How to make anti-PD1 work better with a new player...LAG-3????

Our immune system is a wonder of cell function with checks and balances.  Cells can be turned on to help fight germs and tumors and other yuck we encounter, but can also be turned off so we don't suffer from the body attacking or hurting itself through too much of an inflammatory process (as it does in autoimmune diseases like lupus, arthritis and even asthma).  Here are some terms that might help in understanding the presentation and article below as it relates to how anti-PD1 works, why it might not, and what might be done to make it work better for folks when their cancer/melanoma rears its ugly head again.

Definitions:
YOU HAVE:
1. T-cells - a type of lymphocyte (white cell) with a "T-cell receptor" on the surface.  There are several types of T-cells.
     i)  CD4-T cells - (T helper cells)- express the CD4 protein on their surface and become activated when  exposed to peptide antigen, which is expressed on the surface of an antigen-presenting cell (like bacteria and tumor cells).  When active they increase in number and secrete cytokines that regulate/trigger the immune response to attack the invader.
     ii)  CD8-T cells - (cytotoxic T cells)- express CD8 on their surface and can destroy virus cells, tumor cells, and are implicated in transplant rejection.  They can be "inactivated" so that autoimmune diseases are prevented or decreased. (Many meds to decrease transplant rejection as well as the signs and symptoms of rheumatoid arthritis, ankylosing, and other autoimmune diseases work to do this.)
     iii)  Memory T cells - persist after an infection or vaccine to create immunity.
     iv)  T reg cells - (suppressor T cells)- these cells shut down T cell mediated immunity at the end of an immune reaction.  There are 2 types of the these CD4T reg cells:  Naturally occurring cells that begin in the thymus gland (CD4, CD25, and FoxP3 T regs) and Adaptive T regs that originate during a normal immune response.
     v)  Natural Killer T cells - These T cells recognize a different molecule from other T-cells.  (Instead of peptide antigens, they recognize a glycolipid antigen.)  When active, they can eliminate some tumor and invasive viral cells.

2.  PD1 - also called programmed cell death protein 1, is a membrane protein and a member of the extended CD28/CTLA-4 family of T cell regulators.  PD1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or engulf/digest 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.

3.  CTLA-4 - another T cell regulator, also called Cytotoxic T-lymphocyte Antigen 4, is a protein receptor that down regulates (can "turn off") the immune system.  It is found on the surface of T-cells.

4.  LAG-3 - a molecule on T reg cells that contributes to their suppressor activity.

MEDICINE:
5.  Anti-PD1 - Nivolumab by BMS and Pembrolizumab (MK-3475) by Merck - are monoclonal anti-bodies that block the switch on T cells so that PDL1, produced by tumor cells, can NOT bind with them and turn them off.

6. Anti-CTLA-4 - Ipilimumab/Yervoy - a monoclonal antibody created by BMS that works to activate the immune system by targeting CTLA4, a protein receptor that down-regulates the immune system in melanoma patients, thereby turning ON the T cells.

FROM TUMORS:
7.  PDL1 - a ligand produced by the surface of melanoma tumors that can bind to infiltrating T-cells and turn them off.

Attached here is a presentation by Charles Drake MD, PhD from John Hopkins, from the Perspectives in Melanoma XVII meeting in Baltimore in September 2013, where he gave a review of PD1 biology, and how anti-PD1 works, as well as factors that might make it more effective:
The Basic Biology of PD1 and thoughts about LAG-3

Primary points:  
Anti-PD1 (a PD1 blockade) causes -
    1.  An increased number of CD8 T-cells
    2.  Increased function of those CD8 T-cells
LAG-3:
Alone, anti-LAG-3 is not very effective.  However, when anti-PD1 is combined with a LAG-3 blockade, the effectiveness of the CD8 T-cells is even greater than when either is used alone.  Unfortunately, there was a high death rate in the mice given both.  However, that particular mouse population was genetically engineered to have NO LAG-3, not a normal circumstance.
When does Anti-PD1 work?  In the priming or the effector phase????
This remains somewhat unclear...or perhaps there is action in both phases.  In this data, it seems that when anti-PD1 is on board with the initial antigen exposure....it leads to not only increased discrete numbers of CD8 T-cells, but even greater T-cell function per individual cell.  Therefore, it may be that earlier treatment (prior to advanced disease) is more effective because more T-cells with greater function may be produced.  Additionally, in advanced disease, the addition of anti-LAG-3 (to anti-PD1) seems likely to create more effect.

We already have data indicating that patients who are taking anti-PD1 (MK-3475 for this data set) and are ipi naive have about a 40% response rate while patients who are ipi refractory have a lesser response (28%).  data as discussed by Ribas and Weber
We also know that data shows that with smaller tumor size, there is increased overall survival in melanoma patients treated with anti-PD1. Baseline tumor size as an independent prognostic factor
(Now, on that point, you have to bear in mind that no matter how active ones white cells may be, they can be overwhelmed...with infection (in cases of sepsis)...or with cancer cells....BUT....)
Both these issues may be addressed in a continuation of the ideas presented in the lecture...studied  specifically here:


Restoring Immune Function of Tumor-Specific CD4+ T Cells During Recurrence of Melanoma
Goding, Wilson, Xie, et al.  The Journal of Immunology, March, 2013.
   "Recurrent solid malignancies are often refractory to standard therapies....adoptive T cell transfer may benefit select individuals, the majority succumb to their disease.  ...developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence.  During recurrence, Foxp3 tumor-specific CD4 T cells became PD-1+ and represented more than 60% of the tumor-specific CD4 T cells in the host.  Concomitantly, tumor-specific CD4 T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1...and LAG-3 inhibitory molecules.  Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibody or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.  Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 antibodies overcame the requirement to deplete tumor-specific Tregs.  In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or antibody therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer."

Primary points:
    Initially, blocking just PD-1 with anti-PD1 drugs will allow T cells to kill melanoma cells.  When relapse occurs, the immune response has been further suppressed by CD4 suppressor cells (T regs).  In relapse, reducing the number of T regs (Remember! These are the T cells that shut down the immune response!!) through drugs like cyclophosphamide or radiation...as is done before TIL therapy...plus the combination of anti-PD-L1 OR using anti-PD1 combined with anti-LAG3....showed the restoration of effective tumor killing by T cells.

So....all of this seems a good way of thinking about how to GET THOSE T CELLS FIRED UP!!!!  Initially AND in later stages of cancer progression.  I hope I was able to make it somewhat comprehensible.  Keep it up, you smart and enthusiastic research guys.  And you ratties....both the 4 and 2 legged sorts....hang tough!!!
Love - c

Odds and Ends....

Feeling rather random today.  Lots to think about....

Loyalty...hmmm?  Do YOU have it?  It is one of the qualities I cherish most.  It is also incredibly rare!!!  But, to all my loyal peeps....EVER so much love and appreciation!!!!

Extract of centipede Scolopendra subspinipes mutilans induce cell cycle arrest and apoptosis in A375 human melanoma cells.   Ma, Liu, Qi, et al.  Oncol Lett, 2014, July [e pub]
Yep!!!  One more one, in the category of EVERYTHING kills melanoma! Some folks in China used extracts from this centipede on melanoma cells in a dish and sure enough, it inhibited cell proliferation, caused a break in the normal cell cycle, and the cells died!!!  Just so you know!

Anonymous????  For those of you with distinctive writing styles on the various melanoma boards who suddenly decide to post as anonymous... Why???  And, secondly, it is easy to see who you are.  All anybody has to do is look at the bulletin board posts you've made and they all pop up...even the "anonymous" ones.  Just say'n!!!

MK-3475 and FDA approval.  Scuttlebutt and various somewhat more reliable sources, continue to indicate that Merck's anti-PD1 drug, Pembrolizumab, will gain FDA approval sometime this year.  However, it looks as though, approval will come with the stipulation that the patient has to have failed ipi FIRST!  Happened to have a meeting at work related to a Merck vaccine, replete with company reps.  One was very bright and knowledgeable, so after the meeting business was finished up, and commenting that I realized my topic was not really his bailiwick, I asked, "What have you heard about FDA approval of MK-3475?"  He seemed a bit startled that I was asking about it, but to MY surprise, he actually knew a pretty good bit about the drug, its trials, and the BMS anti-PD1 product, Nivolumab, as well.  Sadly, there was no surprise in that he, too, was under the impression that approval would come this year, with the stipulation it would be indicated for ipi refractory patients only.  He pointed out that once approved, docs could prescribe it "off label" for patients who had NOT yet failed ipi.  I agreed that that was certainly true, however, it would be unlikely for insurance companies to pay for it in that circumstance.  An expected problem that he acknowledged.  Anyhow, he was a nice guy.  Clearly not his call by any means.  And proof...once again...I will ask anybody anything!  Link below just to show that so much of the world doesn't give two hoots about healing patients in any other regard than how it affects their stock portfolio!!!  What'cha gonna do?
Focus on the financial contest...rather than healing patients? 

Delicious lamb chops!!!!  Season chops with salt and pepper.  Place in hot pan with a bit of olive oil.  Turn repeatedly until getting nice and browned on both sides.  Toss in several garlic cloves still in their nature made wrappers.  Toss in a couple of sprigs of thyme and rosemary.  Continue turning occasionally.  When to your desired level of doneness....drizzle with 2 tablespoons of balsamic vinegar and 1 tablespoon honey.  Girl!!!  It's YUM!  (Partially stolen from Jamie Oliver!)

Need a side with those chops?  Cover couscous with boiling water, lid on, and let sit.  Toss 3/4's bag of arugula, 1 chili, 2-3 spring onions, mint leaves and cilantro with the juice of one lime and a good drizzle of olive oil in the food processor and blitz for just a minute.  Once the couscous is ready, toss it with the chopped veggies.  It is so good!  (Also Jamie Oliver inspired!)

Guess that's about as random as it gets.  Much love - c

Smoky Mountain Respite

The best hiking buddies!

Fern Falls

B being very brave!

There is nothing more refreshing to the body and the spirit than a walk in the mountains with friends.  B has much better pics, but these tell some of the story.  It was lovely and learned.  Much love to Don.  Thanks for sharing your world with us.  Love, c

One YEAR since last Nivolumab infusion!!!

I cannot believe how quickly time goes by!  Such realizations make me work even harder to appreciate every minute!

Latest stats:
130 months since melanoma diagnosis
50 months Stage IV
44 months NED
42 months since start of Nivolumab/Peptide vaccine trial at Moffitt
12 months since last dose of Nivo!!!!!

Since my last Nivo dose, I've had follow-up appointments and scans (CT's of neck, chest and pelvis with an MRI of the brain) every three months at first and am now on an every 6 month schedule. My next set will be in September.  The arthralgias, mouth issues, and crazily enough....flares at the peptide vaccine sites...continue occasionally, though not nearly as often or as notable as they were at other times.  The worst recent arthralgias were focused mainly on right hip and knee back in April, with some aches in elbows and shoulders then as well...but they gradually resolved.  I've had two separate episodes of very minor lesions to my tongue and general oral tenderness since March.  They really weren't that big a deal, except that when they start, I fear I'm heading back to where I once was! However, the tenderness resolved in a few days and caused no real trouble.  My vitiligo continues to increase gradually.  My entire chest is pretty much white...which I prefer to the blotchy business!

Still work pretty much full time hours. I feel so lucky to watch my little creatures grow and meet new ones everyday.  I'm running better, faster and longer...so that feels good.  Rosie is kicking my bootie with some track work outs that left me quite sore!  Shows I need to do that more often!

Still playing with my yard, cooking, sewing, reading, friends and family.  Still doing my melanoma research and postings.  There are days I am tempted to stop that business.  But, just when I think I'll morph into an eating and travel bloggess.....I hear from someone with a kind note of appreciation or with desperate questions about melanoma treatments.  And then I figure, I have access and training....and perhaps (???)....a way with words, such that those in need can find  answers (to the extent they exist) in an understandable, comprehensive manner...here.

"Do, what you can't NOT do."  
                               Cloud Atlas, David Mitchell

I shall try.  Much love - c

Anti-PD1 in melanoma: T-cells, the brain, and EVERYWHERE ELSE!!!!

OK...."We begin again!"  For those who know me, or have read this blog closely.....this is a completely stolen phrase...from my professor of geology....my favorite college class ever! A small, slightly chubby, ebullient, Indian would look out on his class after a half hour impassioned lecture on this geologic phenom or another...at all the blank, uninterested, unimpressed, lost, confused, attentive faces...and say, "Are you widst me?"  A more searching look, with a pleading quality to his glance, covers us.....  Now, slightly crestfallen, with a small sigh, "I think no." But, with a straightening of shoulders, and a charitable bent wonderful teachers always seem to possess, he would say..."We begin again!"

And here we are.  "What does anti-PD1 do?" "What does anti-PD1 do in the brain?"  "It can't cross the blood brain barrier!"  "You don't know!"  "What can it do for brain mets?"  "What?"  "What?" "What?????"

We begin again!!!!
For general info on anti-PD1:  background-and-latest-info-on-anti-pd1

I have no idea where the confusion began.  Anti-PD1 drugs have never, NEVER, EVER, done ANYTHING to a TUMOR ANYWHERE!!! Ever. Never. Ever.  EVER!!!!!!!!!!!! It doesn't hurt tumors.  AT ALL!  Not in the body.  Not in the brain.  NO WHERE.  Anti-PD1 is NOT chemotherapy.  Anti-PD1 is IMMUNOTHERAPY. It does NOT kill cancer.  It triggers T-cells.  ONLY!!!!!

"What is anti-PD1?  In the simplest possible terms:  Anti-PD1 drugs are antibodies that block the switch on white cells so that they can now attack melanoma cells.  Specifically, programmed death ligand-1 [PD-L1] is produced by the surface of melanoma tumors.  That ligand binds to the infiltrating T-cells, down-regulating them.  Basically, turning those cells "OFF" to melanoma.  ANTI-PD1 blocks that potential interaction, so that the T-cells can now attack melanoma cells."

 Anti-PD1 NEVER bothers a tumor...ever...at all...never. ever. ever.  Therefore...anti-PD1 doesn't have to cross anything...blood brain barrier...anything.  It only has to turn the white cells... confused, mislead, and turned off by the PD-L1 ligand, produced by the melanoma, back ON!  Then....voila'....back into fighting form...the T-cells kill the melanoma...wherever it may be....brain, buttocks, buccal mucosa...you get the idea...

Here's some data and pictures:

Just to give you some back ground on immunotherapies and the brain....think about ipi:

Phase II trial of ipi monotherapy in melanoma patients with brain metastases.
Authors: Lawrence, et al. 
Ipilimumab, a human monoclonal antibody that blocks CTLA-4 has activity in advanced melanoma.  This phase II trial attempted to assess ipi safety and activity in melanoma patients with brain mets.  Patients had measurable brain mets with at least one lesion >0.5cm and/or 2 lesions greater than 0.3cm, and none greater than 3cm in diameter.  Prior whole brain or stereotactic radiation to non-index lesions were allowed.  Ipi 10mg/kg was given IV every 3 weeks for 4 doses.  Responding or stable patients could receive maintenance ipi at 10mg/kg every 12 weeks.  Total of 72 patients in two arms...arm B still ongoing.  No association between brain edema or cerebral hemorrhage and objective response.  Of 51 patients in Arm A, at week 12: 4/51 had a partial response, 5/51 had stable disease, with additional unconfirmed responses.  Duration of responses ranged from 3 to 12+ months and duration of stable disease ranged from 1-7 months.  CONCLUSION:  Ipi has a similar level of activity in brain and non-CNS lesions.  Ipi worked as well in the brain as it did anywhere else!!!


Tumor-infiltrating lymphocytes and expression of PD-L1 in melanoma brain metastases.  Abstract 9055 ASCO 2014, Berghoff, Kiesel, Widhalm, et al.
"The brain is considered an immuno-privileged organ...." But after examining 46 specimens and measuring all the CD8+TILs, PD1 and TILs, etc, etc....  Melanoma brain mets show considerable TIL PD1 infiltrates and PDL1 tumor cells.

Association of tumor-infiltrating lymphocytes with brain edema and overall survival in brain metastases. Abstract 2012.  ASCO 2014, Preusser, Berghoff, Fuchs, et al.
"Density of tumor-infiltrating lymphocytes (TILs) has a prognostic impact in various extracrainial solid tumors. We characterized TILs in patients with brain metastases."  118 brain mets of patients with a variety of cancers were examined.  They were checked for CD8+ TILs, CD45RO+TILs, CD3+ TILs, and FOXP3+ TILs.  Conclusions:  "Dense TILs infiltrates are common in brain mets and correlate with the amount of peritumoral brain edema and improved survival prognosis."

When I had a recheck in March, 9 months after finishing my Nivo trial...I learned this:
  "Additional Cohort 6 added:

• How this cohort is defined specifically, how many have been enrolled in total, how many may still be enrolled, I do not know, however:
• 5 patients in this cohort were admitted with brain mets.
• 4 were treated (I presume by radiation...though not certain)
• BUT...1 experienced a COMPLETE RESPONSE with just Nivo!!!!!  (Awesome, right???!!)"

Full post that this was extracted from:   what I learned when my Nivo trial was opened to folks with brain mets

PERSONAL DATA:  When I entered my nivo trial, I had a second brain met...after prior SRS treatment of my first brain met and removal of the right upper lobe of my lung for a met there....YES.  I had ANOTHER brain met.  When Dr. Weber asked his radiologists to review my scans...I figure the conversation went something like this:

"He tells us to sit tight and that he is going to call a neuro friend of his to look at the scans as well as radiologists to take a look. Off he goes....

Weber pops back in to tell us that he doesn't really know that it is a met at all. He is going to get the other folks to give their opinion.

On his return, he says that the other radiologist/neuro people couldn't definitively say that the lesion in question was a met. He tells us that to his mind, I have "minimal residual disease" and therefore qualify for his study should I wish to participate in it. I figure the conversation went something like this: Weber = Do you think this lesion is a met? Neuro/radiologist = Well, given her history, probably. Weber = Yes, but, on its own. Can you tell me that this is definitely a met? Neuro/radiologist = Well, not definitely."

Bottom line:  He lets me in.  On scans three months later...after every 2 week dosing of anti-PD1(nivo) and peptide vaccines...the "what's it" in the brain....IS GONE!

Blog post this excerpt was extracted from:    melanoma neverland

Anti-PD1 doesn't attack tumors.  It sets T-cells straight...and they can go anywhere!  Here's old news about how t-cells enter the brain.


I promised pictures:

This slide is from:  Anatomical organization of the brain showing the possible routes of activated T cell entry.  From:  Autoimmune T cell responses in the nervous system, Joan Goverman, Nature Reviews, Immunology, June 2009

  "Activated T cells can enter the subarachnoid space by migrating from blood vessels into the stroma of the choroid plexus and then crossing the blood-cerebrospinal fluid barrier surrounding the choroid plexus stroma, which comprises epithelial cells joined by tight junctions.  Activated t-cells can also enter the subarachnoid space by extravasating through the cell wall of meningeal venules, which consist of endothelial cells connected by tight junctions.  In addition, activated t cells can cross the blood brain barrier surrounding post-capillary venules that penetrate the brain parenchyma, which comprises endothelial cells connected by tight junctions."

So, a lot of noise to try to express simple facts.

1.  Anti-PD1 doesn't kill tumors.

2.  Anti-PD1 unleashes T-cells from the grasp of melanoma so that THEY kill tumors.

3.  T-cells go everywhere.  We have known this for some time.

4.  The latest data regarding melanoma brain mets at ASCO tells us that they are surrounded by TONS of T-cells.

5.  My brain tumor went away after anti-PD1.

6. So did other peoples.

7. T-cells kill melanoma...not anti-PD1.

8. The science does lag behind the theory because folks with brain tumors have historically, not been allowed in anti-PD1 trials...for the most part...or in the expanded access programs as well.

Hope this helps.  Anti-Pd1 doesn't kill melanoma, but the t-cells it releases...DOES! - c

Thanks to the best Daddy......EVER!!!!!

Thanks, for all the pumpkins....

Even when they were weird inside....

And power tools were required....

For ALL the pumpkins....and for putting up with the goblins that came with them!!!!

Thanks for playing...in a tiny, diaper-less pool!

Thanks for learning to saddle and bridle an ornery mule....

And loving those beige socks!

Thanks for worrying when I ate bird poop....

And worrying when I did other things!

Thanks for arranging special fishing trips...even though we had to keep waiting for the hung-over captain to finish barfing.

Thanks for putting up with kids who often looked like this.

Thanks for having bad Karma....so we could all have Bad Karma.

And you know, your Z baby loves you, too!

Thanks for all the fun.  For all the trips you made sure we got to take.  For all the pictures.  For laughing with us when you almost broke your leg hopping over the bench to get in the picture.  For taking care of all of us.  For being the strongest man we know.  For being a constant.  For letting us know we are loved.  For being the best Daddy ever.
Love, Fred, Rosie, Zeno and Karm

Pretty Darn Impressive....a chat between Ribas and Weber categorizes PD1 as such and touches on other ASCO reports

This morning I received this link in my inbox....TWICE!!!  Thanks, Bentie and Steven! The quotes that caught my interest are noted.  The discussion ranged over anti-PD1, comparing the various results, addressed combining ipi and nivo, targeted therapies, the COMBI-D trial, and intralesional therapy....you can check out the whole video/transcript yourself with the link below.

"Pretty Darn Impressive" PD1 data in Melanoma....a chat between Ribas and Weber

Ongoing Breakthroughs in Immunotherapy.  Antoni Ribas, MD, PhD and Jeffrey Weber, MD, PhD
June 12, 2014

PD-1
Weber:  The melanoma... session included 4 very impressive abstracts on PD-1...antibodies... It opened with the first new PD-1 antibody that we have heard of...data from a relatively small study of about 100 patients...had a fairly good 1-year survival rate of 64%.  However, it only had about a 5%-6% response rate. That was pidilizumab (CT-011). ..10 years ago that might have cut it in the melanoma field for further development...[currently] I would be hard pressed to have enthusiasm for it.  This was a very well done study...but I am hard pressed to want to take pidilizumab further, given the current landscape. [see abstract referenced in June 5, 2014 post]

Weber:  In both the nivolumab [BMS anti-PD1] and pembrolizumab [MK3475, Merck's anti-PD1] abstracts (from your own [Ribas] abstract on pembrolizumab with 411 patients), we are looking at an average of about a 40% response rate across a number of different cohorts....and a lesser response rate (28%) in those who failed ipilimumab.  This is consistent with my experience in PD-1 trials, in which the response rate of those who failed [ipi] was 25%-26%....but in those who were ipi-naive, most of whom were previously untreated, we are getting close to a 40% response rate, with 1-year survivals in the range of 67%-69% and an 18 month survival of 62%...we are talking about at least a 24-month median survival, and that's pretty darn impressive from pembrolizumab.  We have high expectations that the drug will receive approval from the [FDA] before the end of the year. [see abstract in June 1, 2014 post]

There was an update by Hodi on the data...presented last year by Sznol...a 107 patient, phase 1/2 trial of nivolumab...This time, survival is in the realm of 17.5 months, across a 100-fold cohort in terms of dose.  Many patients were previously treated with 2-4 regimens, so... pretty beat-up patients...compared to the pembrolizumab patients, but the response rate was still 32%.  [see abstract in June 5, 2014 post at bottom]

...I presented...a 33% response rate in the ipi-naive group; I showed a 26% response rate in the ipi-refractory group. The median survival is excellent, but it's still less than 24 months...albeit in a group of patients who were treated at suboptimal nivo doses and who had already been through multiple regimens.  Nonetheless, the...data were impressive, showing very good survival.  Clearly, any drug with more than a 30% response rate in patients who have been through a median of 3 previous regimens in melanoma is looking very good. That drug [nivo], we assume, is going to come up for registration sometime this year.

Ipi-Nivo Combo
...highlight was ...the abstract...presented by Sznol...an update of the concurrent ipi/nivo study. [see abstract in June 1, 2013 post]...response rate about 45% in an updated expanded cohort of those with nivo at 1mg/kg and ipi at 3mg/kg...for as long as 96 weeks.  The response rate was in the mid-40% range, but of greater importance, the 2-year survival was in the high-70% range..an important landmark in melanoma. ....must be balanced against a 62% rate of grade 3/4 immune-related adverse events, many of which were easily reversible...only about half required an interruption of treatment....Whenever the rate of side effects at grade 3/4 exceeds the response rate, you have to sit up and take notice.  Nonetheless, a 70% plus survival rate at 2 years is outstanding in melanoma.

Ipi as adjuvant 
...Then...heard an ipi abstract from Eggermont on the first large, randomized adjuvant ipilimumab trial ever presented...patients with stage IIIA, IIIB, or IIIC were randomly allocated to ipi at 10mg/kg for a 12 week induction, followed by up to 3 years of treatment every 12 weeks vs placebo.  ...endpoint was progression free survival, and there was a definite difference:  about 26 months vs 17 months..... The rate of grade 3/4 immune related adverse events was 40% or higher.  Many patients had to stop treatment.  Most of these...occurred in the first 12 weeks.  There were a modest number of deaths: 6 deaths in 425 patients who received ipi.  The dose of 10mg/kg is not standard in the US or Europe.  It raises issues of whether this will be taken forward.

Ribas:  Is the rate of toxicity higher than what is seen in the metastatic setting?

Weber:  It was very similar to the metastatic setting....In the big picture, the rate of deaths was low.  The therapy was well tolerated. Most of the patients were stage IIIB and IIIC resected patients, and those are very high-risk patients.

Targeted therapies
Weber:  I was very impressed with Sosman's presentation of the CDK-4 inhibitor combined with the MEK inhibitor 162...a 33% response rate, ...phase 1 study with only 22 patients....Nonetheless, the NRAS-mutated population - which are BRAF wild-type because the 2 mutations are mutually exclusive - was a relatively hopeless cohort in terms of targeted therapy, and now it looks like there will be a useful and efficacious targeted therapy for at least 15% of melanoma patients who are NRAS-mutated BRAF wild-type. 

We heard Flaherty, who gave us an update on the BRF-113220 trial. [see abstract in June 4, 2014 post] ...randomized study with 162 patients, of whom 54 received dabrafenib alone (the BRAF inhibitor), 54 received dabrafenib with a lower dose of the MEK inhibitor trametinib, and 54 received dabrafenib and what we hoped was the optimal dose of the MEK inhibitor.  The updated data showed a clear superior rate of response: 76% vs the mid-50% range for either of the other arms.....there was a 25-month median survival...our institution was the biggest accruer to that trial.  About 20% of our patients at 3-4 years are still on treatment and doing well, with many complete responses over time.  It is a very impressive treatment.  It makes you wonder:  Maybe a BRAF mutated patient who starts on this combination should not receive immunotherapy first.  I would like to know what happened to the patients who failed the combination and then went on to immunotherapy. A debate is raging in our field about whether we should give immunotherapy or targeted therapy first, but I can't argue with a 25 month median survival - the best in any phase 2 trial of a significant size that I have ever seen.

Injectable therapies
Ribas:  ...a randomized trial of an injectable virus called T-VEC compared with granulocyte-macrophage colony stimulating factor (GM-CSF).

Weber:  ...the responses were 16% vs 2%.  Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero.  A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest....that is close to being able to show the satisfaction of the oncologic community that there are benefits to giving this injectable therapy....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma metastasis.....now there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going.  [see abstract and history of intralesional therapy in February 2, 2014 post]


So, there's my best synopsis...all their words...not mine.  Have to say, proud of the selection Brent and I made while looking through hundreds of ASCO abstracts. Only missed a couple that were discussed here.  Also pleased that two experts seem to view the data as I did....in that:
1. CT-011 (pidilizumab) is not worth pursuing.
2. Pembrolizumab and Nivo, the other two anti-PD1 drugs, are serving patients very well, and will probably be FDA approved this year.
3. The ipi/nivo combo offers good results, but somewhat concerning adverse events.
4. The ipi as adjuvant trial (this one was news to me) is certainly interesting, though the 10mg/kg dose is larger than what is routinely given here.  Would those patients still have had good outcomes with fewer adverse events at 3mg/kg?  I hope someone will do THAT adjuvant study!!
5. CDK-4 with MEK looks like it can really help NRAS patients who have had very limited options.  Hopefully, the data will hold up.
6. BRAF combo therapy seems pretty awesome.  What to do first?  Immunotherapy vs BRAFi???  Hopefully that answer will become more clear in the coming year.
7. Intralesional therapy made the "greatest hits" list!  Love it. Combining it with other therapies seems like a win-win to me!

That's a 2014 ASCO wrap-up!  Wishing all of you, especially the ratties....my very best. -c

Just like clockwork...Fred Azaleas!!!

They always know!

Ms. Moulin Rouge/Molon Labe stopped by to wish you the best of luck in the coming year!!!  Happy birthday, Freddie!  Love, mommy

Ipilimumab in combination with other medications for melanoma....per ASCO

Ipilimumab (ipi, yervoy) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that down regulates the immune system in melanoma patients. Alone, it has a response rate of 10-15%.  But, has 4 year survival rates of 37-49%, and 3-10 year survival rates in 17-25% in melanoma patients.  Given its potential, investigators have been examining drugs that can be safely combined with ipi, in ways that will improve response rate.

A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma
Abstract 9098, Kudchadkar, Gibney, Corman, Merek, Weber, et al.

Ipi, at 3mg/kg every 3 weeks for 4 doses was given with concurrent peginterferon at 3mcg/kg weekly for up to 156 weeks.  31 patients.  2 complete responses, 9 partial responses, 3 with stable disease, and 12 with progressive disease in 26 patients evaluable for response so far.  5 patients have not yet completed the first cycle.  Toxicities for peginterferon were dose-limiting with 7 patients requiring dose reduction (nausea, vomiting, leukopenia, dehydration, and hyponatremia). Conclusion:  The combo had a 42.3% response rate.  

Outcome with stereotactic radiosurgery and ipilimumab for malignant melanoma brain metastases.
Abstract 9076, Shoukat, Marcus, Rizzo, et al.

Patients with melanoma brain mets who underwent SRS between 1998-2012 (n=176) were compared to those who additionally received ipi (n-38).  Median overall survival for the cohort was 9 vs 7 months in the non-ipi group.  Patients in the ipi group had a median survival of 28 vs 7 months in the non-ipi group.  No increased toxicity or need for repeated SRS in the ipi group.  Conclusion:  SRS with ipi appears safe and associated with an increase in overall survival in patients in melanoma brain mets.

Preliminary results from a phase 1/2 study of INCB024360 combined with ipi in patients with melanoma
Abstract 3010, Gibney, Hamid, Gangadhar, et al

Indoleamine2,3-dioxygenase 1 is a tryptophan-catabolizing enzyme that is over expressed in cancers and induces immune tolerance by suppressing T-cell responses. It has been well tolerated as monotherapy.  This was an ongoing dose-escalation study of INCB024360 with ipi.  7 patients were enrolled at 300mg twice daily.  5 patients developed ALT elevations after 30-76 days on treatments and enrollment was stopped.  ALT increases reversed with steroids and discontinuation of the drug.  6 of 7 patients had scans before discontinuation and all showed immune response stable disease.   Enrollment was restarted at 25mg twice daily with 8 patients.  1 patient progressed with extensive liver mets.  6 of the 8 patients had tumor reduction by the first evaluation.  Confirmed disease control rate was 75%.  3 patients had confirmed immune response partial response.  A 50mg twice daily cohort is enrolling.   Clinical trial info = NCT01604889.  This study started enrolling in 2012, but as of postings in Feb and March 2014, it seems recruiting is ongoing.  Locations appear to be available in CA, FL, PA, NC, and IL.  It is ipi and drug vs ipi with placebo. Hopefully the lower doses of INCB024360 will not cause problems with elevated liver enzymes.

Phase 1 study of the BRAF inhibitor dabrafenib with or without the MEK inhibitor trametinib in combination with ipi for V600E/K mutation-positive unresectable or metastatic melanoma
Abstract 2511, Puzanov, Callahan, Linette, et al

Patients with Stage IIIC/IV BRAF V600E/K, melanoma with one prior treatment or less are eligible.  10 patients enrolled thus far.  4 had ipi and dabrafenib.  2 had dabrafenib only [thus far]. 4 had ipi/dabrafenib/trametinib.  In the ipi + D group - no dose limiting toxicities were observed.  Most common adverse events = chills, fatigue, hand-foot syndrome, fever, and rash.  Of the 4 patients - 2 are ongoing and 2 had disease progression.  Patients are currently being enrolled at this level.  At the ipi/D/T level - 1 dose limiting toxicity (colitis associated with ipi occurred), most frequent adverse effect = fever, chills, arthralgia, insomnia, and rash.  One patient had renal insufficiency that reversed rapidly.  Of these 4 patients, 1 stopped due to the dose limiting colitis and 3 are ongoing.  Clinical trial info - NCT01767454.  Recruitment began in 2012, but was verified to be continuing as of April 2014.  Participants must have the V600 mutation, measurable tumor, treated/stable brain mets, and NO prior ipi, anti-PD1, Brafi, or MEK. Patients will be given dabrafenib and ipi or dabrafenib + trametinib and ipi.  Locations:  San Fran, LA, Boston, St Louis, NY, Nashville, Houston.

Sending my love to the ratties - c

Pidilizumab (CT-011, aka CureTech's anti-PD1)...the other white meat? Not so much..anti-PD1 drug comparison via ASCO abstracts

Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma
Abstract 9001, Atkins, Kudchadkar, Sznol, Sosman, et al

103 patients with measurable, Stage IV metastatic melanoma, clearly progressive were randomized to two dose levels.  Prior treatments and stabilized brain mets were allowed.  Had to be 6 weeks from prior ipi, but never having had PD-1/PD-L1/PD-L2 blockade.  Overall survival at 12 months = 64.5% with insignificant differences between dosages.  The overall response rate was only 5.9% (using irRC....Remember, that gives you a built in higher response than when using RECIST!!!) . Progression free survival 2.8 months for the best group.
Seriously, CureTech??? You and your researchers state "further studies of pidilizumab in melanoma patients are warranted".  Who are you kidding and who do you think you will get to participate???  Much love and hugs and appreciation to the ratties who already laid it on the line to demonstrate the grand 5.9% response rate and got screwed out of the use of any other anti-PD1 product until the expanded access programs opened. Thanks, Jonathan!!!  But, I think we're done!!!!

Comparing data between trials is very tricky between differences in drug administration, patient sample, statistics used, data examined, and questions posed.  But, just so that you can have some measure of comparison (there have been no head to head studies) here's a little review and breakdown of the reports.  MK-3475 first:

 Clinical efficacy and correlation with PD-P1 expression in patients with melanoma treated with anti-PD1 monoclonal antibody MK-3475
Abstract 3005,  Kefford, Ribas, Hamid, Robert, Daud, Wolchok, Joshua, Hodi, Weber, Patnaik, et al

135 melanoma patients were given MK-3475.  In patients with measurable disease, the overall response rate was 41%.  For comparison with the last article noted here:  PD-L1 expression was associated with improved overall response rate (51% vs 6%) and progression free survival (median 12 vs 3 months). 

Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD1 monoclonal antibody MK-3475
Abstract 3015, Joseph, Schaap, Wolchok, Joshua, Ribas, Hodi, Hamid, Daud, Weber, et al.

365 patients with measurable melanoma were treated with MK-3475 and had a one year overall survival of 69%.

Nivo:

Updated survival, toxicity, and biomarker of nivolumab with/without peptide vaccine in patients naive to, or progressed on, ipilimumab
Abstract 3009, Weber, Kudchadkar, Gibney, et al.

105 patients given nivo, 12 mo overall survival = 65%.

Here's a new abstract out of ASCO for Nivo:


Long-term survival of ipi-naive patients with advanced melanoma treated with Nivolumab in a Phase I trial
Abstract 9002, Hodi, Sznol, Kluger, Topalian, Sosman, et al

107 melanoma patients were given nivo .Overall survival rates = 63% at 1 year, 48% at 2 years, and 41% at 3 years.  32% of patients had objective responses (per RECIST!!!!!)  In patients with PD-L1 positive (18) and negative tumors (23):  the median overall survival has not yet been reached for the positive group and was 12.5 months for the negative group.  The median progression free survival for the positive group = 9.1 months and for the negative group = 1.9 months.
This abstract does address a factor that this post is not really about, but lots of folks are very interested in...whether PD-L1 positive tumors respond better to anti-PD1 products.  It seems as though they did in this sample...but I think we are far from clear answers.  See above for the PD-L1 data from a MK-3475 trial I had already posted.

It seems to me that Nivo and Merck's 3475 are still pretty much neck and neck in the data...though you can find a little better this and a little better that, here and there, depending on the study. What remains absolutely clear is that CureTech's pidilizumab is not even close to having the same results!

Ratties are amazing folks.  love, c

BRAF studies from ASCO...and: NEW study open for BRAF positive NED melanoma patients!!!!

Updated overall survival for BRF113220, a phase 1-2 study of dabrafenib alone versus combined dabrafenib and trametinib in patients with BRAF V600 positive metastatic melanoma
Abstract 9010, ASCO
Flaherty, Daud, Weber, Sosman, et al

BRAF V600E/K positive, metastatic melanoma patients who had never taken either drug were enrolled.  Some were given dabrafenib alone and others the dabrafenib and trametinib combo...both at various dosage rates.  Cross over after progression on dabrafenib alone was allowed.  Updated data shows overall survival at 18 months for dabrafenib alone = 56%, for the combo =67%.
(My thoughts will follow in red!) Bit of an update on an older study.  Bottom line: dabrafenib and trametinib combo = better than dabrafenib alone.


Phase II study of vemurafenib in patients with locally advanced, unresectable stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E
Abstract 9075, J Clin Oncol
Hallmeyer, Hamid, Sorof, Mun, et al

Study was designed to look at response and reaction of stage IIIC or IV melanoma patients (previously treated or not with other therapies) with measurable disease and NON V600E BRAF mutation.  As of October 2013, 10 US sites enrolled 29 patients - 12 with V600K, 17 with non-V600K mutations.  7% of patients had never had treatment, those who had been treated had experienced a median of 2 prior therapies.  At this interim point of analysis:  12/29 (41%) of patients had an unconfirmed response (5 V600K, 3 V600R and 4 other).  Confirmed response was noted in 3 (V600K, V600R, and D594G).  There were no complete responses.  Adverse events were what is known to be typical for drug. Conclusion: Preliminary results - objective responses were attained in patients with rarer non-V600E BRAF mutations.
Small numbers...but patients with mutations other than V600E did respond to vemurafenib.

On-demand Gamma Knife combined with BRAF inhibitors for the treatment of melanoma brain metastases.
Abstract 9083 J Clin Oncol
Marqueste, Carron, Delsanti, et al (out of France)

Cases of radiosensitization after conventional radiation therapy in BRAFi treated patients had caused concern about using this combo.  In this study, blind review by 2 independent observers of brain MRI f/u scans and survival assessment in all patients treated with Gamma knife and BRAFi at a single institution, was completed.  Gamma knife was done on 30 patients who had previously been given BRAFi, 24 patients were under BRAFi treatment (with only 4 of those interrupting the BRAFi for the gamma knife procedure) and 15 patients had Gamma knife before starting BRAFi.  Out of 263 brain mets treated, only 3 edemas and 3 hemorrhages were detected within 2 months of gamma knife and 4/7 were noted later.  No brain met radiation necrosis and no scalp radiation dermatitis occurred.  Neither the MRI features nor the incidence of the rare adverse events were deemed unexpected in such a population.  Conclusion:  This series does not show immediate radiotoxicity nor radiation-recall in BRAFi patients treated with Gamma knife.  Interrupting  BRAFi for stereotactic radiosurgery of brain mets seems useless.
So...the fears about combining BRAF therapy and radiotherapy seem unfounded...combo = good!

Brain mets in melanoma patients:  Associations with BRAF status and age.
Abstract e20037 J Clin Oncol
Marinoli, Cocorocchio, Pennacchioli, et al (out of Italy)

Advanced melanoma patients (271) were tested for BRAF mutations and retrospectively analyzed.  V600 BRAF mutations were found in 53% and were associated with younger age at diagnosis and primary tumor site and had higher incidence of brain, but not of other visceral mets.  In young patients, wild type and V600 BRAF had a comparable incidence of brain mets, but wild-type was associated with a shorter brain met free interval.  In older patients, V600 BRAF had a higher incidence of brain mets and a shorter brain met free interval.  BRAF mutation per se, had no clear impact on overall survival.
OK.  So this is a little convoluted...but - If you are young and BRAF positive, you are likely to have your first primary sooner and greater incidence of a brain met.  If you are young with wild type, your brain met free interval may be shorter.  Older BRAF positive patients flipped...and showed a higher incidence of brain mets and shorter brain met free interval.  Big question here..."young" and "older" = what????   We can use me as a sort of messed up (due to anti-PD1 therapy) test case, as I am BRAF positive, diagnosed initially at age 39, went 4 years before another dermal met with no treatment other than surgical resection of lesion, positive sentinel node, and subsequent complete lymphadenectomy.  Treatment after second met = same, except no positive node.  3 more years before brain and lung mets, treated with SRS and surgery respectively.  Then 4 months and a tonsilar met, surgically removed.  Then, 2 1/2 years of Nivo (anti-PD1) and still NED.  Hmmm.... What will happen next??? 

Survival, response duration, and activity by BRAF mutation status of nivolumab (anti-PD1, BMS-936588) and ipilimumab concurrent therapy in advanced melanoma
Abstract LBA9003

Sznol, Kluger, Kirkwood, Wolchok, et al

53 melanoma patients were enrolled from 2009-2012 and were given ipi and nivo concurrently, then followed by nivo alone (with a variety of dosing patterns). Patients with and without BRAF had similar response. 

NIVO (mg/kg) + IPI (mg/kg) [n]	1-Y OS rate, % [pts at risk]	Median OS, mo	ACAR, %	ACAR by BRAF MT status,* % [n]
				Pos	Neg	Unk
0.3 + 3 [14]	56 [7]	14.8	57	50 [4]	67 [3]	57 [7]
1 + 3 [17]	94 [13]	NR	65	50 [2]	50 [6]	78 [9]
3 + 1 [16]	89 [3]	NR	81	67 [3]	85 [13]	– [0]
3 + 3 [6]	100 [5]	NR	83	100 [1]	75 [4]	100 [1]
Concurrent [53]	82 [28]	39.7	70	60 [10]	73 [26]	71 [17]
Sequenced† [32]	Insufficient followup	13.0	44	44 [9]	47 [15]	38 [8]

 So with ipi and nivo, combo or alone, BRAF status doesn't seem to affect response.

BRIM8:  A phase II, randomized, double-blind, placebo controlled study of vermurafenib in adjuvant therapy in patients with sugically resected, cutaneous BRAF-mutant melanoma at high risk for recurrence (NCT01667419)
Abstract TPS9118, ASCO

Lewis, Maio, Mandala, et al (Aurora, Colorado; Bergamo, Italy; San Francisco, CA; Essen, Germany)

Study for:  Stage IIC, IIIA, IIIB, or IIIC melanoma patients, BRAF V600 positive, and COMPLETELY RESECTED. Must have sentinel lymph node biopsy, even if no clinical or radiological evidence of disease.  If evidence of regional or sentinel lymph node involvement must undergo complete regional lymphadenectomy.  NO prior systemic therapy allowed - including interferon, limb perfusion or radiation therapy.  As of May 2014...still actively recruiting.  Birmingham, AL, Multiple CA sites, CO, FL, Illinois, Indiana, Kentucky, NJ, Michigan, Missouri, NY, NC, PA, SC, TN, TX, WV...as well as other international locations. 
Still actively enrolling!!!!!!!  Before my brain and lung met scenario...I would have qualified and think I would have done this.  Seems to me that using some of these successful therapies when the least disease possible is present is the way to go!

If BRAF and the mutation business is still confusing....I broke it down before.  Check out the link below if interested.  Wishing you all my best.  More from ASCO to come! - c

Explanation of BRAF in melanoma

MK-3475 (Merck's Anti-PD1) for melanoma...ASCO abstracts and my thoughts

Evaluation of immune-related response criteria in patients with advanced melanoma treated with the anti-PD1 monoclonal antibody MK-3475
Abstract 3006, J Clin Oncol
Hodi, Ribas, Hamid, Robert, Weber, Wolchok, et al

3 melanoma cohorts treated with MK-3475 2mg/kg every 3 weeks, 10mg/kg every 3 OR 2 weeks in a phase 1 trial.  Tumor imaging was performed every 12 weeks.  411 patients enrolled.  192 were on MK-3475 for 28 weeks or more as of 10/18/2013.  Tumor flare was seen in 7 patients. In these patients, best overall response was:  complete response = 1, partial response = 4, stable disease = 2.  Atypical delayed response was seen in 6 patients.  The 51 patients with progressive disease, but also WITH evidence of response using immune criteria had favorable overall survival compared with 145 patients who had progressive disease and NO evidence of response via immune criteria.  Conclusion: Conventional criteria such as RECIST may underestimate the benefit of MK-3475 in approximately 10% of treated patients.


Clinical efficacy and correlation with PD-P1 expression in patients with melanoma treated with anti-PD1 monoclonal antibody MK-3475

Abstract 3005, J Clin Oncol
Kefford, Ribas, Hamid, Robert, Daud, Wolchok, Joshua, Hodi, Weber, Patnaik, et al

135 patients received MK-3475 10mg/kg every 2 weeks or every 3 weeks or 2 mg/kg every 3 weeks.  Response was checked every 12 weeks.  Biopsy was required in the 60 days before starting med and PD-L1 expression was assessed.  As of 10/18/2013, all patients had 13 months or more follow-up.  In patients with measurable disease, overall response rate was 41%.  Objective responses were observed as late as 64 weeks, with some conversions to complete response seen as late as 72 weeks,  Median response duration was not reached; responses were ongoing for 87% of responders.  Tumor PD-L1 expression was evaluable in 71 patients with measurable disease.  Of these patients, PD-L1 expression was associated with improved overall response rate (51% vs 6%) and progression free survival (median 12 vs 3 months).  14% of patients experienced drug-related 3/4 adverse events, but there were no treatment-related deaths.  "Conclusion:  MK-3475 induces durable responses...and...although tumor PD-L1 positivity was associated with improved overall response rate and progression free survival, antitumor activity was also observed in patients with low PD-L1 expression."

Lesion-specific patterns of response and progression with anti-PD1 treatment in metastatic melanoma

Abstract 9077
Lyle, Lee, Menzies, Chan, et al (Researchers out of Australia)

Bi-dimensional measurements were taken of every met via CT at baseline and every 12 weeks thereafter.  27 patients evaluated with f/u of up to 54 weeks, had total of 442 discrete mets at baseline.  13 of 27 had had objective response, 11 of these by the first scan.  Median time to best response in patients with an objective response was 24 weeks.  Only 1 of 27 patients had a complete response.  However, 228 of 442 tumors had a complete response and 81% of patients had 1 or more met with a complete response at first scan.  Mets with complete response were smaller than those without it. Complete response rate was highest in lung vs other sites combined. Only 1 complete response met subsequently progressed.  Of 80 new or growing mets at first scan, only 4 (5%) subsequently had an objective response.  "Conclusion: Response to anti-PD1 therapy is rare in mets that are new or growing at first scan."

Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD1 monoclonal antibody MK-3475

Abstract 3015, J Clin Oncol
Joseph, Schaap, Wolchok, Joshua, Ribas, Hodi, Hamid, Daud, Weber, et al.

In phase 1 clinical trial, 411 patients given MK-3475 2mg/kg every 3 weeks, 10mg/kg every 3 weeks, or 10mg/kg every 2 weeks.  Response was checked every 12 weeks.  Of the 411, 365 had measurable tumors at baseline and median f/u of 10 months as of the October 2013 cutoff date. "Median overall survival was not reached, and 1 year overall survival was 71% in all 411 patients and 69% in the 365 patients included in this analysis.  While tumor size greater than 90mm was associated with a worse prognosis, these patients did have a median overall survival of 14 months in the combined data set, suggesting they derive benefit from MK-3475."  "Conclusions: Baseline tumor size is the strongest independent prognostic factor in patients with metastatic melanoma treated the MK-3475." 

Randomized comparison of two doses of the anti-PD1 monoclonal antibody MK-3475 for ipi-refractory and ipi-naive melanoma.

Abstract 3000, J Clin Oncol
Hamid, Robert, RIbas, Wolchok, Hodi, Weber, et al

2 cohorts - ipi naive and ipi refractory.  Patients were randomized to 2 or 10mg/kg every 3 weeks.   Arms were well balanced for known prognostic factors.  No significant differences were noted in overall response rate between the doses.  "Conclusions:  MK-3475 2 mg/kg every 3 wks and 10mg/kg every 3 wks provided similar efficacy and safety in ipi naive and refractory patients."

My thoughts:
1.   Patients with an immune response do better, even if scans don't show it.  To fail to look at the immune response in addition to the scan results may fail to provide an accurate picture of patient progression or success.
2.  PD-L1 expression of the tumor, facilitated a much better response to anti-PD1.  However, some folks with low expression responded as well.  Does that mean PD-L1 expression is pretty essential for a good response to anti-PD1 (51% vs 6% ORR) or do we just not have a good test?
3.  Two abstracts show us that smaller tumors respond better.  So why are we not treating more NED patients???????
4.  Patients seem to respond to anti-PD1 at the start since new or growing tumors at first scan, rarely responded....but sometimes they did.
5.  For MK-3475....2mg vs 10 mg/kg....neither did better than the other.  So...for all of you out there getting less than the 10mg/kg...no worries.  A lesser dose works just as well.
6.  And, as I've pointed out before....give it time!!!  Anti-PD1 can have positive effects...LATER!
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Results of my sister arm....in my Nivo trial at Moffitt -

Updated survival, toxicity, and biomarker of nivolumab with/without peptide vaccine in patients naive to, or progressed on, ipilimumab
Abstract 3009, J Clin Oncol
Weber, Kudchadkar, Gibney, et al.

105 patients with unresectable melanoma, who had failed at least one regimen were enrolled and given nivo at 1, 3, or 10mg/kg.  34 patients were ipi naive.  10 patients had failed ipi with grade 2 or less adverse events.  20 patients had filed ipi with grade 3/4 adverse events.  All of these patients were HLA A0201 positive and were given peptide vaccines along with nivo.  41 patients had grade 2 or less ipi reactions and were not HLA restricted and were given nivo alone.  Median f/u was 15 months.  Median progression free survival was 4.2 months.  Median overall survival was 16.7 months, with a one year survival of 65%.  Median overall survival was similar for ipi naive or ipi refractory.  Of 20 patients with grade 3/4 ipi reactions, only one had a subsequent grade 3/4 nivo reaction and it was different from the one experienced on ipi.  Conclusion:  Median overall survival of 16.7 months with nivo was observed in previously treated melanoma patients naive to or failing ipi.  Prior adverse effects to ipi were not replicated with nivo.

My take:  So...you can fail ipi and/or have a bad reaction to it and you may still respond to nivo and are NOT doomed to experience a repeat of your adverse reaction.  Median overall survival for MK-3475 and Nivo are looking pretty similar. 

Much more to come out of ASCO in the coming weeks.  Stay tuned.  And...how bout a hand for all those ratties?!!!  Wishing you all my best - c