Thursday, July 19, 2018

PEG-arginase and complete remission in immunotherapy-resistant melanoma, a case study


While the relatively recently approved treatment options for melanoma (both targeted and immunotherapy) have been absolutely life saving for many, myself included, there are still far too many of us in need of something else!!!  To that end, here is a case study...

To begin, PEG is polyethylene glycol, a vehicle used to make things soluble in water (or the human body) so that a drug/substance can be administered.  It is use in PEG-interferon, for example.  Arginase is an enzyme that breaks down arginine.  Arginine is an essential amino acid needed for protein synthesis.  It is used in the liver, for example, to help excrete ammonia.  Strangely, some melanoma cells are unable to synthesize their own arginine, making them dependent on arginine from other cells.  So now...there is this:

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma.  De Santo, Cheng, Beggs, et al. J Hematol Oncol. 2018 May 18.

Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism.

CASE PRESENTATION:

A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples. 

Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.

For what it's worth! - c

Friday, July 13, 2018

Sew (and live) Chaotically! ~ TURTLES!!! ~ made up in a Hollyburn skirt and a Polly Top to go with!!!


First....there was melanoma.  Then - there was Sally!!!

Here's the back story:  Inauspicious Beginnings

And the pics:  Sally the Loggerhead Turtle

And more pics:  Beach Scenes

Yes, turtles (and dragonflies) are now an intrinsic part of my life and part of the fiber of my family and friends.
Yentle Garden, around Yertle Creek, sports its own turtle (X's 3!!) figurine!  Creek designed by nature, but controlled and turned into a beautiful garden by Roo (aka Yentle!!  HA!).  Here's one of it's early pics:  The tree
More recently, the turtles continue!  As I turned into the drive just the other day, I glanced over to the new garden plot we've added and this is what I saw!  I laughed out loud!  B is one crazy dude, but very good at watering my plants, tolerating my whims, and ever so cute in his bow ties!!! 
See?????!!!!
Then, a few months ago....I got this beautiful surprise!!!
It was from Ruthie!  She does the BEST wrappings!!!!!  
They are always beautiful, perfectly match their contents, and contain the most amazing gifts!!!  Look at this TURTLE fabric!!!!
Sew ~ after pondering my precious turtle fabric for a bit, its destiny became clear.  I decided it would make a perfect Hollyburn skirt (Sewaholic) and needed a little Polly Top  (By Hand London) to go with! The Polly is bound with my own bias binding and the basic quilting cotton (chosen because I liked the color combo) did not like being eased into the curved bodice, wanting to gather instead.  I let it be, leaving some gathers evenly placed at the curves!  I cut the front of the Hollyburn skirt on the fold rather than in two pieces as prescribed by the pattern, so that I could place my turtles just so!!!  Had to shave off and reshape the sides a bit, but I think it worked!!!  Used my self constructed contoured waistband as mentioned in the post above.
The turtle fabric has the perfect attitude and drape for this skirt!!  
With fabric this fab, waste not want not!!!  There is a special baby on the way, where the love and longevity of the turtle plays a beautiful role as well!!!  May this turtle pillow provide cozy comfort for nursing, rocking into sweet dreams, and stories in the days to come!
With much love, my turtle collection continues to grow - all the bounty:  A turtle a day...  
And Ruthie hits a home run again with Miss Flora, nestled front and center!
Roo got a special prize, too!  It was right up her Owl-ly!!!!  Ha!  Are her flowers not beautiful????
With Ms. Turtle living just beneath!
Sometimes life is a beautiful circle that defies anticipation or explanation ~ requiring only our belief in others, love, and...well, turtles!!!   -  love, les

Wednesday, July 11, 2018

VISTA - an independent negative prognostic factor, but possible avenue for intervention, in melanoma...


As the search continues for ways to predict response and new avenues to attain a response in the treatment of melanoma - there is this:

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Kuklinkski, Yan, Li, et al. Cancer Immunol Immunother. 2018 May 8.

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate and the density of PD-1+ inflammatory cells. The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis and multivariate analysis. Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Get busy researchers!!!  - c

Saturday, July 7, 2018

Circulating tumor cells/DNA in melanoma!!! Have I not mentioned this a ZILLION times????


There are many blood (and other fluid) markers, all much easier to collect that actual tumor samples, that can be used to diagnosis melanoma, determine tumor type, prognosis and response to therapy.  Here's a link to zillions of posts:  Neutrophil-to-lymphocyte ratio and outcomes in melanoma. Yep, AGAIN!!!!!  More here:  Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And there is this (with tons of links within) on circulating tumor cells/DNA alone:  ASCO 2017: Circulating DNA to measure response in melanoma

Now, these:

Circulating Tumor Cells in Stage IV Melanoma Patients. Hall, Ross, Bowman, et al.J Am Coll Surg. 2018 May 7.
Management of stage IV melanoma patients remains a challenge. In spite of promising new therapies, many patients develop resistance and progression. The aim of this pilot study was to determine if CTCs are associated with shortened (180-day) progression-free survival (PFS) following a baseline CTC assessment in stage IV melanoma patients.

A baseline CTC assessment was performed in 93 stage IV melanoma patients using a commercially available immunomagnetic system. The presence of greater than/equal to 1 CTC was considered a positive result. A Cox multivariable regression model was used to evaluate the association between presence of CTCs at baseline and PFS, after adjusting for covariables. Kaplan-Meier curves and a log-rank test were used to summarize and compare unadjusted PFS for patients stratified by CTC positivity.


Median follow-up was 17 months; mean age was 55 years. Thirteen of 93 (14%) patients had no evidence of disease (NED) at baseline CTC assessment. One or more CTC was detected in 39/93 (42%) of patients at baseline. CTCs were not associated with primary melanoma features or NED status. Twenty-eight of 93 (30%) patients progressed within 180 days of baseline draw, with 20/39 (51%) of the CTC positive patients relapsing compared to 8/54 (15%) of the CTC negative patients. In adjusted Cox models, a significant association was found suggesting worse PFS within 180 days for CTC positive patients at baseline (vs. CTC negative).


One or more CTCs at baseline were associated with progression within 180 days in stage IV melanoma patients. This information warrants further study of CTCs as a means of identifying patients at high-risk for disease progression.


Measuring circulating tumor cells can predict response and progression!! And, this.....

Quantitative monitoring of circulating tumor DNA predicts response of cutaneous metastatic melanoma to anti-PD1 immunotherapy.  Herbreteau, Vallee, Knol, et al. Oncotarget. 2018 May 18.

Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.

When circulating tumor DNA was monitored in patients treated with immunotherapy, no significant decrease in the ctDNA measured in the blood was associated with lack of benefit from anti-PD-1 AND an increase in the ctDNA "was 100% predictive of progressive disease, on average 75 days prior to radiological detection."  Think what being able to change treatments, from one that is not working to one that might serve you better, 75 days sooner, could mean for patient outcomes!!!  And, there's this:

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease. Ballester, Glitza, Douse, et al.  J Neuropathol Exp Neurol. 2018 Jun 4.  

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

Here researchers are simply noting that the cerebral spinal fluid can be monitored in the same manner blood samples can be.

I have been noting these reports for YEARS!!!!!!!!!!!!!!!!!!  If I am aware of these options, then oncologists should know about these study results and assay possibilities far better than I.  These minimally invasive, but highly informative tests, should be readily available and utilized as part of the arsenal to diagnosis, predict response, determine progression, find appropriate therapy, and ultimately save lives of melanoma patients ~ TODAY!!!!  - c

Wednesday, July 4, 2018

Skin resident memory CD8+ T cells, stimulated by vaccines, protect against melanoma!!!!


I have long hoped vaccines would play a positive role in melanoma treatment!!  Heck, I was a rattie in one of the arms of my nivo trial that included peptide vaccines.  Here is one of my latest posts on the topic:  ASCO 2018!!! We'll start with melanoma vaccines....and a story!

To sum up that post ~ I, along with my fellow ratties, were injected with 6 painful peptide vaccines (as in, they were administered as an injection into our thighs) every 2 weeks for 6 months along with our intravenous infusion of nivolumab.  It turned out that our particular vaccine did us no good.  It is even possible that the injections "sequestered" our helpful CD8+ T cells at the site of the injections.  There is some evidence that rather than revving up our fighting T cells and having them go attack our melanoma, the vaccines simply attracted them, perhaps even fired them up, but then the little suckers just lazed about at the vaccine sites, like camels at an oasis.  (Do camels do that?  I don't really know.)  Anyhow, additional abstracts about vaccine hopes and dreams and scams are included in the post, but... there is also this:

Dendritic cell vaccine induces antigen-specific CD8+ T cells that are metabolically distinct from those of peptide vaccine and is well-combined with PD-1 checkpoint blockade. Nagoaka, Hosoi, Lino, et al.Oncoimmunology. 2017 Nov 2.

The success of immune checkpoint blockade has unequivocally demonstrated that anti-tumor immunity plays a pivotal role in cancer therapy. Because endogenous tumor-specific T-cell responsiveness is essential for the success of checkpoint blockade, combination therapy with cancer vaccination may facilitate tumor rejection. To select the best vaccine strategy to combine with checkpoint blockade, we compared dendritic cell-based vaccines (DC-V) with peptide vaccines for induction of anti-tumor immunity that could overcome tumor-induced immunosuppression. Using B16 melanoma and B16-specific TCR-transgenic T-cells (pmel-1), we found that DC-V efficiently primed and expanded pmel-1 cells with an active effector and central memory phenotype that were not exhausted. Vaccine-primed cells were metabolically distinct from naïve cells. DC-V-primed pmel-1 cells contained the population that shifted metabolic pathways away from glycolysis to mitochondrial oxidative phosphorylation. They displayed better effector function and proliferated more than those induced by peptide vaccination. DC-V inhibited tumor growth in prophylactic and therapeutic settings. Only DC-V but not peptide vaccine showed augmented anti-tumor activity when combined with anti-PD-1 therapy. Thus, DC-V combined with PD-1 checkpoint blockade mediates optimal anti-cancer activity in this model.

Here, in a petri dish, researchers treated melanoma cells with a dendritic vaccine and a peptide vaccine.  They found that only the dendritic vaccine (NOT the peptide vaccine, further corroborating what we real live ratties found in my study) helped increase anti-tumor activity when combined with anti-PD-1 therapy.  Okay.  As far as that goes....

Okay.  I think this is the perfect place to utilize a phrase I created in my childhood, "What's so about that?????"  Well, maybe nothing.  But now, there's this - (and a link to the entire article if you are so inclined):

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Gálvez-Cancino, López, Menares, et al.  Oncoimmunology. 2018 Mar 19.


Memory CD8+ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8+ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8+ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

You may be thinking, "Interesting, I guess!  But, what's so about that????"

Well, the notation "intradermal" might just be the thing.  It seems from this research that in order to elicit the response Galvez and Lopez are talking about, the vaccine had to mess with the SKIN!!!  Not just be stuck in the body else wise.

Now, give me a minute here.  Remember the mad scientist I live with???  He has been postulating a theory about how triggering a response in dendritic cells and CD8+ T cells that LIVE IN THE SKIN might be the ticket to stimulating the development of vitiligo and thereby a good response AGAINST melanoma for years!

Remember this?  Itching and vitiligo associated with progression free survival after Pembro/Keytruda???!

And this from 2014:  Vitiligo and melanoma  Which includes this commentary:  What I think this says is:  The CD8+ T cells that cause vitiligo, promote response to melanoma.  But, we don't know how. So...the researchers checked a certain type of T cell in mice with no thymus (so the mice couldn't use that part of the process to induce vitiligo) and even so, the active T cells continued to produce vitiligo and protection against melanoma.....and they don't know why!

This from 2015:  Vitiligo....a good prognostic indicator for melanoma!  Which, for the purposes of this discussion is most important for this pic and the commentary beneath it ~


"Vitiligo initiation at site of surgery."  The vitiligo in this poor actual rattie started WHERE THE SKIN WAS CUT!!!!!!!!!!!!!!!!!!!!!

And finally - if you are still with me!!! - there is this from 2011:  Anti-PD-1 is still kicking....

Here, I note:  Apart from that, Brent is developing a rather complicated theory about why which rats, both human and rodent, develop vitiligo, versus those who do not, and thereby have a more positive outcome in regard to their melanoma.  It has to do with the dendritic cells in the skin, their exposure to the melanoma antigen (either from vaccines or from tumor material itself), and the subsequent triggering of the immune response.  I'm telling you...the man is going to win the Nobel Prize for finding the answer to this mess!!  But bottom line, if he's right...does this mean I should be grateful that I am thin, thereby lacking in significant subcutaneous tissue into which the vaccines should have been injected?  Thankful that vaccine material drifted into my dermis either by chance or poor administration techniques by some of the administrators?  Remember Ruthie's dismay when tons of my "Elmer's Glue" came oozing back out of my injection sites? I can't answer those questions, but I'm betting Bentie will figure it out.  I'll just keep reporting.

Okay.  You made it!!!  What all this means, I am not entirely certain.  But, I think research is building more and more of a case about how the skin itself harbors not only evil cutaneous melanoma cells for some of us, but also the key to removing melanoma's protective shroud and killing it!!!  We know that the skin contains:  dendritic cells (of many types!!!), gamma T cells, alpha T cells, CD8+ T cells (specifically the trm [tissue resident memory] cells addressed in this most recent abstract).  We also know that Tissue Resident Memory cells travel up to 2mm per day in the intradermal space.  That's not totally weird or creepy, is it??? TRM's, surveying their territory like a sand shark along the beach, on the look out for tasty minnows or melanoma cells!  Perhaps, the horror of injections that hurt like a booger, then oozed the nasty thick white goo back OUT of the holes poked in my skin, DID make a change in some of my dermal CD8+ Tissue Resident Memory cells.  MAYBE those vaccines did help trigger my vitiligo, as an outward sign of an interior response by my CD8+ T cells against my melanoma.  Maybe the vaccines I was given did not work as initially intended, but did, perhaps, play a role in why I am still here.

Happy 4th.  Here's hoping your dendritic and CD8+ trm cells are busy bees today and every day!!! - c

Saturday, June 30, 2018

Families Belong Together!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!


Yes.  Today.  Across the nation, people marched.  In opposition to the Trump administration's decision to separate children from their parents at our border.  They were separated before we could even determine if the families were here with legitimate claims for asylum or not.  And even if we found that they should return to their countries of origin, are we a people who take children from their parents?????  I don't think so ~ and millions of other Americans don't either!

Here is a link to one report on the thoughts of a nation:  Here Are The Best ‘Families Belong Together’ March Signs - article from Huff Post  As their lead in says, "Toddlers shouldn't be in jail!"








B and an amazing group of human rights advocates did double duty...marching yesterday AND today!!


Today...amazing peeps from Chattanooga gathered....

And....yes.  We marched.  
I helped lead with B working to bring up the rear.  Thanks guys!!  It is a comfort to meet such a wonderful group of peeps - walking in the heat - on behalf of those who cannot.






Unless you are a native American - I'm Irish/German, B is Scotch/Russian - like us, your peeps were immigrants to the great nation that is America.  The Statue of Liberty welcomed my ancestors as she did yours.  Recent immigrants from Honduras, Guatemala, and El Salvador are not here to game the system, do us harm, or "take our jobs".  Rather, immigrants clean things, pick things, and work in conditions that most Americans will not!!!  To the contrary, these immigrants are fleeing circumstances we cannot imagine.  They are leaving their HOME!!!  They are leaving their FAMILY!!!  They are desperate to provide a better life for themselves and their children.  Most undergo what we would consider intolerable circumstances for over a month, just to make it to our border.  There, they ask for asylum.  Something they have the legal right to do.  Still...they are jailed and their children, more than 2,500 of them, have been removed from their parents.  Is this who we are???  Is this what we want our government to do?  Is this how you would want your brother, your sister, your children - treated?

We don't think so.  So we march.  And more importantly - VOTE!!!
Love trumps hate! - c

Thursday, June 28, 2018

Sew Chaotically! - Inari Tee Dress by Names Patterns


I have loved lots of the Named Inari Tee Dresses I've seen floating about!  There is this one in linen by Heather of Closet Case Patterns.  This one in tencel by Dani of Sewing and Cocktails.  And there were these made up by Carolyn with a great tutorial on a sleeve modification which I actually used on mine!!!  I knew I was going to use this bit of unlabeled fabric from a bin in a shop in Walthamstow for an Inari the minute I saw it!!!  It is a textured woven with threads of uneven size in blues and white that I just love.  It did ravel with the least provocation, but was otherwise easy to work with and washes up like a dream.  I used bias binding rather than the facings at the neckline.  Drafted the sleeves as suggested by Carolyn.  Added a couple inches of length.  And attached my sleeve hems so they are to stay down (rather than flip us as directed) because I liked that shape and length better for me.

I love that the drape of this fabric emphasizes the cocoon shaping!




I really like how this turned out.  It is such an easy dress!  I look forward to making a couple more as well as the "top" version.  It is certainly a pattern that will change its look depending on the fabric drape!!  Off to play!  Sew chaotically!! - les

Wednesday, June 27, 2018

Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.


Here's a link to the nice little ad (I mean announcement!!!):  ARRAY pharma gains FDA approval for the Encorafenib/Binimetinib

Here are prior posts on the combo: 
This from May 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 

My review: 
PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.

This from March 2018:  Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!

Here are some snippets from that post:
I report this again only because "they" are!  Institutions, Big Pharma, and researchers like to have their name in lights.  So, I will shine my spotlight once again!  I reported on and evaluated the results of the COLUMBUS study here, back in May of 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 
Now that title statement, is absolutely true and good!!!  In that report, I went to the trouble to look up these stats:

From The coBRIM trial - August 2016 we learned - that when cobinmetinib and vemurafinib were combined, the median overall survival (OS) was 22.3 months and the median progression free survival (PFS) was 12.3 months.

From this discussion of BRAF/MEK and immunotherapy (Nov 2016)  we learned = that generally treatment that was a combination of a BRAF inhibitor and a MEK inhibitor could illicit a response rate of 48-59%, even as much as 70% with some combo's and PFS of 11-12 months.


So, yes...the encorafenib with vemurafenib combo has a better PFS than the combo's noted above ~ at least in this study of the 192 BRAF positive unresectable/metastatic Stage IIIB/C or Stage IV peeps  who were given it below.....

[The abstract followed (you can see it for yourself via the link above).] My synopsis:

But...  Here are some comments I made (in red) in the prior post which provides more info about the trial and trial results than this re-run abstract just posted in the Lancet:

Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial. [Why the hell not???? You could put them in their own separate group, so as not to sully your results Array CEO person!!! And still give them access to the drug!]

In Part 1 of the study, the median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for vemurafenib alone. The improvement in PFS represented a 46% reduction in the risk of progression or death. [That's good, but of course we have learned never to give vemurafenib, a BRAF inhibitor without a MEK inhibitor!!! So that's a bit of a false comparison!]

The objective response rate (ORR) with the combination was 63%versus 40% with vemurafenib. [Again...not comparing apples to apples...we KNOW that response rates are better with a BRAF/MEK combo!!!] With single-agent encorafenib, the ORR was 51%. [This fact can at least be compared to single agent vemurafenib response rate of 40%.]

Grade 3/4 AEs were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. [As previously demonstrated, side effects were DECREASED with a BRAF/MEK combo.]

Okay.  My synopsis is this:  Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS.  This combo showed a PFS of 14.9 months.  Objective response rate was 63% with the comb0.  There was an ORR of 51% to encorafenib alone.  Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending.  OS data for encorafenib/binimetinib has not yet been reported.  OS in most other BRAF/MEK combo's is around 2 years.  The combo discussed here demonstrated fewer side effects than when the BRAFi component was used alone....which is consistent with other reports using a BRAF/MEK combo vs BRAFi alone.

PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.  Hang tough ratties.  You will save us all. - c

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

So....yep.  Pretty good sum up, I'd say.  STILL have no OS data.  Which is possibly good...in that they are having to watch it a long time, because these ratties are still trucking!  Or, possibly not good...and Array and the researchers just haven't wanted to put it out there yet!  (Oh, yeah...I'm definitely in the pocket of Big Pharma, right?  Just a little inside MPIP humor there!!!)  Hopefully, those numbers will be good and the Encorafenib/Binimetinib BRAF/MEK combo will be an improvement over current BRAF/MEK combo's for BRAF positive melanoma peeps.  However, the problem with this trial is just as it so often is with others: 
1.  We don't compare apples to apples. 
2.  We leave out folks (brain mets, LMD, ocular, and mucosal melanoma patients) in serious need....cause WHY????  (Yeah, I actually know.  Those folks do not respond as well to most current therapies and make your products look bad don't they Array, BMS, Merck...and all the rest of you???) 
3.  We don't base trial questions on what we already KNOW!!!
4.  Results are slow in coming.
5.  We saw the same logs over and over.

_______________________________________________
Now, BACK TO TODAY ~ I don't think this approval is necessarily a bad thing at all!!!  But....I do believe in truth in advertising.

Here are a few more deets from the package insert:  OOOOOPS!  Is Array inept or not providing full disclosure???!!!  Cause.....no matter how I look it up, I have not succeeded in finding a working link to the prescribing info for BRAFTOVI, only the one for MEKTOVI seems to be working.  So, I'll suffice it to say that these are basically new BRAF/MEK inhibitors that should be given together for folks with BRAF positive (V600E or V600K) melanoma which is about half of us.  They are administered orally.  They come with about the same side effect profile as all the other BRAF/MEK combo products. 

Here's hoping that many melanoma peeps benefit from the combo.  Here's hoping that someday, clinical trials will be set up in such a way that folks who MIGHT benefit are NOT excluded, that apples are compared to apples, that pharma will realize that we ratties are NOT stupid and can see very clearly when they stack the deck in their favor.

For what it's worth. - c

Sunday, June 24, 2018

Art, information and hope!!! ~ Sketching My Way Through Metastatic Melanoma - by Eleanor Segal


Gotta say!  Folks with melanoma are some of the most amazing peeps I have ever known!!  I am blessed to have come to know so many incredible melanoma friends.  I am very lucky to have Ellie as a dear one for some time.  Not only is she a melanoma superhero, she is a talented artist, and author!!!

Ellie has certainly paid her melanoma dues, from a primary on her thigh in 1989 to abdominal mets in 2013 followed by surgeries, a zillion scans, IL-2. Yervoy, Opdivo, BRAF/MEK, side effects...AND....DRUM ROLL PLEASE ~ NED per last scans in May of 2018!!!  Those results being well maintained on a Tafinlar/Mekinist combo and low dose prednisone! Way to gut it out, sister!!!

In her book, Sketching My Way Through Metastatic Melanoma, Ellie shares her experiences through words and pictures.  She made me smile, feel her worry, and recognize her world as she poignantly shares so much of what we melanoma peeps undergo.  She also informs -  with excellent reports on the way her therapies worked, were administered, and how she dealt with side effects.

Here are some of my favorite pics (comments are mine):

Packing is serious, yo!!!
As is squaring our shoulders and packing away our fears!  Ipilimumab/Yervoy.
ONO4538, MDX1106, BMS 936558, Nivolumab, Opdivo!
The wait!!!!  We've all done plenty of that one, right???
BRAF/MEK, targeted therapy.
For a bit of an interview of Ellie and additional background on her work, here's a link to a write up by the AIM at Melanoma Foundation:  Sketching My Way through Metastatic Melanoma - by Eleanor Segal  as well as a copy of their report below:

Sketching Her Way Through Metastatic Melanoma

Nearly every melanoma patient or survivor that AIM has met has a coping mechanism, hobby, or pastime—something they do to help them in one way or another through their cancer.  The most common one we hear is connecting with other patients through social media.  But others include gardening, cooking, writing, and doing yoga.
Eleanor Segal sketches.  Ellie is 63, married, and a resident of Portland, Oregon.  Ellie always made things, and she went to art school.  She didn’t draw consistently through her life; she did metalsmithing, created lotions and potions, and worked in other media.  But she began drawing again just a few years ago, and now she has sketched her way through metastatic melanoma.
But let’s go back to the beginning.  In 1989, Ellie had a melanoma removed from her right thigh.  All was fine until 2013, when her doctor felt something unusual during a routine pelvic exam, which turned out to be fist-sized lymph node full of melanoma.  After being diagnosed with metastatic disease, she’s had four surgeries, a month of radiation, three types of immunotherapy, and currently, targeted therapy.  
After her metastatic diagnosis, she joined the Portland Chapter of Urban Sketchers, a global organization. Urban sketchers always carry their gear, draw wherever they are from observation, and share their work online.  The goal is not to be a perfectionist—not to spend too much time on any one sketch—but to show the world what they see, one sketch at a time.
So Ellie brought her sketchbook with her to all of her appointments, and she began sketching everything around her, from her Interleukin-2 IV fluid bags to the contents of her hospital suitcase to the view out her hospital window.
“I didn’t do this for therapy, or to help other people,” she says.  “It’s for me.  I make collages, write questions, make lists.  Sketching allows me to observe, process, sort things, and navigate complex decisions.”  Indeed, many of her sketches are combinations of items in the hospital—such as a scale or a pill—combined with details about treatment.  While some patients might take notes, Ellie sketches.
It wasn’t originally a goal to make a book, but she has published a beautiful volume of watercolor sketches entitled “Sketching My Way Through Metastatic Melanoma.”  Her family, friends, and healthcare providers are the lucky recipients of her books, and she has kindly included an AIM bookmark inside each volume, reminding those who receive the books to give to melanoma research.
Thank you, Ellie, for capturing in a beautiful form what so many of us have been through, and for letting AIM share a few of your sketches.  
You can reach Eleanor Segal via email: billellie@comcast.net

Thanks indeed, Ellie!!!  While your art certainly helped you cope with all you have endured, it has become a great boon to the rest of us as well.  Ubuntu!!! [I am because we are.] - love, les

Friday, June 22, 2018

Sew Chaotically! - Archer Button Up, by Grainline Studio


What can I say???  I have loved every Grainline Studio pattern I've made.  The size 8 fits perfectly with no adjustments.  The directions are great.  They make up as shown with no surprises.  There have been multiple Morris Blazers, with more to come!!!  Three Alder shirt dresses!! And a total of 6 Lindens, though only 2 were for me, yo!!!  There were these, then Rosie needed this and this!!!  So, I've been looking forward to trying their Archer Button Up (or basic button-down, as it were)!!








It did not disappoint.  The make is very similar to the Archer Shirt dress.  It plays well dressed up or down.  I made short sleeves with an improvised cuff due to fabric limitations.  I love it!!!  Sew Chaotically!!! - les

Thursday, June 21, 2018

Another possible option for NRAS mutant melanoma patients


Sadly, today's post is in keeping with those of the past two days, in that this abstract doesn't give a great deal of definitive info.  By way of explanation, here is a link to prior posts (with links within) that address treatment for folks with:  NRAS-mutant melanoma

This ASCO 2017 report noted:  NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.

After which I wrote this:  In this study, 224 NRAS mutated melanoma patients were studied. 180 were treated with ipi, 98 with anti-PD-1 and 1 was given the ipi/nivo combo.  The overall response rate was 15% for those treated with ipi and 34% for those treated with anti-Pd-1....which is in keeping with response rates for those drugs generally.

Despite the fairly optimistic (For melanoma world, don't 'cha know???!!) report above, there are other studies (and more importantly ~ real live NRAS friends and peeps) who have struggled with attaining good responses on current therapies.  The mice and researchers now share this:

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma. Echevarria-Vargas, Reyes-Uribe, Guterres, et al. EMBO Mol Med. 2018 Apr 12. 

Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.

Perhaps this will help send therapy for NRAS-mutant melanoma in a better direction.  Hang tough my dear NRAS ratties!!! - c

Wednesday, June 20, 2018

Repeated SRS for brain mets????


Like yesterday's post...not exactly news...but, now this:

Repeated in-field radiosurgery for locally recurrent brain metastases: Feasibility, results and survival in a heavily treated patient cohort.  Balermpas, Stera, Muller von der Grun, et al. PLoS One. 2018 Jun 6.  

Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1-37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12-28 Gy) in 1-5 fractions to the median 69% isodose (range, 53-80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade greater/ = to 3 toxicities.
A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.

So this is a look at only a handful of patients with mixed cancers, but having SRS as a second go round for brain tumors can be helpful with manageable side effects.  (Of course, side effects are much more manageable when you are not the rattie!!!)

For what it's worth - c

Tuesday, June 19, 2018

TIL outcomes with and without melanoma brain mets


So....there is this:

Outcomes of Adoptive Cell Transfer With Tumor-infiltrating Lymphocytes for Metastatic Melanoma Patients With and Without Brain Metastases. Mehta, Malekzadeh, Shelton, et al. J Immunother. 2018 Apr 18.

Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.

So...this is not really news.  Folks with brain mets didn't do as well as those without.  But, still good to know!!  Sounds like for brain mets, you need SRS (or gamma knife radiation) no matter what other therapy you do!!  For what it's worth - c