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  

Chaotic Cookery! - From Someone Else's Table: Portable and delicious cakes (chocolate and apple)!!!

These two cakes are hard to beat for ease of cooking, dependable outcomes, and pleasing a crowd!!  They are substantial enough to tolerate transport without damage and the Apple Cake has become an annual request by my co-workers at our Thanksgiving lunch.  This year I took them both as a thank you for all they do to help me take care of all my little people.  Here are the recipes for you!!!

Bake me a cake, as fast as you can.....

Here's trick for chocolate cakes ~ mix a little cocoa with your flour when you butter then "flour" your pan and you won't have white flour on your nice brown cake!

Just a little morning baking.  Apple Cake.  Fruit compote.  Chocolate Pound Cake, waiting to have its top sprinkled with confectioner's sugar.

Apple Cake

This makes a great coffeecake for breakfast or brunch...or Peddie office lunch!!! 

1 c vegetable oil      2 c sugar       3 eggs, beaten      2 t vanilla

3 c flour       1 t soda      1 t salt       1 t nutmeg

2 t cinnamon      3 large apples, cored and chopped      Nuts, if desired

Sift dry ingredients. Mix wet ingredients. Combine. Stir in apples. Pour into a large baking dish. (This batter is gonna look a little strange for a cake.  Do not despair.  It is OKAY!!!  The apples are going to add liquid as they cook!!!)  Bake at 350 for 30 - 40 minutes.

Icing: 1 c brown sugar     ½ c evaporated milk     ¼ c butter

Cook all ingredients together about 3 min and pour over warm cake.

Chocolate Pound Cake

This cake is so rich and delicious!!  Cream the butter, sugar and eggs well - until super fluffy as they create a lot of your rise!!  Sometimes I use 1/2 milk and 1/2 buttermilk. 

3 c sugar      2 sticks butter      ½ c shortening       5 eggs     1 tsp vanilla

3 c flour     ½ c cocoa      ½ t baking powder      ½ t salt       11/4 c milk

Cream shortening and butter with sugar. Add the eggs one at a time and beat well after each. Sift dry ingredients and alternate with milk as you add them to the creamed mixture. Add 1 t vanilla. Pour into a well-greased and floured tube pan, bake at 350 for 1 hour and 15 minutes. Remove from pan as soon as you take the cake out of the oven. Sprinkle top with confectioner’s sugar once cooled.

Enjoy your chaotic cookery - From Someone Else's Table - c

And....AGAIN....ipi better WITH radiation!

So all the folks in academia are coming to the same conclusion.  Here's a prior post (with even more links within):  Radiation and ipi = better responses than either alone!!! (AGAIN!!!)

Improved Survival and Complete Response Rates in Patients with Advanced Melanoma Treated with Concurrent Ipilimumab and Radiotherapy versus Ipilimumab Alone.  Koller, Mackley, Liu, et al.  Cancer Biol Ther. 2016 Dec 1.  

There is a growing body of evidence supporting the synergistic roles of radiotherapy and immunotherapy in the treatment of malignancy. Published case studies of the abscopal effect have been reported with the use of ipilimumab and radiotherapy in metastatic melanoma, but evidence supporting the routine use of this combination of therapy is limited. We conducted a retrospective analysis to evaluate patients treated with ipilimumab for advanced melanoma at a single institution from May 2011 to June 2015. Patients were grouped into those who had received concurrent radiotherapy while on ipilimumab (Ipi-RT), and those who did not. We then evaluated the treatment response following completion of ipilimumab. A total of 101 patients received ipilimumab in the prespecified time frame. 70 received Ipi-RT and 31 received ipilimumab without concurrent radiotherapy. Median overall survival (OS) was significantly increased in the concurrent Ipi-RT arm at 19 months vs. 10 months for ipilimumab alone. Median progression free survival (PFS) was marginally increased in the Ipi-RT group compared to the ipilimumab alone group (5 months vs. 3 months, p = 0.20). Rates of complete response (CR) were significantly increased in the Ipi-RT group vs. ipilimumab alone, and rates of overall response (OR) in the groups were 37.1% vs. 19.4%. No increase in toxicities was observed in the Ipi-RT group compared to ipilimumab alone. Prospective trials are needed to further clarify the role of radiotherapy with ipilimumab, but these encouraging preliminary observations suggest that this combination can induce more durable responses to immunotherapy.

While all these reports involve ipi and radiation...there is no reason to believe the outcome would be any different with anti-PD1 or anti-PD-L1....we have just been using ipi longer.  So....let's get with it oncologists!!!! - c

Trials for Joshie (and Paulster and others....if needed)....

I've made links to trials first with a brief description below each ~

A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors

This one does note brain mets in past 2 years as well as immunotherapy as a "partial" exclusion.  So I am not quite sure what that means.  Is recruiting in Chicago.

Safety, Tolerability, Pharmacokinetic/Pharmacodynamic and Preliminary Efficacy Study of BMS-986205 Administered in Combination With Nivolumab in Advanced Cancers

This one has the exclusion of if you have taken nivo in a trial with the end point of overall survival.  But, if nivo was not from that sort of trial....it seems to be okay.  I think BMS-986205 in an oral IDO inhibitor.  Info on it alone is a little hard to find.  Also recruiting in Chicago, I think.

Phase 1 Trial of Hu5F9-G4, a CD47-targeting Antibody

"This is a first-in-human, first-in-class, escalating dose trial of an antibody that inhibits an anti-apoptotic signal in human macrophages."   There don't seem to be any exclusions that would be a problem.  It is active in San Antonio and California...and is supposed to be recruiting soon in Michigan.

A Trial of Intratumoral Injections of SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma

This is the dynavax with pembro trial and is recruiting in California, Colorado, NC, Penn, Tx, and Utah. Some arms do have an exclusion for prior immunotherapy...but it looks as though some allow it.  Here's a link about it:  Onclive conference

Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab in Refractory Cancer

This one is recruiting in Maryland, NY, Penn, and Tx.  You have be off any steroids for a couple of weeks...but there doesn't seem to be any other exclusion that would affect you.  However, you do have to be positive for B7H3, a surface antigen, that they will test your tumor for.  It is good to know that something like more than 94% of melanomas ARE positive for this antigen.


Safety Study of MGA271 in Refractory Cancer 

This one is enoblitzumab alone.  Recruiting in Cal, Chicago, Mass, NC, Penn, and Nashville.   There seem to be NO problematic exclusions.  Still need to be positive for B7H3.  Here's an article about enoblitzumab:  https://jitc.biomedcentral.com/articles/10.1186/2051-1426-3-S2-P177

Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

No problematic exclusions, I don't think.  Not sure this is really worth much when you need a response in a hurry, since both vaccines and immunotherapy take time...but -  Recruiting in Virginia, Cleveland, Ohio, NC and Atlanta.

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors or Lymphomas

This was first mentioned by Brian on MPIP.  It is pretty cool.  They analyze your tumor to see what "other" drug...usually used in other cancers....might be effective on yours.  They are doing it in a couple places in Chicago and a zillion places across the US.  Sometimes melanoma that is unresponsive to typical drugs WILL respond to those usually used in breast cancer and others because of its genetic makeup.

Then there are a variety of intralesionals combined with immunotherapy....T-VEC, PV-10, etc.

Not sure how much this helps.  Hang in there dear Josh and Paul.  Thanks to all the ratties.  And for all of you - Hug your dear ones...and enjoy every moment.  - love, c

P.S.  Remembered this one overnight!!!

Study of the Safety and Tolerability of Urelumab Administered in Combination With Nivolumab in Solid Tumors and B-cell Non-Hodgkins Lymphoma 

There do not seem to be any exclusion obstacles.  It is recruiting at Stanford, Moffitt, John Hopkins, in Boston, Chicago, NYU, Penn, Tx and even France, Germany and Spain!!!  Even better, I happen to know of 2 melanoma patients who had been progressing in dire ways despite every treatment in the book who are currently at Yale (I think), undergoing this therapy and for the first time are better or at least no longer progressing.   Here's some additional info...albeit from the company!

http://news.bms.com/press-release/bmy/phase-12-data-combining-urelumab-opdivo-nivolumab-hematologic-and-solid-tumors-sug

- c

Sew Chaotically! - Italian Linen Jacket - B5143

B actually picked out this beautiful Italian linen when we were in Vancouver from Atex fabrics

I wasn't sure what I was going to do with it at the time...but finally decided I wanted to make a loose, swingy jacket with it.  See the inspiration and discontinued pattern I found below:

Even though I normally make a 10 or 12 in the Big 4 patterns, this older pattern brings the weird marketing scheme that is sizing to light.  Based on measurements, I cut a size 14!  And while I did have to take a good bit off the side seams....I needed the size for my shoulders.  I also added a couple inches to the length of the shortest jacket pattern (the one in green above) because though I wanted to keep it just below the waist.....a long waisted girl's gotta do what she's gotta do!!!

It turned out rather more 'fancy' than I had anticipated.  And those embroidered dots made Bernie have 95 conniptions which made ME have 995!!!  I had liked the look of all the buttons down the front of the "inspiration jacket" but with the dots I knew it would be too distracting...not to mention unbelievably DIFFICULT.  I chose button placement VERY carefully to avoid any bumpage!!!

I played with sleeve length a good bit...and finally settled on this one with a large turned up and top stitched cuff.

Despite the tension woes (mechanical and emotional!) it gave me and Bernie to sew....I think it turned into a unique and pretty piece.  I like the swing and back pleat!  Thanks for finding it, B...and for putting up with my chaotic shouting with the stitching!!! Sew chaotically!!! - c

Factors predictive of response, progression and OS with dabrafenib and trametinib

Melanoma big dogs compile results of patients on dabrafenib and trametinib: 

Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials.  Long, Grob, Nathan, Ribas,..., Flaherty, et al.  Lancet Oncol. 2016 Nov 15.

Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF^V600E-mutant or BRAF^V600K-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma.

We did a retrospective individual data analysis based on all published randomized trials that included treatment-naive patients with BRAFV600E-mutant or BRAFV600K-mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomized trials. Patients with untreated brain metastases were not permitted to enroll in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analyzed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analyzed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov: BRF113220, number NCT01072175; COMBI-d, number NCT01584648; COMBI-v, number NCT01597908.

617 patients were included in this analysis with a median follow-up of 20 months (range 0-48); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months), median overall survival (25·6 months), 1-year progression-free survival (48%) and overall survival (74%), and 2-year progression-free survival (30%) and overall survival (53%) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68%) and overall survival (90%) and 2-year progression-free survival (46%) and overall survival (75%), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8%) and overall survival (40%) and 2-year progression-free survival (2%) and overall survival (7%). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4 months).  Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets.

Not surprisingly, folks with a low LDH and less than 3 organs involved had the best results.  Additionally, when folks did progress, those that did best in that case simply had increase in their baseline lesions or developed lesions NOT in the brain.  

Now....let's make things better!!! - c

Chaotic Cookery! - From Someone Else's Table: Stuffed cabbage and meatballs!

I've made lots of meatballs and lots of stuffed cabbage using different recipes, but this new to me recipe, inspired by Mario Batalli's latest in his - Big American Cookbook,  was really good!!!

Stuffed Cabbage (and then some)

1 large head of cabbage        1 pound ground beef        1 pound ground pork

2 cups cooked rice (In my case I had 1 cup left over rice and added 1 cup bread crumbs to make up the difference, but I think 2 cups of either would be fine.  I also dampen my bread crumbs with milk when using them in meatballs or meatloaf....a trick I learned in another Batali recipe!)

2 onions, grated     2 tsp fennel seeds     2 tsp ground coriander     s/p to taste

Supposedly one can dunk the whole cabbage into boiling water and peel off the leaves.  Once outer ones are removed, dunk some more, peel more and so on.  This process has never worked that well for me...so, I usually just peel and then blanch the leaves (and other bits) I've collected.  Once you have your cabbage leaves prepped...set aside and simply mix all ingredients listed for the filling.  Stuff leaves with the meat filling and fold over.  Give ornery bits that wouldn't come apart in nice leaves  a rough chop and tuck them along side the nice rolls as shown below.  If you're like me and have (or plan to have...cause it's worth it!!!) left over filling - roll them into meatballs and place on greased baking sheet. 

Tomato Sauce:  One onion, grated    2 cloves garlic, minced   s/p  (add basil and/or oregano if you just want a yummy spaghetti sauce...but I don't recommend it for this dish) - Saute in olive oil til tender.  Add about 1/2 c red wine and cook down.  (You may use broth or just proceed to the next step if you don't wish to use the wine.) Add 1 large can tomato sauce and 1 small can chopped tomatoes.  Simmer for at least 30 minutes...longer is fine and perhaps better.

All of this can be done a day before and refrigerated if you like.  When ready to bake - Pour about 1/2 to 1 cup chicken broth (enough to cover bottom of your baking dish) over cabbage rolls.  Top with a smattering of tomato sauce.  Cover pan with foil and bake for about an hour at 350.

Meanwhile, (or beforehand)  bake off the meatballs, at 400 degrees for 10-15 minutes, depending on the size of your balls, turning once at about 7 minutes.  I like to do this when I'm making the sauce and put them in it then which adds to the flavor!!!

Before baking and adding sauce.

Boil up some noodles, toss with sauce and meatballs and serve your cabbage rolls along side.  YUM!

Enjoy!  Cook chaotically - From Someone Else's Table....to yours. - c

Analysis of IL-2 after ipi in melanoma - and a bit more

IL-2:  An old drug in melanoma, tough to take, recognized to have a response rate around 10%, though about 4-5% of those can be durable.  Now, researchers are looking for ways to use it to improve responses when combined with other drugs.  There was this from 10/2016:  Killing melanoma (in mice) is enhanced in cells treated with reovirus and radiation OR with a combo of tumor-antigen-targeting-antibody, IL-2, anti-PD1 and a T cell vaccine!!!!

Use as an intra-tumoral agent from 7/2016:  Report on intratumoral IL-2 with intratumoral ipi for nonresectable Stage III/IV melanoma 

And this out of ASCO in June:  ASCO 2016 - immunotherapy after HD IL-2 and vice versa - HD IL-2 after anti-PD1 

Now there is this:

A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma.  Buchbinder, Gunturi, Perritt, et al.  J Immunother Cancer. 2016 Sep 20.

High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored.  The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed.  A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death.  In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

And this:  

Clinical Response Rates From Interleukin-2 Therapy for Metastatic Melanoma Over 30 Years' Experience: A Meta-Analysis of 3312 Patients.  Bright, Coventry, Eardley-Harris, Briggs.  J Immunother. 2016 Nov 21.    


Interleukin-2 (IL-2), initially used in 1986, can induce clinical regression-complete responses (CR) and partial responses (PR) of metastatic malignant melanoma. IL-2 has been used alone or in combination, and in different dosage schedules, as an immunotherapeutic agent for melanoma treatment. This meta-analysis aimed to document and evaluate the spectrum of reported clinical response rates from the combined experience of almost 30 years of IL-2 clinical usage. Clinical trials using IL-2 for metastatic melanoma therapy that reported: dosage, combinations, study details, definitions and clinical CR, PR, and overall response (OR) rates were included. A meta-analysis was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. In total, 34 studies met inclusion criteria, with 41 separate treatment arms. For all IL-2 treatment modalities collectively, the CR rate was 4.0%, PR 12.5%, and OR 19.7%. CR pre-1994 was 2.7% versus 6.1% post-1994. High and intermediate-IL-2 dosage showed no CR difference, while low-dose IL-2 showed a nonstatistical trend toward an increased CR rate. The highest CR rate resulted from IL-2 combined with vaccine at 5.0%. The meta-analysis showed that IL-2 immunotherapy for advanced metastatic melanoma delivered a CR rate of 4% (range, 0-23%) across nearly 30 years of clinical studies, with gradual improvement over time. The significance is that, contrary to popular belief, the data demonstrated that CR rates were similar for intermediate versus high-IL-2 dosing.

Keep on keeping on, dear ratties!!! - c

Radiological evaluation of response to melanoma treatments

Another reason liquid assays (as discussed here last month:  Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma! ) would be so helpful:

Patterns of response to anti-PD-1 treatment: an exploratory comparison of four radiological response criteria and associations with overall survival in metastatic melanoma patients.  Khoja, Kibiro, Metser, et al. Br J Cancer. 2016 Oct 4.  

Radiological assessment of response to checkpoint inhibitors remains imperfect. We evaluated individual lesion and inter-patient response by response evaluation (RECIST) 1.1, immune-related response criteria (irRC), CHOI and modified CHOI (mCHOI) and correlated response with overall survival (OS). Thirty-seven patients with 567 measurable lesions treated with pembrolizumab in the Keynote 001 trial were studied. Association of response with OS was determined.  Response varied according to site; lung lesions had the highest rate of complete response (69 out of 163 (42%) vs other sites 71 out of 404 (18%). Delayed response post first scan was seen in 2 out of 37 (5%) deemed progressive (PD) by RECIST and 2 out of 14 (14%) deemed PD by irRC. Modified CHOI criteria showed response of 38% (14 out of 37). Change in tumour size and density on first follow-up assessment was associated with OS with each 1000 mm² increase in tumour size from baseline increasing the hazard of dying by 25.9%.  Response defined by any criteria had superior OS. Response by any criterion was prognostic. Novel patterns of response and changes on treatment in tumour density suggest complex anti-tumour responses to immunotherapy.  

Then there is this report on using ultrasound to determine progression vs pseudo progression ~
 
Ultrasonographic findings can identify 'pseudoprogression' under nivolumab therapy.   Imafuku, Hata, Kitamura, et al.  Br J Dermatol. 2016 Nov 22. 

'Pseudoprogression' is often seen in patients with melanomas who are treated with immune-checkpoint inhibitors such as nivolumab or ipilimumab. We sometimes evaluate metastatic lesions by imaging tests such as CT or PET-CT. 'Pseudoprogression' usually occurs upon the initial administration, which may make it difficult for the physician to determine the disease condition. In our two cases of metastatic melanoma treated with nivolumab (anti-PD-1 antibody), we examined the ultrasonography (US) of target lesions that could be accessed from the body surface, such as those of the regional lymph node or subcutaneous metastasis. In both cases, the US revealed a lesion approximately 10% greater in size after 40-50 days of nivolumab administration, even though the blood flow inside the tumour was reduced by about 20% within 50 days. From about 100 days after blood flow reduction was detected by US, the tumours began to decrease in size. However, contrast CT was unable to detect the association between tumour size and tumour blood flow. The present cases suggest that US could be a powerful tool for differentiating between 'pseudoprogression' and real progressive disease in patients treated with cancer immunotherapies such as those involving immune-checkpoint inhibitors. The misdiagnosis of progressive disease can lead to unnecessary alternations in the current treatment. Therefore, the US findings in our study could be clinically useful and educational for physicians.  

Good data to know when depending on radiology studies as evaluation of status and progression.  But wouldn't it be nice to just do a blood draw????  At least some of the time???? - c