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

Sew Chaotically! - Inari Tee Dress by Named 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

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

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

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

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

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

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

Sew Chaotically! - Another By Hand London, Polly Top

As a last 'remnant' (Ha! Ha! Sewing humor!!!) of Rosie's closet clean-out, she gave me a cotton gauze scarf she never wore, to use in some capacity as I desired.  When questioned, she said, "I don't know how.  But, I'm sure you can come up with something to do with it!!!"  

Well, it sat for a minute and I remembered this:  Sew Chaotically! - Tale of 2 tops - Polly and Sally???? 

The Polly top is great.  The curved front is a miracle of fitting without darts.  Not sure how it would do for those more fully endowed, but for those belonging to the Itty Bitty Titty Committee, it is lovely!!!  Oh!!!  Did I mention that the lovelies at By Hand London give it away for FREE??!!!
Check this out:  Please welcome the Polly Top sewing pattern! (Oh yes, and she's free).

So with the aforementioned scarf and a bit of gauze fabric left over from a top I made for Ruthie last year ~ I made this!!!

I fully lined the front with the yellow gauze....

....while leaving the back un-lined and employed bias binding for all finishes.

Isn't she the cutest????

I think Polly and Roo are a great combo!!!

And a lily, cause...well...pretty and matching!!!  Enjoy your Saturday and...Sew Chaotically! - les

Trial option for folks with uveal melanoma with IMCgp100

For a very long time folks with brain tumors, LMD, mucosal and uveal melanoma have been left out most trials that brought current melanoma therapies FDA approval.  Things have improved a bit for brain met folks - but new approaches and entry into trials to try them remain hard to find for those other melanoma peeps.  This data and the trial options listed at the bottom of the report offer some hope and options for uveal folks.

Here's the link and the report from OncLive, May 2018:

Novel Immunotherapy Shows Early Efficacy in Uveal Melanoma

IMCgp100, a novel immune-based treatment, demonstrated a 1-year survival rate of 73% (46%-88%) for patients with heavily pretreated, advanced uveal melanoma, which is nearly double the historical expectations for patients with the disease, according to lead investigator Richard D. Carvajal, MD.

At a median follow-up of 12.8 months, the median overall survival had not yet been reached in the phase I study. The objective response rate with IMCgp100 was 11% among (2%-30%), with 5 additional patients (26%) showing signs of stable disease with minor responses (greater than/= to10% reduction in target lesions). The median progression- free survival (PFS) with the treatment was 24.3 weeks, and 62% of patients remained alive and progression free at 1 year.  (See table)

“Advanced uveal melanoma has a 1-year overall survival rate of approximately 40%, and no cytotoxic, targeted, or immunological therapy has been previously identified to meaningfully improve outcomes,” Carvajal said at the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting, where he presented the data. Carvajal is director of Experimental Therapeutics and the Melanoma Service at Columbia University Medical Center in New York, New York.

“The 73% 1-year overall survival we observed in the heavily pretreated patients with metastatic uveal melanoma treated with IMCgp100 is quite notable,” he said. “We are excited about the continued development of IMCgp100 for patients with this disease.” IMCgp100 is the leading candidate in a new class of investigational therapies targeting the T-cell receptor (TCR) called immune-mobilizing monoclonal T-cell receptors. It contains 2 functional ends, 1 that targets the soluble affinity–enhanced TCR and the other an anti-CD3 single-chain variable fragment. The TCR end binds to the melanoma-associated antigen gp100, and the effector end activates an antitumor CD3-positive T-cell response.

 IMCGP100 Clinical Efficacy Findings

Dose Escalation Strategy

The dose escalation study included 19 patients across 4 dose levels ranging from 54 μg to 73 μg. The study utilized an intrapatient escalation strategy: on day 1 of the first cycle, patients received IMCgp100 at 20 μg, which was escalated to 30 mcg on day 2 of cycle 2. This was followed by enrollment to 1 of 4 cohorts testing a range of doses (54 μg, 64 μg, 73 μg, and 68 μg).

Dose-limiting toxicity in the form of abnormal liver function tests was observed in 3 patients. Two of these events were seen in the 4 patients who received the highest dose, which was subsequently reduced to 68 μg. This dose was identified as the maximum tolerated dose of IMCgp100 and will be further explored in phase II trials.

The median age of patients was 55 years, and the ECOG performance scores were 0 (74%) and 1 (26%). Participants had undergone a median number of 4 prior therapies (range, 0-8), which included chemotherapy for 95% of patients and prior immunotherapy for 68%. Prior immune therapy included ipilimumab (47%), pembrolizumab (32%), and nivolumab (16%). All patients had liver metastases, and lactate dehydrogenase levels were greater than the upper limit of normal for 73% of patients.

In terms of responses, the median time to objective response was 27.8 weeks and the median duration was 24.1 weeks. The disease control rate (responses plus stable disease) was 53% at week 16 and 32% at week 24. There were no complete responses, and 26% of patients developed progressive disease as their best response, which occurred mostly in doses below 68 μg.

A pharmacokinetic (PK) analysis of the study showed consistent dose-dependent activity. The half-life for the drug was determined to be 6 to 8 hours across all doses above 20 μg.

Evidence of T-cell infiltration was seen using immunofluorescence in pharmacodynamic assessments. Immune activation was seen in the tumor after 3 weekly doses of IMCgp100, which was consistent with T cell redirection, the researchers noted.

Following treatment, there was a temporary reversible decrease in peripheral lymphocyte counts, which is indicative of lymphocyte trafficking. Immunofluorescence analysis of biopsy samples after 3 doses of IMCgp100 showed high levels of lymphocyte trafficking into the tumor, with persistent lymphocyte infiltration. At progression, there were high levels of PD-L1 expression, gp100 antigen expression, and CD8 T cells present in the tumor.

All patients in the study experienced treatment- emergent adverse events (TEAEs), with 79% having a grade 3/4 event. The most common all-grade TEAEs were pruritus (90%), pyrexia (84%), fatigue (84%), hypotension (74%), chills (63%), nausea (68%), dry skin (63%), and peripheral edema (63%). The most frequent grade 3/4 TEAEs were fatigue (16%), hypotension (16%), erythema (16%), and macular rash (11%).

The skin toxicity observed in approximately two-thirds of patients persisted during the first 4 weeks of treatment and then began to taper off. There were no grade 3/4 skin toxicity events beyond 4 weeks, and by week 7, skin toxicity events reached a plateau, with approximately 26% of patients having a rash beyond 100 days of treatment.

“While research is still ongoing, I am encouraged by the results from this phase I study in ocular melanoma. We are committed to progress research to benefit patients,” Carvajal said.

A pivotal phase II trial is enrolling participants with uveal melanoma to further test IMCgp100 compared with investigator’s choice of systemic therapy, which could include the CTLA-4 inhibitor ipilimumab or the anti–PD-1 agent pembrolizumab. The open-label phase II study plans to enroll 327 participants, with an estimated primary completion date of July 2020 (NCT03070392).

In addition, a phase II portion of the study reported at ARVO is now open for additional participants. This expansion cohort of the study hopes to enroll 150 patients. The estimated completion date for this expansion trial is December 2018 (NCT02570308).

For what it's worth.  Fingers crossed! - c

Sew Chaotically! - Another little casual/exercise top!

I have had such fun making these little exercise tops for Roo!!!  The first couple were made from scraps, while the last two were made with a little more thought, specific material selection, and care!!  But, they have all been a party in the back!!!

This burned out knit from MOOD turned out even better than expected!! I picked it and the purple up during a knit sale they were having.  Like the purple, per Roo's request, it was lengthened about 2 inches.  Given a curved hem, and per one top I have and others I've seen in photos, I created a pattern piece for this back!!!  Yes.  It hurt my small brain, which is completely devoid of spatial relation aptitude, but I really like how it turned out!!!

Such a cutie!!  Then we were off to class, where the 8 1/2 month pregnant instructor ~
 KICKED.  OUR.  BOOTIES!!!!!

Sew (and exercise!!) chaotically!!! - les

ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

Okay.  One of the many zillion dollar questions in melanoma (for those who are BRAF positive) is:  "What treatment should I do first ~ BRAFi or immunotherapy?"  Right now [SPOILER ALERT!!!] we don't know, though the report below is trying to figure that out (at least for Stage III patients). And before I get to the report/ad for the study now enrolling:  Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma (NeoTrio)  ...here's a little review on adjuvant vs NEOadjuvant treatment.

In adjuvant trials or treatments, like the one I participated in, the melanoma patient must have all of their "measureable" melanoma removed.  (Would that we really could have ALL of our melanoma removed!!!) In real terms this means that all positive nodes or lesions that are visible on scans are surgically removed.  Additionally, though it depends on the study, if one has brain tumors, patients can have them zapped and if, over a certain period of time (this varies study to study) they do not recur, and the area fails to light up on subsequent scans, the patient may join the adjuvant trial/treatment, at which time they are given the treatment du jour.

In NEOadjuvant treatments/studies, patients keep the lesions they have and start the treatment du jour.  Sometimes after a certain amount of therapy the lesions are then removed, if they have not evaporated with the treatment, sometimes not.

Here is a March 2018 report I put up:  BRAF/MEK before surgery as well as after is MUCH better, than just AFTER surgery for melanoma!! Plus trial still recruiting resectable stage III/IV melanoma peeps.  Clearly you can read the entire report and abstract for yourself, but this was my take:

In this study of only 21 stage III/IV patients who had never taken BRAF/MEK, whose tumors were BRAF positive, and could be removed surgically, were divided in 2 groups. Folks with "metastases to bone, brain, or other sites where complete surgical excision was in doubt" were excluded.  7 got standard of care:  complete excision of their tumor and "consideration" of adjuvant therapy.  21 got the BRAF/MEK combo (dabrafenib and trametinib) BEFORE surgical removal of their lesion as well as AFTER!  Ten of the 14 treated with BRAF/MEK before and after excision were alive without disease progression "vs none of seven in the standard of care group".  These results were deemed so good that this phase of the trial was stopped and only the neoadjuvant/adjuvant arm is continuing, and in fact, recruiting.

This is great news.  However, I do see several flies in this report.
1.  You researchers left out some folks in serious need of care...folks with brain, bone and other mets that you didn't see as a winning ticket.  I've been one of those peeps and was given adjuvant care.  Those folks need neo-adjuvant/adjuvant care as much (or more!!!!) than anybody!!  Here's a small tirade on their being left out of clinical trials:  A really good review of treatment data for Melanoma Brain Mets!!! (And this is from 2015!!!!!!!!)
2.  These are really small numbers...in both arms.
3.  The fact that the 7 in the standard care arm were eligible for "consideration" of adjuvant care is pretty lame.  That language tells me that some chose to forego adjuvant care!!!  So OF COURSE!!! ~ those who had no additional care did less well!!!!  To provide greater clarity and benefit, the authors should have clearly defined the standard of care group in regard to whether they actually utilized BRAF/MEK after resection or not.
4.  Finally, I really don't care for the major drama, yet lack of real information, posed in this categorization of the 7 peeps in the standard of care group:  "more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group".  At first blush it seems that all of the 7 are dead, along with the 4 out of the 14 in the neo/adjuvant group!!  Come on, Amaria!  You have better writing skills than this!  Some of these peeps may well have passed, but it is also possible that ALL these folks are alive, albeit with disease progression.  Clarification of that could easily have been included in this abstract and is hopefully made more clear in the actual published article.

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One more pertinent side note - Researchers have been working on seeing how things go for melanoma patients who are treated with immnotherapy (like anti-PD-1) COMBINED with targeted therapy (BRAF/MEK) for a while now.  Here are some reports:  ASCO 2017 (with links to the "whole she-bang") BRAFi and anti-PD1/PD-L1

Now, there's this:

Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: A phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial). Gonzalez, Menzies, Saw, ... Georgina V. Long. ASCO 2018. 

Background:  BRAF targeted and CTLA-4/PD-1 immunotherapies have high response rates and improve survival for patients (pts) with metastatic melanoma, however, most still die of this disease. It is hypothesised the activated cytotoxic T cell infiltrate that occurs early during treatment with BRAF/MEK inhibitors is potentiated by adding checkpoint inhibitors, resulting in improved response and survival. While trials combining BRAF/MEK inhibitors and anti-PD-1/L1 antibodies are underway in the metastatic setting, the neo-adjuvant (neo-adj) setting provides an opportunity to test different treatment schedules in small cohorts of pts. Tissue and blood biomarkers can be drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response, biomarkers of efficacy, and to select the best schedules to take forward to larger-scale trials.

Methods: Eligible pts with BRAF V600 mut, stage IIIB/C/D, resectable and measurable melanoma are evenly assigned to 3 cohorts (n = 60). All pts undergo complete macroscopic resection (RES) at wk 12 and receive neo-adj therapy for 12 wks preceding RES, followed by 40 wks of adjuvant (adj) therapy. Cohort 1 receive sequential therapy with D+T for 2 wks, then 4 pembrolizumab (pembro) doses until wk 12, and 3 wkly pembro after RES. Cohort 2 receive concurrent D+T and 3 wkly pembro before and after RES. Cohort 3 receive 3 wkly pembro for the entire treatment course. Pembro is given at a flat dose of 200mg. Ultrasound of known disease areas is undertaken during the neo-adj period. CT and FDG PET/CT are used to measure response and exclude progression in theneo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, wk 1, 4 and 12. The primary endpoint is the complete pathological response rate at RES following 12 wks of therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analysis. First patient enrolled 29Nov2017. Clinical trial information: NCT02858921

Best as I can tell they are going to take 60 Stage III patients with measureable disease, and put 20 into each of 3 groups.  The groups are treated as noted below, per ClinicalTrials.gov
Group 1 = 
  Sequential D + T, THEN Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 2 weeks, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 2, 4, 6, and 9, then once every 3 weeks from week 12 for 50 weeks
Group 2 = 
 Concurrent D + T AND Pembrolizumab

Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks

Group 3 = 
Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.

It seems to me that they should have offered immunotherapy followed by BRAF/MEK in a Group 4, so there could be a complete answer, but I guess that's just me.  CT's and PET/CT's along with blood and tumor sample testing will be used to follow patients and determine results.

Important stuff.  Good luck, ratties.  And...thanks. - c