Research that makes you scratch your head - brain power to kill cancer and sleep disordered breathing, relative to melanoma outcomes??? Ummmm, okay.

I don't know how to introduce these reports any better than as "head scratchers"!!!  Here we go!

Modulation of anti-tumor immunity by the brain's reward system.  Ben-Shaanan, Schiller, Azulay, et al.  Nat Commun. 2018 Jul 13.

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Hmm... Okay...
1.  We have known for years that fewer MDSC's is a positive sign when dealing with melanoma.  Here's a bunch of posts and data on myeloid derived suppressor cells (MDSCs) and their role in melanoma .  In fact, I noted this in 2014 in regard to outcomes in my trial:

"MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."

2.  In the entire article, linked here if you choose to read it ~  Modulation..., the authors note: 

"Epidemiological evidence supports a connection between the patient’s mental state and cancer survival, Nevertheless, many of these studies have yielded inconsistent results, and our understanding of the central neuronal mechanisms underlying the effect of emotional states on cancer is limited. Moreover, most research in this field has been focused on negative emotional states, such as stress and depression, while the impact of positive mental attributes on cancer biology is largely unknown."  

Don't get me wrong, I believe in "HAPPY"!!!  We all feel better and do better when all is right in our world!  Duh!!!  However, keeping your ass happy when dealing with the reality of a deadly disease, the pain and cost of treatment, the pain and emotional cost to loved ones, the economic and personal value lost due to unemployment when you are too sick to work... I could go on!  Melanoma is NOT easy.  Putting on a happy face, no matter how real (or not) it may be, will not cure your melanoma nor protect you from it!!!  Here's some real data and a bit of a rant:  ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!

3.  But, I digress.  In this study, researchers gave real live little ratties either a type of lung cancer or melanoma.  And because we already know that part of our immune system serves us well in fighting cancer (our CD8 t cells and natural killer [NK] cells for instance) while other parts (like the MDSCs) actually SUPPRESS anti-tumor responses and let tumors thrive...the researchers note:  "...by depleting and adoptively transferring MDSCs, we showed that these cells are both necessary and sufficient to mediate the effects of reward system activation on tumor growth."  In order to test that, very roughly, they made a happy drug ("...we used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to specifically control reward system activity...") which they got into these poor little ratties heads {for realz!!!} by attaching it to a cold virus and zapping it into their brains with SRS.  Damn!  It sucks to be a rattie!!!  For the control, they did all the same stuff, just minus the happy pill.  So, according to these researchers, this process allowed the zapped with the happy pill ratties' dopaminergic neurons to get busy with their secretions and stimulations - ultimately impacting the bone marrow, which impacted the MDSC's, making them LESS immunosuppressive.  There.  By the way, the effect was less in the melanoma injected ratties than it was for the lung cancer ratties....so the researchers actually abandoned the melanoma critters mid-way the study and just used the lung cancer critters.

4.  All in all, this is probably much ado about nothing as it relates to us human melanoma ratties.  EXCEPT!!!  As I said above and in 2014:  "There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."   So, if this is part of the process to get us there - so be it!!

Now, this...

Sleep-disordered breathing is independently associated with increased aggressiveness of cutaneous melanoma.  A multicentre observational study in 443 patients.  Martinez-Garcia, Campos-Rodriguez, Nagore, et al.  Chest.  2018 Jul 27.

Sleep-disordered breathing (SDB) has been associated with a greater incidence and mortality of cancer, although such findings are inconsistent. However, no large studies are currently available to investigate this association in patients with a specific type of cancer. This study seeks to assess potential relationships between SDB severity and aggressiveness markers of cutaneous melanoma.

443 patients with a diagnosis of melanoma underwent a sleep study within 6 months of diagnosis. General demographics were collected, along with melanoma characteristics and polygraphic parameters consisting of apnea-hypopnea index (AHI) and indices of both continuous and intermittent night-time oxyhemoglobin desaturation (DI4%). Exploration of independent relationships between SDB and various objective melanoma aggressiveness markers (Breslow index, presence of ulceration, presence of regression, mitotic index, stage of severity, damage to the sentinel lymph and spreading of the melanoma) was performed.

Patients in the upper tertiles of AHI or DI4% were 1.94 and 1.93 times more likely, respectively, to present with aggressive melanoma (Breslow index greater than 1mm) than those in the lowest tertiles of these sleep attributes after adjustment for age, gender, tumor location and body mass index. This association was particularly prominent among patients less than 56 years with Breslow index greater than 2 mm. The presence of the additional markers of aggressiveness was also associated with higher AHI and DI4% values.  The severity of the SDB was independently associated with greater aggressiveness of cutaneous melanoma, particularly among younger patients.

Hmmmm.....well.  
1.  Maybe folks who are more worried about their melanoma sleep less well!!!  And sleeping less well about having a potentially deadly disease is completely legit!!!  
2.  Then again, maybe these particular melanoma peeps are less happy about their life and therefore invite melanoma in, like the sad rats in the previous study???  (Y'all know that is NOT what I think!!  Right????)  
3.  Maybe younger folks with melanoma lesions of greater than 2 mm in depth were at greater risk anyway!!!!  Cause that's a thing!!!!  With melanoma: You can never be too rich or too thin! But, you can be too young!!!
4.  Finally, no matter what you think of this report (and I don't think much!!!!) ain't no way insurance is going to pay for sleep studies just because you've been diagnosed with melanoma.  It's hard enough to get them to pay for scans we actually need!!!

Head gett'n itchy yet???  Sometimes we have to think, laugh, yawn, and plain out hope researchers are getting SOMEWHERE that will actually make a difference where we need it!!! Hang tough, ratties!!  c

B cells within the tumor aid response in patients with melanoma, sarcoma, and renal cell carcinoma

Here's a link to a new report out of MD Anderson:  B-cell enrichment predictive of immunotherapy response in melanoma, sarcoma and kidney cancer

Which states, in part:

Studies published today in Nature conclude that enrichment of B cells, a type of immune cell known for producing antibodies, in TLS was predictive of response to checkpoint blockade in patients with melanoma, soft-tissue sarcomas, and renal cell carcinomas.

Checkpoint inhibitors offer the potential for long-term survival to patients across many cancer types, but not all benefit equally. Researchers previously have identified several useful biomarkers of response, which are helpful in identifying patients that may or may not benefit from checkpoint blockade.  The current studies conclude that the presence of B cells and their location within TLS, which act as a lymph node within the tumor, is critical for response to checkpoint blockade, suggesting a dynamic interaction between several components of the immune system.

Mature B cells in tumors of responders suggest active role in tumor immune response

An MD Anderson-led study found that B-cell markers were the most differentially expressed genes in responders relative to non-responders, and B cells in the tumors of responders appeared to be more mature and specialized. These findings were first presented at the 2019 American Association for Cancer Research Annual Meeting.  “These findings open up a whole new area ― that B cells are actually big drivers in cancer immunotherapy, specifically checkpoint blockade,” said corresponding author Jennifer Wargo, M.D... “This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”

The team analyzed samples from patients with advanced melanoma receiving neoadjuvant, or pre-surgical, checkpoint inhibitors as part of a clinical trial sponsored by MD Anderson’s Melanoma Moon Shot...  The researchers also studied a group of patients with metastatic RCC being treated with neoadjuvant checkpoint blockade...   Tumor samples were collected from patients at baseline and during treatment ...

In each cohort, the expression of B cell-related genes was significantly higher in responders and was predictive of response to checkpoint blockade. These findings were further corroborated in an analysis of curated melanoma samples from The Cancer Genome Atlas, in which high expression of B-cell markers was associated with significantly improved overall survival.

“These data indicate the importance of cell types other than T cells, such as B cells, in the anti-tumor immune responses generated by immune checkpoint therapies,” said Sharma. “There is a great need to identify biomarkers of response to therapy, and these data may allow for future studies focused on developing composite biomarkers that represent both the T- and B-cell responses.”

The researchers determined that B cells were localized in the TLS, and the density of B cells and TLS in the tumor was higher in responders. Further analysis of these infiltrating B cells showed that those in responders expressed more markers of mature and differentiated B cells, such as memory B cells and plasma cells.

“Through these studies, we find that B cells are not just innocent bystanders, but are themselves contributing in a meaningful way to the anti-tumor immune response,” said first author Beth Helmink, M.D., Ph.D., fellow in Surgical Oncology.  [Red highlight = mine]  

So - news, but not news.  Meaning we've long known that there is a wide array of tumor markers and cells that determine response - whether these bits and bobs block the immune system and work to protect the tumor or facilitate immune response and try to do away with tumors in our body.  It isn't  surprising that B cells contribute to that as well.

Here are a zillion prior posts on such markers and cells, which begins with this from 2016:  Biomarkers - blood components, circulating tumor cells AND of the tumor itself Biomarkers. Sounds important. What are they? What can they really tell us?

We know that everything from floating bits of DNA in our blood stream, to antigens, to eosinophils, to the absolute number of monocytes and lymphocytes, to neutrophils, to t cells, to myeloid derived suppressor cells can help or hurt us in the fight to rid ourselves of melanoma and other cancers.  Speaking of MDSC - here's a bit of a definition:  MDSC; the Most Important Cell You Have Never Heard Of  However, if you are Jeff Weber or a reader of this blog - you have!!!

Here are a few reports on the mystery of the MDSC:  Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good. 

In fact, in looking at t-regs from the ratties in my study, from this report put out in 2014, My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts... it was noted that: 

MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients.

So, YES!  Let's tweak our tumor battle field.  Let's boost the cells that help us and diminish those that don't.  I am confident that these tiny bits and bobs play a huge role in the lives of human ratties who respond to immunotherapy and those who don't.  And, yes, MD Anderson, I've written about your Moon Shot, too - in 2012 ~ Melanoma. Moon Shot. Curiosity. Will.i.am. The best 5th grade teacher in the world.

C'mon Man!!!  It's 2020!!  While great strides have been made, we've got a long way to go!  So let's get there! - c

Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good.

Myeloid Cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab.  Gebhardt, Sevko, Jiang, et al.  Clin Cancer Res. 2015 Aug 19.

Ipi improves survival of patients with metastatic melanoma.  Since only about 20% of patients experience long-term benefit, reliable markers are needed to predict response.  Analysis of blood of 59 Stage IV melanoma patients was analyzed before treatments and at different times during treatment.  An early increase in eosinophil count during treatment with ipi was associated with an improved clinical response. In contrast, elevated numbers of monocytic myeloid-derived suppressor cells (moMDSCs), neutrophils, and monocytes were found in non-responders (n=36) as compared to levels in responding patients (n=23).  Non-responders also produced more nitric oxide and granulocytic MDSCs expressed higher levels of PD-L1 ... suggesting their enhanced immunosuppressive capacity.  Upon the first ipi infusion, non-responders displayed high serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.

So....folks with increased eosinophils do better.  Folks with increased numbers of myeloid-derived suppressor cells, neutrophils, and monocytes do not.  Here is more data to support the same findings:

Lab values that may predict response to Ipi

Eosinophilia and a positive response to nivo and pembro

In this link Weber talks ipi and combo's, several immunotherapy combo's are discussed...but the relevant part addresses the blood work from the folks taking nivo in my study:
 

Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.


Here, in a synopsis of articles about the positive effects of combining immunotherapy and radiation, Radiation for melanoma, better when combined with immunotheapy!, once again....patients do better when MDSCs are few and far between:  Concomitant with tumor regression from radiation, they noted that radiation and anti-PD-L1 worked together to reduce the local accumulation of tumor-inflitrating myeloid-derived suppressor cells (MDSCs)... {Note:  Remember, these are the bad guys that block your T cells.  In my study, the folks with high levels of MDSCs did least well, while those with the lowest levels did better.  That's why, some researchers, like Weber, are talking about depleting these cells in patients FIRST...then administering anti-PD1 or other immunotherapies!!}  So...the data acquired in this study demonstrated evidence of the interaction between radiation and T cells....and a basis for the rational design of combination therapy with immune modulators and radiotherapy.

Really thinking the idea about depleting MDSCs at the start may really be the way to go here!!!  Best - c 

Weber presentation on ipi combo's and combo's coming soon!

Here is a link to Weber's presentation in Paris July 2014:
Combination therapy presentation by Weber

My synopsis:

Nivolumab (anti-PD1) and ipilmumab (anti-CTLA-4) given concurrently-
Nivo at 1mg/kg and ipi at 3mg/kg for 4 doses then followed by nivo alone for 96 weeks.
Best results so far, but with significant toxicities.
Trial requires that when dose limiting toxicity develops, patient must stop trial.
Weber feels you can treat the patient with steroids and then safely resume with nivo alone.
Positive or negative BRAF status did NOT matter in regard to response.
PDL1 tends to "fall out" as a factor...folks positive or negative for it could still respond to concurrent therapy.
In concurrent cohorts = 43% overall response, 17% complete response, 79% 2 year survival
Though that still leaves 50% of patients who did not respond.

Nivo and ipi given sequentially-
Group with nivo first, followed by ipi - another with ipi first, followed by nivo
He is working on the study currently with Hodi.
The hope is that a higher dose of ipi can be administered in this manner without invoking dose limiting toxicity and yet increase response rates.

Ipi and Tvec-
The idea here is that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic ipi.
Overall response rate of 56%, with 6 of 18 patients acquiring complete responses.
Weber likes the idea of priming tumors locally and following with systemic therapy, either ipi or anti-PD1.

Ipi and INCBO24360 (an IDO inhibitor)-
The problem with immunotherapy is that there are suppressive influences in the immune system - the absence of effector cells, the presence of t-reg suppressor cells (activated by LAG-3), myeloid suppressor cells, IDO (which is generated by antigen presenting cells as well as T-cells)....all working to prevent an immune response against melanoma! In this study, an IDO inhibitor was given (at either 25 or 50mg) orally, twice daily, everyday.  Ipi was given at 3mg/kg every 3 weeks.
Was well tolerated.  33% response rate.
Immunotherapy naive patients did better.
This study speaks to the ability to overcome micro-environmental immune suppression as well as increase the influx of effector cells by decreasing IDO.

Nivo and peptide vaccine-
Idea was that if you gave multi-peptide vaccine you could amplify the immune response against the peptide, and get a better response from nivo.  No evidence that this worked at all, though nivo itself did well.
100 patients, initial ones got peptide vaccines with escalating nivo dose, depending on cohort, every 2 weeks for 6 months, then nivo alone every 3 months for 2 years.
Cohort was added (later) that allowed patients who had dose limiting effects on ipi-
20 evaluable patients as one dropped out.
Got nivo alone (no vaccine).
8 confirmed partial responses and 3 stable patients at 24 weeks.  All patients who responded still remain in remission, with one being out 1 1/2 years.
Only 2 patients had dose limiting toxicity on nivo...rash and pneumonitis.
However, these were not the same DLT that they had experienced on ipi.
40% response rate.
Most anti-PD1 trials haven't allowed patients with prior bad responses to ipi.  Weber feels as these patients go to doctors seeking anti-PD1 as it comes on the market, they should be treated with it!
Back to general results-
The presence of peptides or not, ipi refractory or naive - made no difference in results.
26% response rate in these very ill patients, s/p multiple treatments.
NOTE by Weber:  The pembro studies demonstrate a significant difference in response rate between ipi naive and ipi refractory patients [with refractory doing less well].  "It makes you wonder- Are these drugs really the same?"
Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.
There was worse overall survival in female patients.
Given responses in this group with 2 1/2 year end-point of anti-PD1 infusion...Weber questions whether patients really need to continue anti-PD1 infusions until progression as the Pembro trials/indications have been written.

Ipi and Peg interferon-
Ipi at 3mg/kg every week for four doses with 3mg/kg peg interferon sub-q weekly for up to 3 years.
30 patients. 1 compete response. 13 partial responses. 3 with stable disease.  46% response rate.

Planned combo's-
Pembro and T-vec
Pembro and IDO inhibitor
Pembro plus BRAF plus MEK
MEDI 4736 and anti-PDL1
Nivo and anti CD137 (to start in the next month or so!!!)
Nivo and anti-LAG-3
Adjuvant ipi and Nivo (now being expanded with 1,500 patients!!!!)
     So far, in patients in the first cohort - there has been a 45% response rate, with only 20 patients and only at 8 month f/u...no relapses, and includes patients with Stage IV/IIIC melanoma.

So there you have it folks.  Hope this helps! - c

My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts...

 How very strange it is to look back!!!  4 years.  It seems like yesterday.  It seems like ages ago.  Anti-PD1 was an unknown.  Only a handful of patients had taken it in a couple of studies.  Neither ipi (yervoy) nor the BRAF inhibitors were FDA approved.  The Merck product, Keytruda, did not exist.  I am surprised to be here.  I can hardly believe I, and my fellow ratties, managed the every other week routine for 6 months:  Work 12 hours shifts Mon, Tue, Wed.  Drive to Atlanta on Thurs.  Fly to Tampa.  Get rental car and dinner.  Rest up at the good ol' La Quinta.  Friday am - Hop over to Moffitt at the butt crack of dawn for labs, office visit, injections, infusion.  Drive like mad back to the air port.  Fly to Atlanta.  Drive the two hours back to Chattanooga.  Back to work on Monday.  I've since discovered that many in my trial did not work during their treatment.  Though, some did and many continue their busy lives today while taking Keytruda as well as ipi combined with nivo!  For the remaining two years, Tampa visits and infusions were just every 12 weeks.  It seemed like a holiday!  I missed three work days over those 2 1/2 years.  There are those who said I was nuts and would have demonstrated better judgment by taking off more...but that's not how I roll.  And I was so lucky.  Lucky to be in the trial.  Lucky to be able to AFFORD to be in the trial.  Lucky to be NED going into it.  Lucky to have the support system I had while dealing with it.  Lucky for my battalion who marches with me...still.

It is hard to say what I thought would happen.  I really didn't expect much.  I certainly didn't look upon Nivo as my "cure" as so many seem to today on various boards, chat groups and forums.  Don't get me wrong.  I was thankful for the option.  Brain mets, lung mets, tonsilar mets, another brain met in rapid succession had made me well aware that something was desperately needed to break that cycle.  My only options were IL2 or interferon, since after every met, surgery rendered me NED....a boon and a reason to be refused from every other trial!  I still don't know what my future holds.  But, neither does anyone else.  I just worry about those who seem so certain that the anti-PD1 drugs will be their personal deliverance when the 30-40% response rate tells us that there are a large number of us who will be disappointed.

Having spent a lifetime reading research reports, case studies... it is surreal to read one that you know refers to your own experience.  It seems cold.  A little wrong somehow. "33 patients were enrolled.  10/33 patients relapsed. Of the 10 relapsed patients, five died due to metastatic melanoma; three were rendered free of disease surgically and remain disease-free at 2, 27 and 54 weeks after relapse.  One patient had spontaneous regression...and has been free of disease for over 3 years.  One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib."

My thoughts about the report and results:

SIDE EFFECTS:
"Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrated immunologic activity with promising survival in high-risk resected melanoma..."  Well tolerated?  Hmmm....  As compared to what?  A relaxing day of hikes along mountain trails, followed by a warm shower, good book by a cozy fire and delicious dinner?  Arsenic?  Dick Cheney's idea of simple Q & A?  There is no doubt that many have endured far more difficult treatments.  Still vaccine injection site reaction, fatigue, rash, itching, nausea, diarrhea and arthralgias were common.  Hypokalemia (low potassium...something that can be life threatening), enteritis, colitis, hypophysitis, and thyroiditis were certainly no fun for some of my fellow ratties.  There was one patient with grade 1 pneumonititis. Wonder who that was?  Maybe me, maybe not.  It is very strange to have those who do not have melanoma, have never been given those miserable vaccines or taken anti-PD1 even once, determine the quality of another's experience.

BRAIN METS:
"Ten patients had resected brain metastases."  Well...that's not entirely accurate.  Mine was not "resected" it was zapped via stereotactic radiation.  Not certain about anyone else.   Only 2 of these ten patients have relapsed.  One developed a lung met which was resected and she remains NED.  The other apparently had significant CNS disease at induction, though researchers were unaware at the time, "and expired 3 weeks from initiation."  Despite such a loss, this is a pretty remarkable outcome for folks post melanoma brain mets, given our shelf-life of just 6 months or so without treatment.

RADIATION:
"Radiation therapy was administered to 18 patients prior to or after surgery including nine with resected brain metastases." The study doesn't speculate and all I can do is that...but with more and more research looking at retrospective data and new studies specifically examining radiation combined with ipi, anti-PD1 and the BRAF inhibitors...I have to believe that this combo is working positively for those zapped ratties in my trial.  (Much more to come on this topic in 2015!!)

PD-L1
There have been hopes that testing tumors for various biomarkers would tell docs which patients would respond to which drug.  PD-L1 was one of those. 28 of us had our tumors tested.  I still don't know what mine showed.  But, in our study, "there was no significant association between PD-L1 and relapse free survival in this patient population, although there is a non-statistically significant trend towards better RFS in those whose tumors were PD-L1 positive..."  For whatever that is worth.  I suspect the test for PD-L1 is not quite good enough just yet and there is more to be learned on this subject.

MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients.

RELAPSE FREE SURVIVAL:
"A retrospective study....showed a median overall survival of 12 months in stage IV melanoma patients undergoing metastasectomy."  Yet, my ratties and I have demonstrated an "impressive relapse-free survival...of 47.1 months and a median overall survival not yet reached with over 32 months of follow-up."  For me, I am now: 
136 months post melanoma diagnosis
56 months post Stage IV melanoma
50 months NED
48 months post start of nivo/Opdivo trial
18 months post my last infusion

It has been a strange, yet wonderful ride.  Here's to the ratties!  Here's to 2015! Much love - c

Blood markers associated with clinical outcome of melanoma treated with ipi

Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab.  Martens, Wistuba-Hamprecht, Geukes Foppen, et al. Clin Cancer Res. 2016 Jan 19.

[This study was done as an attempt to] identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Frequencies of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier- and Cox-regression-analysis including calibration and discrimination by C-statistics. Low baseline LDH, absolute monocyte counts (AMC), Lin-CD14+HLA-DR-/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. 43.5% of patients presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS in the main study and additionally in an independent validation cohort. A baseline signature of low LDH, AMC and MDSCs as well as high AEC, Tregs and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g. PD-1 antibodies, is warranted. So...common themes we have been seeing lately:  LOW LDH, AMC and MDSC's bode well for those treated with immunotherapy.  More related info here: LDH: LDH as predictor of outcome Being female with low LDH and no ulceration...good with BRAFi White cells: Neutrophils as prognostic predictor MDSC's: Markers for response to immunotherapy T-regs: How to make anti-PD1 work better Have a beautiful weekend! -c

What to expect in Ipi vs Nivo Trial as adjuvant for resected melanoma???

The ipi vs nivo trial for resected Stage III and Stage IV melanoma is now recruiting!!!  Check out some info about adjuvant melanoma treatments and the trial reported here:  

New ipi vs nivo trial for resected melanoma

So what can patients expect?  These ratties will most certainly teach us a great deal.  However, the results of my NED arm from the nivo trial I have participated in can give some idea about how the Nivo/Opdivo arm in this trial might go for prospective patients.  Remember we were testing results of Nivolumab in NED vs NON-resected melanoma as well as doses that ranged from 1-3-10mg/kg and for some of us, combined with peptide vaccines as well.  (The vaccines provided no benefits, so no worries about missing out on that!!!) That report and review are here:

Results from 33 ratties in my Nivo/Opdivo trial - published!

Thoughts on my nivo/opdivo trial results, 4 years later

With this sum up from the published results:
"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."  AND:  "Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable."  Dosage (1, 3, 0r 10mg/kg) did not seem to have significant effect on relapse rate or adverse events.  AND:  "Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant."  BUT, lower MDSC levels at the start did demonstrate a positive effect:  "There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients."

But, what about the folks who are in the adjuvant ipi arm?  Here is an article reporting on a study that examined just that.

Adjuvant ipilimumab vs placebo after complete resection of high-risk stage III melanoma:  a randomized, double-blind, phase 3 trial.  Eggermont, Chiarion-Sileni, Grob, Drummer, Wolchok, Schmidt, Hamid, Robert, Lebbe, Weber, et al.  Lancet Oncol. 2015 March 31. [epub ahead of print]

"We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.  We did a double blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis greater or equal to 1mm or intransit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not had previous systemic therapy for melanoma from 91 hospitals located in 19 countries.  Patients were randomly assigned (1:1)....to receive IV 10mg/kg ipi or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years. ...Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints."

Between July 10, 2008 and Aug 1, 2011 951 patients were enrolled.  475 = ipi.  476 = placebo.  At a median f/u of 2.74 years there were 528 recurrence-free survival events: 234 = ipi vs 294 = placebo.  Median recurrence-free survival was 26.1 months for ipi vs 17.1 months for placebo.  3 year recurrence-free survival was 46.5% for ipi vs 34.8% for placebo.  

Most common grade 3-4 immune related adverse events in the ipi group:  GI (75 vs 4 in placebo), hepatic (50 vs 1), endocrine (40 vs none).  Adverse events led to treatment discontinuation in 245 patients in ipi group and 182 of these were in the initial treatment period of 4 doses.  5 patients died due to drug related adverse effects in the ipi group.  3 due to colitis (2 of which had GI perforation), 1 with myocarditis, and 1 with multi-system failure with Guillain-Barre syndrome.

"Adjuvant ipi significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma.  The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences...for endocrinopathies.  The risk-benefit ratio of adjuvant ipi at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value."

My thoughts: 
1.  Folks in my trial were much higher risk generally as we were all Stage IV patients (status post brain and lung mets, etc.) at the start, though Stage III peeps were added later.  
2.  I don't know the drug dosages to be used in the coming trial for either ipi nor nivo.  Nivo doses haven't seemed to have that much effect on adverse events, but ipi has proven that the higher the dose the more frequent those events. 
3.  The numbers of patients in the NED arm of my study were obviously very small.  The greater numbers expected for the coming study will certainly provide a great deal more information.
4.  Unlike many phase 3 trials (the ipi one noted above for example), both arms of the currently enrolling trial are likely to derive some benefit!!
I wish you all my best!   - c

Slides from Paris Melanoma Meeting addressing ipi combos

Covering much of the same territory as my prior post  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/09/weber-presentation-on-present-ipi.html
However, this presentation is in slide form, allowing you to see the data a bit differently.  Here is a synopsis with presentation linked below:

For ipi and nivo...combo or sequential:

• 43% ORR with 17% CR's and 82% in remission for all concurrent ipi/nivo patients
• 62% grade 3-4 AEs (LFTs, lipase, amylase, rash, colitis)
• BRAF status, PD-L1 tumor staining NOT associated with response
• Response in sequential patients associated WITH ipi PK levels prior to starting anti-PD1
• Concurrent 2 yr OS 79% = "IMPRESSIVE" 

Eval of T-VEC (Talmogene Laherparepvec) and ipi combo:

• Unresected, untreated Stage IIIB/IV, 18 patients
• 4 CR, 6 PR, 3 SD, ORR = 56%
• Only 3 grade 3-4 AEs from ipi
• Results may address the hypothesis that T-VEC may prime an immune response amplified by ipi

INCBO24360 and ipi:

• Target inhibition of IDO achieved at 25-50mg BID
• 33% RR and 33% stable disease
• Toxicity = increased LFTs
• Immunotherapy naive patients did best
• 10 of 12 patients required no further therapy

Nivo in patients naive to OR progressed on ipi:

• NO diff between ORR, PFS, and OS between ipi naive and ipi refractory patients [This is different from what studies have shown with Keytruda! More info on above post.]
• High pretreatment MDSC (myeloid derived suppressor cells) increases in T-regs associated with poor outcome [better explanation of this on blog post linked above]
• Perhaps combining anti-PD1 with MDSC or T-reg depletion would make it more effective

Paris Melanoma Meeting July 2014

Wishing all the ratties my very best! - c

I've said it before, I'll say it again - ENOUGH ALREADY! No more interferon for melanoma!!! (Or placebos - for that matter!!!)

I had to make a hard decision about utilizing interferon (or not!!) back in the dark ages of melanoma - 2010:  Oncology visit limbo.....

Since then, we have learned definitively, that interferon does NOT provide any survival benefit for melanoma patients!  There was this in 2016:   Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!

BUT, we were STILL looking at interferon as adjuvant:  ASCO 2016 - Two Adjuvant studies for Stage III/IV - with interferon vs pembro vs ipi - still recruiting 

Finally!  In  February 2017, there was this:  For Stage II/III melanoma patients: Interferon NO BETTER than observation!!!!  and in November of that year, in a discussion among Melanoma Big Dogs, this conclusion was drawn:  Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!! 

However, Kirkwood (and others) can't seem to get the facts straight in their heads!!!  Earlier this year I wrote:  Kirkwood needs to STOP!!! NO MORE INTERFERON!!! Geeze!!!!

Now....there's this:

United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.  2019 ASCO.  Rarhini, Lee, Hodi, et al.  J Clin Oncol 37, 2019.

Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3. The prespecified efficacy boundary was crossed. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS  and RFS in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. 

Not news.  Stop with the interferon already!!!  Plus, there's this:

Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma.  Butterfield, Vujanovic, Santos, et al.  J Immunother Cancer. 2019 Apr 24.

Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects.

Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8⁺ and CD4⁺ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation.

The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8⁺ and CD4⁺ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8⁺ and CD4⁺ T cell subsets in clinical responses.

DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC.

JUST.  STOP!

And at this point....placebo?  Really????  There's this:

Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.  2019 ASCO.  Eggermont, Chiarion-Sileni, Grob, et al.  J Clin Oncol 37, 2019.

Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS and distant metastasis-free survival (DMFS), assessed by an IRC, and overall survival (OS) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those greater than/= to 18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168

	RFS		DMFS		OS
	Ipi	Pbo	Ipi	Pbo	Ipi	Pbo
No. of events	273	323	247	292	173	223
5-year rate	43.9%	32.5%	49.9%	39.8%	65.2%	54.1%
7-year rate	39.2%	30.9%	44.5%	36.9%	60.0%	51.3%
Median (yrs)	2.7	1.5	5.0	2.4	NR	7.8
HR (95% CI)†	0.75 (0.63-0.88)		0.76 (0.64-0.90)		0.73 (0.60-0.89)
Log-rank p-value†	0.0004		0.0018		0.0021

Of course, Stage III melanoma peeps who were treated with ipi instead of placebo have done better!!!  DUH!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

We do not need to waste time, money and other resources on melanoma trials that utilize placebo or interferon as the comparator any longer.  While these are follow-up reports to pre-existing studies, and the data should be presented, it is unfortunate that some researchers STILL try to harken back to these variables.  NO.  MORE.  We have effective FDA approved treatments in the realm of immunotherapy, targeted therapy and intralesional therapies - across patients using them as adjuvant and to treat active disease.  Create studies that make sense.  Compare apples to apples.  No more placebo or interferon based studies!  ENOUGH!

But, through the storm....

...beauty remains, brightening the shadows, in a lighter shade of pale.  Wishing a beautiful weekend to you all.  c

Melanoma madness links!! ASCO and others....

Hey guys! Don't have the time or energy to give you my usual print out and assessment on these just now!  However, in the spirit of access and knowledge, I still wanted you to have them.

So....here you go:

Galectin's GR-MD-02 Positive in Phase Ib Study With Keytruda

Why Yervoy's Resurgence Will Gain Momentum

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Lifestyle Modifications and Policy Implications for Primary and Secondary Cancer Prevention: Diet, Exercise, Sun Safety, and Alcohol Reduction

New Era in the Management of Melanoma Brain Metastases

Combination Immunotherapy Development in Melanoma Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy Patterns of Response and Progression to Immunotherapy Emerging Strategies in Systemic Therapy for the Treatment of Melanoma Challenging Cases: Management of Immune-Related Toxicity The Role of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma. Hieken, Kane JM, Wong.  Ann Surg Oncol. 2018 Oct 3.  Completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma patients has been guideline-concordant standard of care since adoption of lymphatic mapping and SLN biopsy for the management of clinically node-negative melanoma patients more than 20 years ago. However, a trend for omission of CLND has been observed over the past decade, and we now have randomized, controlled clinical trial data to help guide treatment recommendations. Publication of these data prompted an American Society of Clinical Oncology-Society of Surgical Oncology 2018 clinical practice guideline update for these patients. Systematic review of current evidence supports a selective, individualized approach to CLND for SLN-positive melanoma. For low-risk, low-volume micrometastatic disease, SLN biopsy may be both diagnostic and therapeutic, and close clinical follow-up with imaging or CLND are reasonable options for appropriately selected patients. For higher-risk patients, omission of CLND requires careful consideration of risks versus benefits, relevant histopathology, and individualized patient discussion. This should address patient comorbidities and life expectancy, the predicted likelihood of additional positive nodes, availability of imaging surveillance, likelihood of adherence to imaging and clinical follow-up, consequences of regional recurrence, and the prognostic value of complete nodal staging and its impact on adjuvant therapy recommendations or clinical trial participation. Data on long-term outcomes, cost, and patient-reported quality of life measures are not yet available. Prognostic Value of Low Tumor Burden in Patients With Melanoma. Poklepovic, Carvajal.  Oncology (Williston Park). 2018 Sep 15. The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence.   Predictors of Sentinel Lymph Node Positivity in Thin Melanoma Using the National Cancer Database. Conic, Ko, Damiani, et al.  J Am Acad Dermatol. 2018 Sep 18.  Following melanoma excision, patients often receive sentinel lymph node biopsy (SLNB) for further staging. Limited data regarding predictors of SLNB positivity in thin melanoma are available.  To evaluate predictors of SLNB positivity in thin melanoma.  Patients with cutaneous melanoma, Breslow thickness great than/= to 1.00 mm who received a SLNB were identified from the National Cancer Database in the period from 2004-2014 (n=9,186). Predictors of SLNB positivity were analyzed using logistic regression.  In a multivariate analysis, patients with age less than 60 and Breslow thickness greater than 0.8mm were at increased risk for positive SLN. Moreover, on multivariate analysis, presence dermal mitoses increased odds of SLN positivity by 95%, ulceration by 63% and Clark level IV-V by 48%. Patients without ulceration but with dermal mitoses had 92% increased SLN positivity.  Limited survival data available.  Younger age, Breslow thickness greater than 0.8 mm, presence of dermal mitoses, ulceration and Clark level IV-V are positive predictors of positive SLN. While the new AJCC system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.   Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. Wang, Salem, Cohen, et al.  JAMA Oncol. 2018 Sep 13. Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.  To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.  We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Systematic Review and Meta-analysis of the Prognostic Significance of miRNAs in Melanoma Patients.

Sabarimurugan, Madurantakam Royam, Das, et al.  Mol Diagn Ther. 2018 Sep 27. 

Melanoma is the most aggressive and deadly form of skin cancer. The molecular variability involving microRNA (miRNA) expression plays a significant role in melanogenesis, which leads to poor prognostic effects in melanoma. Since there is a scarcity of comprehensive data on the prognostic role of miRNAs in melanoma patients, this study focuses on filling this knowledge gap through a systematic review and meta-analysis.

The included studies were extracted from several bibliographic databases between 2012 and 2018 using multiple keywords according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) for different survival endpoints were compared to the high and low expression levels of miRNAs. The mean effect size of HR values was estimated using a random-effects model of meta-analysis. Inverted funnel plot symmetry was used to assess publication bias. Subgroup analysis was carried out individually for multiple miRNAs across different studies.

A total of 24 studies across eight countries were included, of which 16 studies were eligible for meta-analysis. Twenty-five miRNA expression levels were studied from 2669 melanoma patients to estimate the association between the prognostic role of miRNAs and survival outcome in these 16 studies. The overall pooled effect size (HR) for up- and downregulated miRNAs was 1.043, indicating that the miRNA expression increased the likelihood of death in melanoma patients by 4.3%. Subgroup analysis for miRNA10b, miRNA16 and miRNA21 showed a poor prognosis. The quality assessment revealed that 16 studies were good quality and eight studies were of fair quality. 

This is one of the first pooled meta-analysis studies on the role of miRNAs in the prognosis of melanoma. Our findings are inconclusive but suggest that miRNA expression could predict poor survival in melanoma patients. Therefore, miRNA expression could act as promising prognostic marker for melanoma.  

Induced Vitiligo due to Talimogene Laherparepvec Injection for Metastatic Melanoma Associated with Long-term Complete Response.

Iglesias, Ribert, Barreiro,   Acta Derm Venereol. 2018 Oct 3. 

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.

Huber, Vallacchi, Fleming  et al.  J Clin Invest. 2018 Sep 27.

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.  

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).

Mitchell, Hamid Smith, et al.  J Clin Oncol. 2018 Sep 28.

Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in greater than/ = to 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application.

Tray, Weber, Adams.  Cancer Immunol Res. 2018 Oct;6.

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation.

And because y'all know I've been yelling about biomarkers for years, here are links to my prior posts on the subject:  

Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...)  

MHC proteins and how they work if you are taking anti-CTLA4 (ipi) or anti-PD-1 (Opdivo or Keytruda) in melanoma  

Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And here is an update on the Columbus Trial....with my prior notes:

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!!!!

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Dummer, Ascierto, Gogas, et al.  Lancet Oncol. 2018 Sep 12.

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF^V600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.

COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF^V600E or BRAF^V600Kmutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.

Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (35·9-37·5). Median overall survival was 33·6 months (24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib. The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF^V600-mutant melanoma.

The ASCO Educational Book looks like it might be helpful to melanoma peeps...so you might keep that in mind as an additional resource in the future.  Remember to read critically.  Use your common horse sense.  Don't fall for everything everybody is selling.  Take good care and remember I love you.  - C