ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....

Over the next bit, I am going to be digging into a presentation by Dr. Jeffrey Weber - see it for yourself here:  Immunotherapy for cancer: the journey so far, and where are we headed? Cancer Crosslinks 2018

With so many Stage III melanoma patients now gaining access to adjuvant care and all the inherent questions pertinent to that, combined with the fact that adjuvant treatment is what I attained for my melanoma journey, albeit as a Stage IV patient, I will start there.  Before we get into the weeds, here is an overview of current approved therapies for melanoma I wrote in 2017 that sadly, other than a change in dosing options for the administration of Opdivo, has not needed any significant updates since:  Melanoma Intel: A primer for current standard of care and treatment options
Here is an article that does pretty much the same thing, written in 2018:  Melanoma treatment in review

LATE ADDENDUM:  FINALLY!!!! There was reason to update the primer - April 2022 - Primer for Current Melanoma Treatments - New and Improved Version 2022!!!!

I recently penned some information for a Stage III patient dealing with the confusion that a melanoma diagnosis and adjuvant treatment can engender, and it seems a pretty good place to start:

It is very easy to get confused with all the "data" floating around.  Numbers repeated in the media (as opposed to medical literature) and unfortunately even occasionally tossed around in doctor's offices without clear explanation can create more confusion than clarity.  One of those oft quoted bits is the "50% survival rate" of melanoma patients vs various low rates from 10-20-something % that "melanoma patients used to have".  All of this can get confusing really quickly because you have to make sure you are talking about the right drug, used in folks in the stage you are discussing AND the right category of "response". Are the studies describing "response rate", "progression free response", "overall survival", or what?????? Those categories can mean very different things.  Further, I've seen lots of patients misunderstand the significance of the FDA approval dates for both targeted and immunotherapy as ADJUVANT vs the date of their approval for melanoma overall.  

Here's a little breakdown of FDA approval dates:

The first targeted therapy for BRAF positive melanoma patients was approved in 2011.  Targeted therapy for adjuvant use in melanoma was approved in 2018.

The first effective immunotherapy with its 15% response rate in Stage IV melanoma was ipilimumab (Yervoy - an anti-CTLA-4 product) ~ approved in 2011.  Its approval for use as adjuvant was in 2015.

Anti-PD-1 immunotherapy products, Nivolumab (Opdivo) and Pembrolizumab (Keytruda) were approved for unresectable/Stage IV melanoma in 2014.  Both have roughly a 40% response rate in those patients with a similar side effect profile that is less severe than that of ipi.  Opdivo was approved in combination with ipi for metastatic patients in 2015.  That combo is currently in trials as adjuvant.  Opdivo was approved for use as adjuvant in melanoma patients in 2017.  Keytruda was approved for adjuvant use in Stage III patients 2019.  {LATE NOTE:  Keytruda was also approved for Stage II patients in 2021.}

As a person who was likely somewhere between the 28th - 36th person in the United States to take nivolumab, via a clinical trial in the ADJUVANT arm as a Stage IV melanoma patient in 2010!!!!!!!!!!!! - I know from experience that it makes a HUGE difference in having a collection of data and information behind your treatment option and NOT!!!! Here's a little story that tells the history of Opdivo or as I took it - MDX-1106 - if you are interested:  Love Potion...or Patient...#9!!!!! 

The date of FDA approval for use in melanoma patients generally matters - even to those who are using it as adjuvant today.  In the case of Opdivo, it means that under FDA approval (apart from the fact that melanoma ratties in the United States had been taking Opdivo since 2009) melanoma patients were treated with Opdivo since 2014. Studies from us ratties as well as data that grew with the 2014 approval consistently show that folks with Stage III and Stage IV inoperable melanoma have response rates of around 40% when Opdivo is used as a single agent and through that use we learned what dosage to administer, the likely side effects, rare adverse events that might be encountered, how long they last, and how best to treat them. Important information that you do not have when a drug is first being used to treat a particular disease.

In all that trial and error - ie learning - researchers discovered that folks with melanoma responded best to immunotherapy when they had the least possible disease burden. This leads us to adjuvant therapy. Adjuvant therapy is given to a person when their tumor has been removed by surgery and/or radiation. Despite knowing since my trial - though the data wasn't published until 2014 - that we 33 ratties (2 stage IIIC and 31 Stage IV ) did very well when we took Opdivo as adjuvant, the FDA did not see fit to approve Opdivo for adjuvant use in melanoma until 2017. You can see the results of the adjuvant arm of my study here: C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published! 

It notes: "Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up." REMEMBER - we have learned even more since then!!!!!!!!!!!!!!!!!!!! 

Here is a report on ipi vs nivo in the adjuvant melanoma setting from 2017:  Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!!

That study shows ~ Recurrence free survival at 18 months: 66.4% for nivo 52.7% for ipi
OVERALL recurrence free survival was 70.5% for the nivo group (vs 60.8% for ipi) at 1 year...but...when you pull out the Stage IV folks the number was 63% for nivo vs only 57% for ipi.

NOW! When you break things down further, as the info above is beginning to show, folks who are Stage III do better than folks who are Stage IV no matter what you do or don't do to them. So you can't just take all the information gleaned from Stage IV patients and throw it at Stage III patients as fact. For instance, in the last report in this post from 2019, that addresses Stage III melanoma patients treated with Yervoy (which we already KNOW from the other report does NOT work as well for melanoma patients whether Stage III or Stage IV when used as a single agent compared to anti-PD-1) vs placebo noted in this link:  I've said it before, I'll say it again - ENOUGH ALREADY! No more interferon for melanoma!!! (Or placebos - for that matter!!!) You will see that Stage III melanoma patients, even treated only with ipi, had an "overall survival rate of 60% at 7 years". To be fair the placebo group had an OS of 51.3%. Hell, even I lived as a Stage IIIB melanoma patient for 7 years with no treatment beyond surgery before advancing to Stage IV and am still here after brain and lung mets and my nivo trial and remain NED for melanoma.

Bottom line - comparing apples to apples matters. The amount we have learned about anti-PD-1 since melanoma ratties started taking it in the States in 2009 and after it gained FDA approval for use in melanoma patients in 2014 makes a world of difference to all of us.

Now for the report from Dr. Weber, which begins with a review of immunotherapy for melanoma generally:

 Does immunotherapy work for patients with melanoma brain mets?  YES!!!

And with that history, we begin to explore immunotherapy as adjuvant for melanoma -

 This led to an intergroup trial testing 3 vs 10 mg/kg ipilimumab vs IFN-alpha -

Yep - this was me and my fellow ratties.  I was in Cohort 1.

This data justified a trial of adjuvant nivolizumab versus standard ipilimumab -

 NEXT - pilot nivo with ipi data justified a new adjuvant trial of nivo + ipi vs nivo with new biomarkers -

Forgive the blurry slides I've reproduced here.  Check the link at the top to view them for yourselves.  Hope this helps.  We've come a long way, though we have further to go.  Coming soon - the furture of immunotherapy for cancer....
Ratties rock! - c

Melanoma treatment guidelines from Melanoma Big Dogs

As much as we've learned about melanoma, there remains much we do not know.  Yet, even with the limited available treatments, the stage and indications for use, what to do about side effects, what to do next, remains confusing for patients and oncologists alike.  To that end, I put together this primer a couple of years ago:  Melanoma Intel: A primer for current standard of care and treatment options  (Unfortunately, to date, it has required no up-dates other than the dosing schedule for nivo!)

There is also this post regarding adjuvant treatment, including data from a presentation made by Jeff Weber, MD (Melanoma Big Dog extraordinaire!): ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....

And finally, also with the help of Weber's presentation, what may be coming in the way of immunotherapy and other treatments:  The future of immunotherapy and cancer - per Weber

 You can find more articles on most any particular treatment by entering the word in the search bubble to the top left if you are interested.  Now, as we head into ASCO 2020, Melanoma Big Dogs have put together guidelines for the use of systemic therapies in melanoma ~

Systemic Therapy for Melanoma: ASCO Guideline.  Seth, Messersmith ... Weber ... Agarwala, Ascierto ... Faries ... Sondak, et al.  J Clin Oncol. 2020 Mar 31.  To provide guidance to clinicians regarding the use of systemic therapy for melanoma, ASCO convened an Expert Panel and conducted a systematic review of the literature. A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

Click on the link included to search for specifics from the guidelines.  Hang tough peeps.  We're getting there! - c

Why doesn't immunotherapy work for all melanoma patients?

WHY?????  And what should we do when it fails?  Dismaying questions with no clear answers, right?  But, researchers are working on them!

First - what to do when immunotherapy fails?

What to Do When Anti-PD-1 Therapy Fails in Patients With Melanoma.  Mooradian, Sullivan.  Oncology, April 2019.

Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti-PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1-directed therapy is not enough.

You should be able to get the entire article via this link: 
https://www.ncbi.nlm.nih.gov/pubmed/30990567

Note:  We already know that combining ipi with anti-PD-1 provides improved response rates as compared to anti-PD-1 as monotherapy, though for some, even that is not enough.  Here is a primer of basic melanoma treatments I put together that covers some of the treatments described above:
Melanoma Intel: A primer for current standard of care and treatment options

But, back to the first question ~ as Fierce Biotech put it in their article linked here:  What causes immuno-oncology drug resistance? 2 research teams uncover clues! 

The article notes: 

Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.

Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.

First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.  The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.  The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment. 

The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors," said senior author and Sanford Burnham Prebys professor Ze'ev Ronai, Ph.D...

The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.

In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.  The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed "the protein was in fact being made at some point, and that it wasn't being degraded,” senior author Robert Blelloch, M.D,. Ph.D.... said... “That's when we looked at exosomes and found the missing PD-L1."  In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.  They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.  Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.

SO...two very different things are addressed within this article....
1.  The cooties in our gut make a difference.  I've been writing about this for some time.   Here is a recent report with links to many more within:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!    Side note:  Additional studies show that you have to consume the real deal.  Probiotics out of a bottle won't do the trick.  In fact, attaining your cooties that way may actually DECREASE your response to immunotherapy.
2.  The whole PD-L1 positive vs NOT positive thing!  We have long known that having PD-L1 positive tumors does not guarantee a response.  AND... folks with tumors NEGATIVE for PD-L1 can still sometimes gain one!  Here are a bunch of reports addressing the PD-L1 conundrum!

There is also this report on the same research in the NY Times from April: Cancer’s Trick for Dodging the Immune System, where the author notes:

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.  The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.  The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.  The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.  The new study is part of a growing body of research that suggests that even when tumors don’t have this PD-L1 molecule on their surfaces, they are still using the molecule to trick the immune system.  Instead of appearing on the surface, the molecule is released by the tumor into the body, where it travels to immune system hubs, the lymph nodes, and tricks the cells that congregate there.

“They inhibit the activation of immune cells remotely,” said Dr. Robert Blelloch, associate chairman of the department of urology at the University of California, San Francisco, and a senior author of the new paper.  The U.C.S.F. scientists discovered that they could cure a mouse of prostate cancer if they removed the PD-L1 that was leaving the tumor and traveling to the lymph nodes to trick the immune system. When that happened, the immune system attacked the cancer effectively.

Furthermore, the immune system of the same mouse seemed able to attack a tumor later even when the drifting PD-L1 was reintroduced. This suggested to Dr. Blelloch that it might be possible to train the immune system to recognize a tumor much the way a vaccine can train an immune system to recognize a virus.  The work was done not in humans but in laboratory experiments and in mice, and it is not clear whether the results will translate in people. Dr. Ira Mellman, vice president of cancer immunology at Genentech, called the findings “a most interesting result.”  “But as with all mouse experiments, you get insight into basic mechanisms, but how it translates to the human therapeutic setting is unclear,” said Dr. Mellman. He is skeptical, he said, but plans to meet shortly with Dr. Blelloch to discuss the implications of the work.  The new research dovetails with other recent studies, including a paper published last year in the journal Nature that showed that PD-L1 molecules released from skin cancer tumors can suppress the body’s immune function.  When these bits of PD-L1 travel outside the cell, they are known as exosomal, and the discovery of their role is one of many fast-moving developments refining an area of medicine that has become among the most promising in decades.

Late last year, the Nobel Prize was awarded to two scientists — James P. Allison of the M.D. Anderson Cancer Center in Houston, and Tasuku Honjo of Kyoto University in Japan — who did groundbreaking work in immunotherapy.  An explosion of additional research is aimed not only at refining the therapies — which can have profound side effects — but also at searching for other molecules involved in the perilous dance between cancer and the immune system.  Far more study is needed. But Dr. Blelloch said the findings have him looking for ways to take the next steps into turning the discovery into a concrete therapy.  Interfering with the PD-L1 traveling to lymph nodes “can lead to a long-lasting, systemic, anti-tumor immunity,” the paper concluded.

While this research leaves us with plenty of unanswered questions...it is the first in a long while that begins to answer the PD-L1 conundrum!!!    Here's a link to a related article from Nature if you like to read all the science for yourself:  Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response  

Hopefully, more complete answers and treatment solutions will be developed SOON!!!  Hang in there, ratties! - c  

Lucky Bugs!

The minute B got home the other day, he rushed upstairs to tell me this tale.  While shopping in Wally World (I know!!!) he saw a beleaguered dragon fly resting on a box piled with others in the aisle from which a gentleman  was removing items as he stocked the shelves.  Well, in Morris Land, an endangered dragon fly or turtle will never do.  You may remember these stories of Sally: Inauspicious Beginnings  and  Sally the Loggerhead Turtle.  And of course there is the story of the dragon fly: Ratties and Hope

Since all of that is a given, B enlisted the aid of the unsuspecting fellow stocking shelves, and one of his boxes, in shooing the poor critter aboard so that B could anxiously march him outside to freedom.  (I need to ask if the ticket checker at the exit required a receipt!!!)  B reports that the fly looked quite sad indeed, with his legs all akimbo and wings hanging rather limply.  However, with a bright smile on his face, B finished up, "But, once I got him outside, and he saw a tree....BZZZZZZZ!  He just took off!!"

Here he paused to proudly show me this pic!!!

That man cracks me up!!!  I told him he probably unleashed the most amazing dragon fly ever, who had been facing his doom in the frozen nether regions of the Walmart freezer, having been shipped over from Brazil, but now rescued and released, will attack all Zika carrying mosquitoes and save the world from pestilence!!!!

In other news, if you hadn't caught it buried in the "Happy Anniversary" post, I got the results of my scans and remain clear of melanoma, almost to the day I had my first melanoma excised in 2003.  So, I can repeat, with the confirmation of CT's of the neck, chest, abd and pelvis with an MRI of my brain that I am...

156 months (13 YEARS!!!!) post my original melanoma diagnosis in 2003 at age 39
76 months Stage IV (more than 6 years!!!)
70 months NED
68 months after starting nivo (Opdivo)
38 months (more than 3 years) since my last nivo infusion in June of 2013

I attained my lab results as well and my thyroid, adrenal glands, kidneys, and liver all remain in good working order.  The fact that I am cold has NOTHING to do with my thyroid function and EVERYTHING to do with people who keep the air conditioning set too low!!!!  I am not at all anemic with my hemoglobin much better than it ever was during my trial.  Not sure if that had anything to do with my Opdivo treatment.  I suspect it had a lot more to do with incredibly frequent blood draws involving fairly significant quantities of blood as well as blood cell damage from leukophoresis!  Whatever the reason, I'll take it.  My LDH is the low side of normal (118 with norms of 117-242).  For grins and giggles we also had a lipid profile done.  My cholesterol level was not something I had particularly cared about when I figured I was going to die from melanoma, but thought perhaps at this point I should have it checked after all.  There was a little mix up in the processing of it, so last night when I got home from work, I found this note at my desk:

I know who to get to write my "condition of health" letter when I run for president!!!!

I laughed and laughed.  For all that I do exercise and eat healthily, B works much harder and more dedicatedly than I.  And while he does not need cholesterol drugs or anything close, I have to say, I think he was a little jelly!!!

For reference, here's a little primer on a lipid profile:
Total cholesterol measures all the cholesterol in all the lipid particles.  Less than 200 is good.
High density lipoproteins (HDL) is the cholesterol in the HDL particles and is called the "good" cholesterol because it carries excess cholesterol to the liver for removal.  40 and above is good.
Low density lipoproteins (LDL) as you might expect is the cholesterol in the LDL particles and is the "bad" cholesterol as it is the part that can build up in the walls of blood vessels and contribute to atherosclerosis.  Less than 100 is good.  Less than 70 is better.
Very low density lipoproteins (VLDL), also called triglycerides.  These fatty bits help store calories and give you energy, as well as help build cells and hormones, however, they also contribute to hardening of the arteries as they ferry other lipoproteins around.  Less than 150 is best.


All in all, like the dragon fly, I too, am a lucky bug.  Thanks for listening.  I hope you laughed. It has been a tremendously hard time for many of my melanoma peeps lately.  It feels weird to write of my good fortune sometimes, but perhaps it will shine a small light, a little glimmer of hope, for those in need. Thanks to B and all of you who take such good care of me.  Love, laughter and hope to you all. - les

PS....I just got...TODAY....a letter from Blue Cross Blue Shield (Via eviCore...ANOTHER middle man in their lovely system!!) stating they have approved my request for an MRI of my brain.  Today.  My scans were done on the 25th!  Freaks.

PSS....If you would like the gift of a big laugh of pure silliness and joy!  If you are a woman over 30...and even if you are not...you've got to check out Jeanne's blog post from today:  ...or just me... amen!     I actually LOOOOVE some of the outfits.  Fly your freak flag high, my ladies.  AND give no shits!!! - c

Long-lasting complete responses in melanoma patients after TIL therapy

Here are a couple of previous posts on TIL:

From April:  TILs (tumor infiltrating lymphocytes) - advancing as melanoma immunotherapy and new trial 

From May: TIL - Tumor infiltrating lymphocytes (a bit of a primer)

This was published in March:

Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL-2 regimen.  Andersen, Donia, Ellebæk, et al.  Clin Cancer Res. 2016 Mar 22.

Adoptive cell transfer therapy (ACT) based on autologous tumor infiltrating lymphocytes (TILs) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus interleukin-2 (IL-2) classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL-2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL-2 regimen.

25 patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL-2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier:NCT00937625).

Classical IL-2 related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor reactive T cells. Moreover, induction and persistence of anti-melanoma T cell responses in the peripheral blood was strongly correlated to clinical response to treatment. TIL-ACT with a reduced IL-2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable to TIL-ACT followed by HD bolus IL-2.

Basically, this study looked at doing pretty much the old-fashioned version of TIL:  Harvest cells from a tumor, grow cells, give old-time chemo to deplete the patient's existing t cells, infuse t cells that have been grown, then follow with IL-2 as usual...BUT in this case - with a decreasing dose in hopes of retaining the benefit and minimizing the suffering IL-2 can produce. Of 25 patients, there were 3 complete response and 7 partial ones.  Median overall survival was almost 22 months.  Not surprisingly, tumor regression and clinical responses were related to the greater number of t cells infused and the persistence of the anti-melanoma t cell responses in the patient's blood.

For what it's worth. - c

Intralesional IL-2 combined with anti-PD-1 for melanoma - and links to additional intel on intralesional/intratumoral therapies

From the moment I started seeing research about them, I've been a big fan of intralesional therapy ~  drugs injected directly into accessible melanoma tumors.  My Primer for Melanoma Treatment  contains a link that covers a great deal of what is known about them.  As I note there,

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 -  is also being used

From earlier this year:  In-transit melanoma metastases and PV-10 vs isolated limb perfusion, an update...

There was this update in 2018:  Reports on Intralesionals for melanoma - T-VEC, SD-101, and Dendritic cells

Here are two more reports from 2018:  T-VEC in melanoma, after progression on immunotherapy and BRAFi with good results! 3 case reports... and In-transit melanoma. Two "new" treatment options!

And from this summer, there is this:

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.  Rafei-Shamsabadi, Lehr, von Bubnoff, and Meiss.  Cancer Immunol Immunother. 2019 Aug 17.   

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4⁺ and CD8⁺ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

These are drugs I would certainly try, especially in combination with immunotherapy, should I have the need.  For what it's worth. ~ 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!

                                     -------------------------------------------
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