Melanoma Intel: A primer for current standard of care and treatment options

I answer questions on melanoma boards or via email about treatment options at least every other week. It suddenly dawned on me that putting the information together in a blog post would save me repeated re-writes and help folks in the process.  HOWEVER, 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.  It is also primarily directed toward those of you who are Stage III/IV.

As recently as 2010, NONE of the current, most effective treatments for melanoma were FDA approved. And no matter what option you think fits you best, it is essential that you be seen by an oncologist who specializes in...or at the very least, has treated many patients with...melanoma.  Here's the down and dirty:

SURGERY

Surgery remains a good choice for melanoma. Clearly this is the case for new cutaneous lesions!!! Once a lesion is gone...it's gone!! This results in an immediate decrease in your tumor burden – always a good thing. However, if by chance you are looking for a clinical trial (though these days, especially for newly diagnosed Stage 3b and Stage IV patients, there are many viable treatment options without resorting to that) they sometimes require “measurable disease” so leaving at least one tumor in place would be required. This would also be the case if you were looking to utilize 'intralesional therapies' {info below}.

RADIATION

Radiation, when combined with immunotherapy, can be a very good treatment option for melanoma. Together, radiation and immunotherapy, illicit responses in melanoma 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 located elsewhere in the body. We have learned that whole brain radiation (WBR) is not effective in melanoma and can lead to debilitation. While there are those who avail themselves of this treatment due to extreme circumstances, it should not be the recommendation right out of the box for those with brain tumors. Even multiple tumors can be treated simultaneously with SRS.

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 our immune system. Common side effects include – fatigue, rashes, joint pain. More complicated side effects are inflammation in 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)

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 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.  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!!! It was approved for melanoma (Stage IV or unresectable Stage III) in 2011. It was approved as an adjuvant treatment for melanoma in 2015. Ipi is 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 continue 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.    Here are two resports:  Melanoma patients...alive and kicking 10 years after ipi!  and  Ipi for melanoma...the data keeps pouring in...and it's pretty good!  Patients experience more side effects with ipi than they do with anti-PD-1 products.  Ipi at 10mg/kg produces more side effects than ipi at 3mg/kg.  Ipi is also FDA approved in combination with nivolumab (2015) and is being studied currently in combination with pembrolizumab. {More info below.}

Anti-PD-1

      

First you have to understand that 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 (You can read it here!!), but basically, in 2014 Nivo was approved for the use in advanced melanoma patients 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 with ipi, in advanced melanoma patients, no matter BRAF status.  It gained approval in 2017 as an adjuvant treatment option for patients with melanoma!  This is seriously good news!!!  It means 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!

From the November 2015 link - Here are more ways Opdivo has been approved and is helping others:

• Advanced renal cell carcinoma (11/23/2015)
• Advanced non-squamous non-small cell lung cancer - after platinum based chemo (10/9/2015)
• In the Nivo/Opdivo with Ipililmumab/Yervoy combo for BRAF V600 advanced melanoma (10/1/2015)
• Advanced non-small cell lung cancer - after platinum based chemo (3/4/2015)
• For melanoma, after failing ipi, and if BRAF positive, BRAFi (12/22/14) 

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

Pembro was similarly approved for melanoma in 2014.  Since then it has been approved in various algorithms for NSCLC and head and neck squamous cell cancer

Response rate and side effects for advanced melanoma patients:

Both anti-PD-1 drugs 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 can be durable!!!  There is every reason to expect that responses to anti-PD-1 will be at least as durable (and probably more so) than those to ipi.  This post includes neat charts regarding response and durability to Pembro:  Dr. Daud reviews ASCO 2016 - immunology updates for melanoma

Side effects are similar for both drugs and are those typical for immunotherapy, but less severe than those encountered with ipi. On the topic of side effects...they SHOULD be treated!!!  As quickly as possible, often with a break from medication and immunosuppressive drugs as required.  While oncologists not familiar with immunotherapy may fear decreased therapeutic response if steroids are used...THIS IS NOT THE CASE!!!  Here's a post (with multiple links within related to treating immunotherapy side effects:  Yep! Immunotherapy can work in the brain...and pseudoprogression can be real!!

Dosing:

Pembro is dosed at 200 mg IV every 3 weeks.  Nivo is dosed at 240 mg IV every two weeks or 480mg IV every 4 weeks, endpoints vary per doc, patient and institution. When ipi is combined with nivo, response rates in melanoma rise to 50+%, though side effects do as well, though 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. 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:  Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  Additionally, most folks can go on to tolerate nivo alone, once their side effects are brought under control with a medication break and/or steroids.  Pembro in combination with ipi is being studied.

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.

DRUGS, administration, and side effects:

BRAF inhibitor (BRAFi) drugs include:  Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Sorafenib (Nexavar), and Encorafenib
MEK inhibitors (MEKi) include:  Trametinib (Mekinist), Cobimetinib (Cotellic) and Binimetinib (not yet given a brand name)

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 (Here's a post out of ASCO this year:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS) 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.  And...in the realm of 'the latest and greatest', researchers are working on combining BRAF/MEK with immunotherapy.  Here's a recent post on the topic with more links within:  ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

DECIDING on immunotherapy vs targeted therapy in the BRAF positive patient - can be tricky! Here is a post addressing that issue via a discussion between melanoma experts:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

INTRALSIONAL (also referred to as 'intratumoral') THERAPY

Intralesional drugs include (but are not limited to):

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 this post from this year's ASCO reports on all of them: All things intralesional/intratumoral

FUTURE TREATMENT OPTIONS

Despite the success that these therapies have had for many melanoma patients, myself included, they are insufficient for far too many!  Luckily, research and drug development continues.  Many researchers have noted that combo's are likely to be the future of melanoma treatment.  Work is ongoing on IDO inhibitors, ERK inhibitors, vaccines (though I fear we are not there yet), new anti-PD-1 and anti-PD-L1 drugs, anti-LAG-3, CD47 blockers, HDAC inhibitors, and more.

I hope this primer will be helpful.  What has served me best in attaining effective treatment for my melanoma has been seeking out a melanoma specialist 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....thanks, 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!!  - c