melanoma which is about half of us.  They are administered orally.  They come with about the same side effect profile as all the other BRAF/MEK combo products. 

Here's hoping that many melanoma peeps benefit from the combo.  Here's hoping that someday, clinical trials will be set up in such a way that folks who MIGHT benefit are NOT excluded, that apples are compared to apples, that pharma will realize that we ratties are NOT stupid and can see very clearly when they stack the deck in their favor.

For what it's worth. - c

BRAF/MEK combo's for melanoma analyzed ~

About half of melanoma patients are BRAF positive.  A strange delineation that I tried to explain in 2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!  Only melanoma peeps who are BRAF positive will gain an effect from the BRAF/MEK combo (targeted therapy).  Since 2010, ratties have taught us much about how targeted therapy works and should be used.  Back in the day, we didn't realize that combining a BRAF inhibitor with a MEK inhibitor led to fewer side effects and greater efficacy.  Or that alternate dosing could help avoid resistance.  Or how best to handle side effects.  Now there are many combo's available for use as targeted therapy.  But, as no direct comparison studies have been made - what combo is best?  Now, there's this:

Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma.  Hamid, Cowey, Offner, et al.  Cancers (Basel). 2019 Oct 24.

No head-to-head studies exist comparing BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) combination treatments for BRAF-mutant melanoma. A side-by-side analysis of randomized phase III trials is presented that evaluated dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. The baseline characteristics, efficacy, and safety were compared: COMBI-v (dabrafenib/trametinib versus vemurafenib); coBRIM (vemurafenib/cobimetinib versus vemurafenib); and COLUMBUS (encorafenib/binimetinib versus encorafenib and vemurafenib). Vemurafenib was the control arm in all studies. The data sources included literature databases, European public assessment reports, U.S. Food and Drug Administration review documents, and prescribing information. The baseline characteristics were similar, except for coBRIM, which had a higher proportion of patients with elevated lactate dehydrogenase (LDH) levels. The median progression-free survival (PFS) and overall response rate (ORR) were similar across the trials, although numerically higher values were observed with encorafenib/binimetinib. In contrast, the median overall survival (OS) was numerically longer with encorafenib/binimetinib (33.6 months) compared to dabrafenib/trametinib (25.6 months) and vemurafenib/cobimetinib (22.3 months). Among vemurafenib arms, PFS, ORR, and OS were similar, despite variations in the baseline LDH. Each combination displayed a unique safety profile, with higher incidences of pyrexia with dabrafenib/trametinib and photosensitivity reactions with vemurafenib/cobimetinib. This analysis of BRAFi/MEKi combinations for BRAF-mutant melanoma, while limited as not a direct head-to-head clinical trial, highlights the differences in tolerability and efficacy that may be useful for therapeutic decision making.

So, there you have Hamid's take on comparing three of the BRAF/MEK combo's.  Their conclusions were pretty similar to my own in this post from 2018:  Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

Then, there's this:

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.  Holbrook, Lutzky, Davies, et al. Cancer. 2019 Oct 28.

Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.  A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates; the clinical benefit rate; the time to response; the duration of response; and safety.

A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.

Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

Okay.  Good.  But, I don't find these results that "new".  Small numbers were evaluated and we already knew BRAF/MEK worked in the brains of folks with BRAF positive melanoma.  To me, the best "news" of the article is that even those previously treated with BRAF/MEK were able to gain a response.  

Finally, there's this:

Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma.  Ribas, Daud, Pavlick, et al.  Clin Cancer Red. 2019 Nov 15.  To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF V600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). Median OS was 31.8 months in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. A subset of patients with advanced BRAF V600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Again.  Nothing really new here.  As I noted at the start, we have known for years now that folks treated with a BRAF/MEK combo do better than those treated with BRAFi alone.  The best take away from this, is the fact that given targeted therapy is known to have responses that are less durable than those for responders to immunotherapy - overall survival plateaued at 39% at 4 and 5 years out.  Something amazing ratties like Dick K (aka Richard K - thanks to spam blockers) have been demonstrating for some time.  NOTE:  For additional comparison, this post includes a report on the 5 year outcomes for the Dabrafenib/Tramedtinib combo:   Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

Hang tough ratties.  You save us all! - c

Primer for Current Melanoma Treatments - New and Improved Version 2022!!!!

Originally posted in 2017, sadly, this primer has needed little in the way of updates since.  Still, there have been a few FDA approvals, meds I didn't include in the first rendition, and some news in the research so it is getting a reboot. Initially created to save re-writes for those in need, I still answer melanoma questions on boards or via email at least every other week, but want to emphasize that this is not an all inclusive listing.  Rather, this is a basic guide to use in starting your research or discussions with your provider regarding melanoma care.  As recently, as 2010, NONE of the current, most effective treatments for melanoma were FDA approved.  Since then, doctors have become more knowledgeable about consistently offering and better skilled in managing these treatments.  Still, it is essential that you be seen by an oncologist who specializes in, or at the very least, has treated many patients with melanoma.  Sometimes a picture is worth a thousand words ~ 

Here we go:

SURGERY

Surgery remains a good choice for many melanoma patients.  Clearly this is the case for a new cutaneous lesion.  Surgery results in an immediate decrease in your tumor burden - almost always a good thing.  However, with data showing good results in NEO-adjuvant treatment, the possibility of using intralesional therapy, or if you are looking for a clinical trial, there are times when measurable disease is needed, so a discussion of these things before surgery is important.  However, for patients with advanced disease decreasing tumor burden through surgery remains an important option for increased survival.  This 2019 report addresses some of the conundrum:  Cut it out!!! Prolonged overall survival following metastasectomy in Stage IV melanoma 

RADIATION

Radiation, when combined with immunotherapy or targeted therapy, can be a very good treatment option for melanoma.  Together, radiation and systemic therapy can illicit responses that are greater than either treatment used as a single agent.  However, targeted radiation (SRS - stereotactic radiation or Gamma Knife) is the most effective whether you are talking about brain tumors or lesions in the body.  We have learned that whole brain radiation (WBR) is not the most effective way to treat melanoma and can lead to debilitation.  While there are those who must avail themselves of this treatment due to extreme circumstances, it should not be the first recommendation right out of the box for those with brain tumors.  Even multiple brain mets can be treated simultaneously with SRS.   Here are zillions of reports regarding the effectiveness of using radiation WITH immunotherapy: Radiation WITH immunotherapy  Here is a report from 2019 regarding the use of radiation prior to targeted therapy:  Better melanoma results with radiation BEFORE BRAFi (at least in this report)

IMMUNOTHERAPY

These are treatments that push our immune systems into action.  Side effects (as you might imagine) are usually related to an 'over activation' of the immune system.  Common side effects include - fatigue, rashes, joint pain.  More complicated side effects are inflammation of the lungs (pneumonitis) and colon (colitis) with difficulty breathing and wheeze or diarrhea and abdominal discomfort, respectively.  Patients can experience problems with thyroid function and other glands of the endocrine system.  Responses take time.  Experts are known to advise other docs to be 'patient with the patient!'  Immunotherapy works best with the lowest tumor burden.

Old school immunotherapy

Interferon

Discovered in 1957, interferons are a type of signaling proteins released by cells in response to viruses, bacteria, parasites, and tumors that help rally the immune response of the body against these invaders. In the early 1980's researchers and pharma were finally able to produce interferon for use as a medical therapy. There are many forms, used in treating various conditions (some more effectively than others) from multiple sclerosis to leukemia to melanoma. Often given as subcutaneous injections (though there are eye drops and inhalation forms), interferon causes significant side effects with fatigue, flu-like symptoms, hair loss, pain, depression and increased risk of infection due to neutropenia (decreased white cells) being common. Unfortunately, we have learned that in melanoma, interferon has a clinically insignificant effect on progression free survival as well as overall survival.

IL-2 (Interleukin 2) also known as aldesleukin, proleukin, and/or sylatron

Similarly, IL-2 is a signaling molecule that directs the actions of white blood cells in getting rid of invaders. Isolated in 1979, by the early 80's pharma (Ceta, Amgen, Roche) were in a mad dash to get a drug to market. It was FDA approved in 1992. It has been used in the treatment of HIV, renal cell carcinoma, and melanoma. Though it can be injected subcutaneously on an outpatient basis, in melanoma it is most often given in an IV infusion, with side effects (extreme swelling, rash/peeling skin, hallucinations, among other horrors) such that patients must be in the hospital, in an intensive care setting, for infusions that are given every 8 hours for up to 15 doses or as the patient can tolerate. It is also used in a low dose regimen with old school TIL therapy as a way to jump start the immune system after chemo has been given to eradicate existing regulatory T cells and new T cells grown from the patient's tumor have been infused.  See this 2021 report:  TIL - A report out of ASCO 2021 and incredible words from one of Melanoma's Most Fearless and Inspiring Leaders  It is also being studied as an intralesional (see below). Ultimately, we now know that the use of high dose IL-2 in melanoma can produce a complete response in about 5-6% of the patients, with some of those responses being durable (lasting).  

Current Immunotherapy (also referred to as Check Point Inhibitors)

Ipilimumab (Brand name = Yervoy, slang = 'ipi') – anti-CTLA-4 monoclonal anti-body

Ipilimumab is a monoclonal anti-body that is used to restart the immune system by targeting CTLA-4, a protein receptor that actually turns the immune response OFF!!! The concept of using anti-CTLA-4 antibodies to treat cancer was developed by Dr. James Allison, for which he was awarded a Nobel Prize in 2014.  It was approved for melanoma (Stage IV or unresectable Stage III) in 2011. It was approved as an adjuvant treatment for melanoma in 2015. However, we have since learned that melanoma patients with advanced disease respond much better to the ipi/nivo combo rather than ipi as a single agent and folks in need of adjuvant therapy do much better with one of the anti-PD-1 products.  Ipi as a single agent was administered via an IV infusion every 3 weeks, for a total of 4 doses, at 3mg/kg for Stage IV patients and 10mg/kg for adjuvant therapy. Some adjuvant treatment plans continued ipi at that same dosage but every 12 weeks for up to 3 years. Melanoma patients given ipi can attain a response rate of about 15%. Responses can be durable.   Patients experience more side effects with ipi than they do with anti-PD-1 products and ipi is the bad boy of side effects in the ipi/nivo combo.  Ipi at 10mg/kg produces more side effects than ipi at 3mg/kg.  The ipi/nivolumab combo was FDA approved in (2015).  In that treatment, patients are given an infusion of ipi at 3 mg/kg after nivo at 1mg/kg is given on the same day, every 3 weeks, for 4 doses, followed by one year of nivo as a single agent. 

Anti-PD-1 (Brand names = Opdivo and Keytruda, Nivolumab and Pembrolizumab respectively.)

      

Background:  PD-1, also called programmed cell death protein 1, is a membrane protein and a T cell regulator, first discovered to be an immune checkpoint in 2000.  PD-1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or digestion of debris or pathogens). Compared to CTLA-4, PD-1 is keyed to specific tissues with the PD-L1 ligand, while CTLA-4 is less specific.

PD-L-1 is a ligand present on the surface of melanoma tumors (as well as some others) that can bind to infiltrating t-cells and turn them off!!

  

ANTI-PD-1 (the drugs) are monoclonal antibodies that block the switch on T cells so that PD-L1, on the surface of melanoma tumor cells, does NOT bind with them and turn them off....thereby allowing these cells to carry on and destroy melanoma tumors.

Sometimes pictures tell the story better:

    Nivolumab: (Brand name = Opdivo, slang = 'nivo') - anti-PD-1 monoclonal antibody

I wrote a little story about the development of nivo here, but basically, in 2014 Nivo was approved for the use in advanced melanoma patients only AFTER they had failed ipi and, if BRAF positive, BRAF inhibitors as well.  In November 2015 it was approved as a first line drug for unresectable or advanced melanoma BUT you had to be BRAF positive.  (A cosmically ridiculous judgement since we already had studies proving that BRAF status made little to no difference in response!!)  Finally, in 2016, based on the results of the  Checkpoint-067 study, nivo was approved for use alone or in combination with ipi, in advanced melanoma patients, no matter BRAF status.  And in 2017, it gained approval as an adjuvant treatment option.  This was seriously good news!!!  It meant even if you are Stage IV with all tumors removed (or zapped) - you can still take nivo.  Or, if you are Stage III with melanoma that went to your lymph nodes - you can take nivo!   Since then, nivo has also been approved for use in NSC lung cancer, urothelial and renal cell cancers, gastric and esophageal cancers, hepatocellular carcinoma as well as head and neck cancers.

      Pembrolizumab: (Brand name = Keytruda, slang = 'pembro') - anti-PD-1 monoclonal antibody

Pembro was similarly approved for advanced melanoma in 2014.  Since then it has been approved in various algorithms for NSCLC, head and neck squamous cell cancers, Hodgkins lymphoma, and endometrial cancers.  In 2019, it was approved for adjuvant treatment of Stage III melanoma and for Stage II adjuvant melanoma in December of 2021.

Response rate and side effects for advanced melanoma patients:

Both anti-PD-1 drugs as single agents effect about a 40% response rate in melanoma. They can work in the brain and the body.  Median time to response is about 3 months.  But, there are outliers, with documented responses, that do not occur until 6 - 9 months.  Here's a cool graph...

Here's a post with more info: Time to Response...Ipi vs Nivo and ipi 

Responses to immunotherapy have proven to be durable!!!   This post includes neat charts regarding response and durability to Pembro: Dr. Daud review from ASCO 2016   There is this from 2020:  Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice  And this from 2021:  ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

Side effects are similar for both drugs and are those typical for immunotherapy, but less severe than those encountered with ipi.  As expected, the ipi/nivo combo has greater side effects than when nivo or pembro are used alone.  On the topic of side effects...they SHOULD be treated!!!  As quickly as possible.  At times, a break from medication and immunosuppressive drugs are required.  While oncologists not familiar with immunotherapy may fear decreased therapeutic response if steroids are used...the preponderance of the data indicates that THIS IS NOT THE CASE!!!!  Clearly, one should not take immunosuppresive drugs unless absolutely needed.  Many patients require varying doses of steroids in order to tolerate necessary, life saving melanoma treatments  and go on to do well!  Further, folks with pre-existing autoimmune disease can be managed on immunotherapy and gain a response as well.  Here are a zillion reports on all of that jazz:  What to do about immunotherapy if you need steroids or have a pre-existing autoimmune disease?

Dosing:

When Pembro is used as a single agent = is dosed at 2mg/kg with max of 200 mg IV every 3 weeks - for one year as adjuvant, end point undefined for advanced melanoma patient.  Nivo as single agent = is dosed at 240 mg IV every two weeks or 480mg IV every 4 weeks - for one year as adjuvant, endpoints vary for advanced melanoma patients. When ipi is combined with nivo, response rates in melanoma rise to 50+%, though side effects increase as well - mostly due to ipi.  For the combo, dosage is:  nivo at 1 mg/kg followed by ipi at 3 mg/kg on the same day, every 3 weeks for 4 doses, then nivo alone at 240 mg q 2 wks or 480 mg q 4 wks. endpoint varies. Many patients cannot tolerate all 4 doses of the ipi/nivo combo due to side effects.  However, outcomes can be good even if you have to stop early. Here's a report from ASCO 2016:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  Further, the ASCO 2021 data (link above) notes "Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N."  Finally, most folks who cannot tolerate the combo can go on to tolerate nivo alone, once their side effects are brought under control with a medication break and/or steroids.  

   Anti-PD-1 (Opdivo) plus Anti-LAG-3 (Relatlimab):

In March of 2022, Relatlimab (an anti-LAG-3 drug) was approved in combination with Nivolumab for advanced melanoma patients in the form of a new drug combo - Opdualag.  Here is a report that covers lots of pertinent data- FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

TARGETED THERAPY

At this point in melanoma, the only approved targeted therapy is for patients whose tumor is positive for the BRAF V600 mutation.  About 50% of melanomas are.  However, researchers are looking at drugs that could target other points in the molecular pathway of melanoma.  This diagram shows what I mean by "pathway"...

A Melanoma Molecular Disease Model (See the link below for credit and more info)

Here's just one example from March of this year:  What tangled 'paths' we weave: Nilotinib for KIT mutated melanoma and Buparlisib for the PI3K pathway in melanoma brain mets

But....for current purposes....I am focusing on the BRAF mutation.  Here's a post I made a bit ago that really breaks down what BRAF is, what it means in melanoma, and how the drugs work:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

Usually when we combine drugs, we end up with increased side effects. However, in the case of BRAF targeted therapy we now know that BRAF inhibitors should ALWAYS be given with a MEK inhibitor.  Strangely enough, when the combo is given, patients experience better response rates, DECREASED side effects, and DECREASED rates of tumor work-around.  The only exception is when MEK inhibitors are used as a single agent in specially mutated patients.

DRUGS, administration, and side effects:

BRAF inhibitor (BRAFi) drugs include:  Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Sorafenib (Nexavar), and Encorafenib (Braftovi)
MEK inhibitors (MEKi) include:  Trametinib (Mekinist), Cobimetinib (Cotellic) and Binimetinib (Mektovi)

These drugs are administered orally.  So that's super cool.  Dosing depends on the particular drug.
Side effects include joint pain, rashes, extreme sun sensitivity, development of benign skin cancers, fevers and sometimes liver toxicity.

EFFECTIVENESS and tumor work-around:

For patients who are BRAF positive, BRAF inhibitors combined with a MEK inhibitor have impressive response rates, clearing tumors rapidly, and often completely, in about 70-80% of patients and are effective in the brain and body. However, those responses are not very durable, with most tumors learning to work around the inhibition in about 7-9 months. BUT!!!!  By using an "alternate dosing schedule" (one that is varied, rather than absolute with an 'every so many hours daily' dosing pattern), combining BRAFi with MEKi, as well as the development of the newer drugs that time can be stretched out a bit.  Furthermore, despite the statistics, there are some melanoma peeps whose melanoma has been successfully managed for years on BRAF/MEK combo's!!  Finally, some melanoma specialists use BRAF/MEK combo's in BRAF positive patients, to rapidly decrease the tumor burden, then switch the patient to slower acting, but more durable immunotherapy.  Picking which targeted therapy to use can be difficult.  Here are two posts that attempt to pull response rates and PFS out of the data ~

From 2018:   Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

From 2019:  BRAF/MEK combo's for melanoma analyzed ~

IMMUNOTHERAPY COMBINED WITH TARGETED THERAPY -

In 2020, the PD-L1 blocking antibody Atezolizumab (Tecentriq) combined with Cobimetinib (Cotellic) and Vemurafinib (Zelboraf) was FDA approved.  Here is a report from 2019 that links to other reports on combining targeted and immunotherapies and includes data from the early atezo/BRAFi/MEKi trials - Treating melanoma by COMBINING targeted therapy AND immunotherapy!

INTRALSIONAL (also referred to as 'intratumoral') THERAPY

Intralesional drugs include (but are not limited to):

T-VEC - also called OncoVEX, Imlygic, or Talimogene Laherparepvec - uses the herpes virus with GM-CSF and is the only intralesional currently FDA approved (2015)  However, the following (and others) have been used in clinical trials:
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 - see note above, is also being used

These drugs are injected directly into a relatively superficial melanoma tumor.  They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy.  I summarized response rates, side effects, and pretty much everything else current about these drugs in these posts which include many links within them: 

From 2021 - Intralesionals for melanoma - some new reports

Out of ASCO that year - Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

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I hope this primer will continue to be a helpful jumping off point for those in need.  What has served me best in attaining effective treatment for my melanoma has been seeking out a melanoma specialist (or at least an oncologist who cares for many melanoma patients) and never being afraid to ask questions. Asking this question of my doctor may have been the most beneficial:  "What treatment would you recommend if it were YOU or your brother, sister, wife, father, mother.... in need?"

I wish you all my very best. Hang in there.  And as ever, with enduring thanks to the ratties! - love, c

P.S. If all the acronyms are driving you crazy, here's a post that defines at least some of them:  Melanoma abbreviations ~ and random thoughts on posting melanoma crap-ola....
P.S.S.  A sense of humor really does help!!  AND FINALLY - while not all inclusive, this post from 2019 includes a list of world class melanoma specialists:   Internationally renowned melanoma specialists:  - c