Patients vs Docs - Treatment goals for cancer patients

Also from the Boston Conference, Society for Melanoma Research -

Differences in the value that patients and physicians place on durable survival: implications for the treatment of advanced melanoma.  Shafrin, et a.

Cancer patients value therapies that offer long-term durable survival gains, but it is unknown whether physicians place similar value on durable survival. To address this issue, we surveyed patients with advanced stage melanoma and oncologists. We measured the share of respondents who selected a therapy with a fixed survival duration (ie,nonvarying therapy) versus one with a variable survival profile, with some patients experiencing long-term durable survival and others experiencing below-average survival. Initially, both therapies had the same average survival, calibrated to ipilimumab long-term survival data.We then applied parameter estimation by sequential testing to calculate the length of nonvarying survival that would make respondents indifferent between it and the therapy with durable survival. We also tested whether patient preferences were sensitive to adverse event (AE) severity. In our sample of 81 patients and 91 physicians, 63% of patients preferred the therapy with durable survival compared to 30% of physicians. The average patient preferred the therapy with durable survival even if the nonvarying treatment had 13.6 months longer average survival.  The presence of more severe AEs did not change these preferences.   In contrast, the average oncologist preferred treatments with fixed survival unless the survival had 7.5 months shorter average survival compared to the treatment with durable survival gains. These findings suggest patients value therapies that provide a chance at durable survival, and this result holds even when compared to therapies with more severe AEs. To reinforce the tenets of patient-centered care, physicians should take into account melanoma patient preferences for treatments with durable survival.

I found this research question and result very interesting.  While I have questioned docs and therapies and the choices we all make relentlessly over the past 30 plus years as a healthcare provider and the past 13 plus years as a melanoma patient...I had never thought about it this concretely...this succinctly.  It is hard to say what I would choose - sitting here - not currently being REQUIRED to choose a therapy at this moment....  BUT.  As I was reading this report for the first time, I was thinking that I would definitely choose as the majority of cancer peeps did.  I want the thing that will fix me....not just help me!!!  I mean, we all do what we can when we are running out of options...but yes...if the options were:  This treatment will help you....but this one could cure you....  Yeah.  I want that last one.  Thus far I am luckier than ever so many melanoma folks in that my one blitz of SRS, surgery and nivo has served me well, leaving me NED and with manageable side effects, though, in the flavor of truth in reporting, my tongue has a serious case of road rash as I type...again....over three years post last dose of nivo....BUT, a small price to pay!!!  Reading this brought back a thought I had when taking nivo in my Phase 1 trial and wondering what deleterious effects it might have on me and if it was going to work.  I felt exactly like Demi Moore's character in GI Jane, when she was told that she was to be pulled from her training program for investigation, but promised if cleared, she could repeat her training, she replied, "I can't go through this shit again!"  Melanoma treatment is so hard and miserable and expensive and time consuming and such a damn crap shoot, that it presses upon the body and psyche like an unbearable weight.  Yet...so many brave souls do more than just bear it. They survive and prosper and light our way.  Ultimately, these thoughts, this report, and the limitations that life itself presents to us all, makes at least one point very clear to me.  Doctors should evaluate patients, explain their condition, work to find all available treatment options and present them, but PATIENTS should have the ultimate choice in the treatment they find right for them. Because it doesn't seem that docs and patients agree - and docs aren't the ones who could lose.

Bless you one and all. - les

Melanoma blogging - a look back - and forward ~

A site I hadn't used in a while recently came up in some of my research and included a list of melanoma blogs.  A quick glance showed me that I knew most of the writers, many of whom have passed.  I looked through the rest.  I then perused a few other sites that keep a fairly up-to-date collection of melanoma blogs.  The results of my completely handy, rather than scientific project, found that of 40 melanoma blogs, 13 peeps were gone, and 20 were abandoned without explanation...many some years ago. Only 7 (and these numbers don't include mine) were still active.  From the disease process last documented in some of the blogs, it is likely their writers are no longer with us.  However, as some of the others were clearly Stage 1 or 2 at the time, I am hopeful that they are alive and well and have simply moved on to other things.

It is a crazy little world that I participate in.  Blogging real data about melanoma is time consuming and sometimes difficult work - NOT like digging ditches or surviving terrible diseases and the ravages of their treatments, by any means!!  But still.  I am contacted by lots of folks whose needs I cannot meet, but whose stories will be a part of me forever.  I am frequently harassed by complete whack jobs selling a variety of strange products and services. These are deleted quicker than you can say, "Bob's your uncle!"  Others inform me, with great authority, about what I should and shouldn't include/post on my blog. Some of these I answer, often scathingly (I am sad?/proud? to say!!).  Most join Bob.  Then, there are those I've met through this process who are now dear friends, having given me far more than I have ever shared with them.  Yet, losses over six years take a toll.   Like Judi Dench's character in Mrs. Henderson Presents, "I can't bear the feeling of helplessness.  I always think there is something I can can do.  Sometimes of course, there is nothing."  I don't know how long I will be able to keep this up.  Adding the sewing, cooking and travel sections Sew Chaotically!, Travel Chaotically!, and Chaotic Cookery! - From Someone Else's Table (though I know by the number of views that these posts are not most of my melanoma peep's cup of tea - and that's okay!!!) has helped sustain me by virtue of their prettier, sillier, more laughable and creative aspects.

My family and friends decided long ago that I'm completely nutters...confirmed by many observable facts:  The fact that I continue to work this hard in melanoma land.  Because I am a maniac, running around from one PASSION to another within my routine day.  And passion it is!!!  Books!  Music!  Friends!  Art!  Travel!  Kiddos!  Melanoma!  Food!  Gardening!  That I get unbelievably tickled when folks find my blog via search terms like:  "black silky chicken", "Morris Blazer", "Fredda Branyon", or "periwinkle".  Knowing my jokes are rarely funny, but my routine comments are.  And that's just a start...

I'm not sure how long I can keep doing whatever it is that you call this.  But, I promise, I will not disappear without a trace.  I - or someone - will let you know where I've gone...when I 'm done.

But for now, I will continue to try to be a friend....this friend....

I believe that together, we can find what we need.  Happy New Year.  - with love, les

Sew Chaotically! - Marled grey easy sweater - M6844

I made a sweater!!!!

Long slouchy sweaters are a 'thing' this year!  I'll break a sampling down for you, from left to right above:  Belfast Cardi, $198.00, Sundance - Realm Cardi, also $198.00 from Sundance - The CELESTE Coatigan (I kid you not!!!!  Hee hee!) for $178.00, Boden - and the simply named, Cardigan, for $129.00 from Prana.

So....with that 'style factor', being 5' 9", and Rosie's wisdom to advise that I use as much of this delicious totally washable sweater knit from Mood as possible!!!!....

I made the simplest, longest version on the bottom left, above.

I made size "medium", labeled as 12-14 since I wanted this to be a little on the larger size and I normally make a 10-12.  And I think it turned out well with no modifications in that regard.  The pattern actually nips in a bit at the waist, to give it some nice shape despite the easiness of the garment - something reviewers on Patternreview.com had commented on positively as well.

The material, while soft and lovely, (2 yards of "Moonbeam slubbed cotton-rayon" from MOOD @ $14.00 per yard) was very stretchy due to its loose weave.  I cut the pattern out one layer at a time and tried to move it as little as possible as it frayed like a booger!!!  I serged all the seams, though  I actually hemmed it on my regular sewing machine....after serging the bottom edge and hand hemmed the sleeves after same.  I also hand tacked the open collar from the bottom of the sweater to about breast level on both sides as it was a little too 'flimpy' to stay in place on its own.

The sleeves are full length, though I have shoved them up as usual!!

It is soft and cozy and washes up very well!!!  A truly Celestial Cardi for 28 bucks!!! Sew Chaotically! - c

One more time: Immunosuppressive therapy to manage side effects to immunotherapy does NOT affect response! New report.

I get asked repeatedly...and so many docs seem to have fallen behind the learning curve on this:

Do steroids and other drugs that suppress the immune response, when NEEDED for immune related side effects caused by immunotherapy, also diminish the critical response required to get rid of melanoma?

The short answer is no!!!  Here's info from two melanoma experts, published October 26, 2016 ~

Toxicities associated with checkpoint inhibitor immunotherapy - From UpToDate, with Postow and Wolchok

In the report it states:   "The need for immunosuppressive therapy to manage irAEs does not appear to affect the response to checkpoint inhibition."

It is a really good report.  Check it out with the link above if you are interested.   - c

Sew Chaotically! - A Rosie Red Party Dress - V1424

This easy to wear, wash and sew ponte from JoAnn's has found many uses!!!  You'll see more about that later!

The girly girl said she liked this one!!!

Sewwwww....that's what she got!

With....a funky little choker to match!

Silly bug!

Not really a difficult make.  It is fully lined.  Comes together rather well.  May not have made the pleats exactly as the pattern suggested, but they work and are completely finished on the inside. The hardest part was the last step - which is to attach all four shoulder bits - front to the back.  Rather fiddly and hard to keep as pretty as I liked.  Also, I had some concern, if done as recommended by the pattern, that they would fail to be strong enough to support the weight of the dress over time.  So, to fix all those issues I encased each in a bit of grosgrain ribbon after stitching.  Then...on a whim...made a very Keeping up with the Kardashians Choker to match!!!

I think she liked it!!! Sew chaotically! - les

More trial options for those who have been through it and then some! Oh, and ~ MERRY CHRISTMAS, with love and hope!!!

All we really need is love from dear ones, an effective treatment plan, and a little hope.

Here's a previous post with links to trials for those who have been through many melanoma treatments and still need a little something MORE!!!  -  Trials for Joshie and Paulster and.....

And here's another option, thanks again to researcher sublime - Eric!

A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas

This one specifically states: "CA-170 is a rationally designed and orally available, small molecule that directly targets the Programmed death-ligands 1 and 2 (PD-L1/PD-L2), and V-domain Ig suppressor of T cell activation (VISTA) immune checkpoints and results in activation of T cell proliferation and cytokine production. This is a multi-center, open-label, Phase 1 trial of orally administered CA-170 in adult patients with advanced solid tumors or lymphomas who have progressed or are non-responsive to available therapies and for which no standard therapy exists."

And INCLUDES:  "Tumor for which standard therapy, including approved anti-PD-1 or anti-PD-L1 therapy, when applicable, does not exist or is no longer effective."   

EXCLUSIONS do state: 

1. Radiotherapy within the last 21 days;
2. Primary brain tumors or CNS metastases;

(I'm guessing that means that treated brain mets...at least 21 days post treatment WOULD be accepted...but it is a little unclear.)  Recruiting in CA, CO, FL, Penn, NC, and TN.

I don't know much of anything about this particular treatment.  VISTA is a molecule involved in the regulation of immune response by T cells.  It has an effect on a different and earlier part of the process and works through inhibiting myeloid derived suppressor cells (MDSC's).  It may be synergistic with anti-PD1, anti-PDL1 and 2, as well as CTLA 4.  The specific molecule in this study,  CA-170, inhibits PDL1, PDL2 and VISTA.  This is a first in human study so what this will and won't do remains a question.  I will post anything more I do find, but...ratties end up teaching us all don't they?

Weber talks about some of this here:  The Future of Melanoma Treatment

Reminder of the importance of myeloid derived suppressor cells here:  Markers for response to immunotherapy   (Or put "Myeloid" in the search bubble for even more.)

And while this past year in melanoma world has been one of pain and loss and struggle for far too many, I, and many of my peeps, remain blessed to be here...still.  Not only are we HERE....we are not alone!  We have our dear ones.  And we have formed a formidable family....one with the other.  As folks, most of whom have never met, we absolutely KNOW one another.  We SEE, one another.  We truly CARE for one another.  And we DO lift one another with HOPE!  As eloquently noted by Michelle Obama ~

"Hope is necessary. It's a necessary concept and Barack didn't just talk about hope because he thought it was just a nice slogan to get votes. He and I and so many believe that — what else do you have if you don't have hope? What do you give your kids if you can't give them hope?"

It's true isn't it?  Without hope, even the brightest day, with all it's gifts, becomes dark and impossible.  So....on this most hopeful of calendar days - I wish you peace, and love, and hope.

Thanks to each of my peeps - near and far - for what you share with me each day. Merry Christmas, c

 PS  Gotta love Christmas in TN.  Just had a great run with B in shorts with a temp of 69 degrees!!!  First run in a while, as smoke from the surrounding wild fires had been causing dangerously bad air quality and limited my outdoor exercise.  But...skies are clear now - global warming not withstanding!!  Sending warm sweet wishes to all of you and your critters!! - les

The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

This interview/report is pretty cool and clear.  I'll just let the Wizard break it down - 

Novel Immunotherapy Combinations May Be the Future of Melanoma Treatment

By Caroline Helwick December 10, 2016  The ASCO Post

Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies. — Jeffrey Weber, MD, PhD

The future treatment of melanoma may rely on combinations of immunotherapy agents beyond the current checkpoint inhibitors, and they are entering clinical trials, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, who has spearheaded clinical trials in melanoma. At the 2016 European Society for Medical Oncology (ESMO) Congress, Dr. Weber gave attendees a taste of what’s to come in this tumor type.

“It’s become obvious that multiple checkpoints exist that are both antagonistic and agonistic molecules controlling adaptive immunity and innate immunity,” Dr. Weber said. He counted more than 50 members of the immunoglobulin or tumor necrosis factor (TNF) receptor superfamilies that could act as controlling or regulatory molecules.

In other words, the pipeline is rife with drugs that will target far more than cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). T cells also express TIM-3, LAG-3, GITR, and other factors, which, if agonized or antagonized, could boost an immune response and yield potential clinical benefit. They include many receptor agonists, “which press on the gas pedal,” he added, and receptor antagonists, such as CTLA-4 and PD-1, which “release the brakes.” In addition to antibodies in development, up to 15 new indications could be approved for the current CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) inhibitors, Dr. Weber predicted.

A High Bar to Surpass
The best results so far in advanced melanoma have been achieved by the combination of the anti–PD-1 agent nivolumab (Opdivo) and the anti–CTLA-4 agent ipilimumab (Yervoy). Nivolumab/ipilimumab yielded a 2-year survival rate of 63.8%, vs 53.6% for ipilimumab alone, in the CheckMate-069 trial.²

“In developing new checkpoint inhibitors, that’s the number we will have to be beat. If you want to add an inhibitory or agonistic molecule, you must at least match this, with less toxicity, and that’s a daunting challenge,” admitted Dr. Weber. “The fact that anti–PD-1 was developed early on sets a very high bar, which ironically could be a significant barrier to the successful development of other checkpoint inhibitors.”

Dr. Weber expects all new checkpoint agents to be tested in combination. Although 64% survival at 2 years is “fantastic,” he said, “at the end of the day, at least half the patients will need other therapy.” In all the tumor types for which these agents are important, “there is space for improvement,” he added.

Rationale for Novel Combinations
Immunotherapy combinations, with anti–PD-1/PD-L1 agents as backbones, will be driven by four key aims:

1. To bring T cells into tumors and overcome suppression of the immune system: For this, anti–PD-1/PD-L1 agents can be combined with anti–CTLA-4, immune-activating antibodies of cytokines, Toll-like receptor agonists, oncolytic viruses, indoleamine 2,3-dioxygenase (IDO) inhibitors, macrophage inhibitors, and targeted therapies.
2. To generate de novo T cells: This might be accomplished by vaccines, T-cell receptor–engineered adoptive-cell transfer, and chimeric antigen receptor–engineered adoptive-cell transfer.
3. To increase immune recognition: Stimulators of interferon genes (STING) agonists and interferons may help here.
4. To facilitate T-cell infiltration: This will be especially important for “cold” tumors that are deficient in T cells; the aim is to turn these “cold” tumors into “hot” ones. T-cell suppression, which occurs via multiple active and passive processes, must also be overcome.
These aims will be the mission of novel agonists, including anti-ICOS, anti-GITR, anti-OX40, anti-41BB, and anti-CD27, and novel antagonists, including anti–LAG-3, anti–TIM-3, anti-VISTA, anti-A2AR, anti-TIGIT, and IDO inhibitors.
“With T-regulatory cells, M2 macrophages, myeloid-derived suppressor cells—each a different lineage that requires a different maneuver to overcome—it’s amazing that any of this works at all,” he commented.

Sampler of Novel Combinations
Novel immunotherapies are not expected to be particularly potent as single agents, but in combination with other checkpoint inhibitors or targeted drugs, they are showing promise. More than a dozen combinations (including some triplets) are in phase II and phase III trials, including the following agents:

• Ipilimumab plus IDO inhibitors, talimogene laherparepvec (also known as T-VEC), interferon, and nivolu­mab/histone deacetylase (HDAC) inhibitor
• Nivolumab plus anti-CD137, TRAIL-R2 antibody, and LAG-3 antibody
• Pembrolizumab (Keytruda) plus IDO inhibitor, talimogene laherparepvec, BRAF/MEK inhibitors, interferon, and JACK/STAT inhibitor
• Atezolizumab (Tecentriq; anti–PD-L1) plus BRAF/MEK inhibitors
• Durvalumab (anti–PD-L1) plus BRAF/MEK inhibitors.
  

“Looking at all the mouse data from almost every antibody, results are better with combinations than with single drugs alone,” he said. “Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.”

Promising Early Data
Early data suggest that, for mutated patients, checkpoint inhibition plus BRAF and MEK inhibition is a powerful approach. In a study of the anti–PD-L1 antibody atezolizumab plus vemurafenib (Zelboraf) and cobimetinib (Cotellic), all patients in a 16-patient study had a reduction in target lesions; 3 patients had complete responses.³ The anti–PD-L1 antibody durvalumab plus a BRAF and MEK inhibitor produced a 69% response rate in another study, and all responses were ongoing at the time of analysis.⁴ In KEYNOTE 022, pembrolizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) produced tumor regression in almost all patients.⁵

Novel Combinations in Melanoma

• The future treatment of advanced melanoma may involve combinations of agents, with anti–PD-1/PD-L1 and anti–CTLA-4 as backbones.
• The pipeline is replete with agonistic and antagonistic molecules that target new checkpoints.
  

Pembrolizumab plus the IDO inhibitor epacadostat produced responses in 56% of 61 patients (63% of treatment-naive patients), and a disease control rate of 78% (and 75% of treatment-naive patients).⁶ Hepatotoxicity can be an issue with epacadostat, but it was not concerning in this study, he said.

One of the “more innovative” compounds targets OX40, an agonistic molecule that is expressed on activating T cells. An antibody against OX40 has shown significant and long-lasting antitumor activity in a mouse model of ovarian cancer when paired with an anti–PD-1 antibody.⁷ “This combination looks very impressive,” Dr. Weber commented. “You see very long survival [mean of 80 days, vs < 40 days for either agent alone], and, in fact, many of these mice were resistant to re-challenge. It’s clear that an adaptive immune response is promoted by the combination.”

An OX40 antibody (MOXR0916) was also combined with the PD-L1 inhibitor atezolizumab in a phase Ib study in solid tumors, but only 2 responses were observed among 51 patients, which he considered “disappointing.” However, this regimen will be further tested in melanoma and in other histologies with demonstrated responses to atezolizumab.

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

Wishing strength and peace to all my fellow melanoma ratties and fighters.  We've come a long way, baby!!!  And though there are miles to go...We Will GET THERE!!!! - love, c