BRAF Positive Melanoma....study comparing treating with anti-PD-1 alone or combined with BRAF/MEKi

One of the MANY hard things in melanoma is simply picking a treatment option!  Here is some interesting data looking at whether or not to take anti-PD-1 alone or in combination WITH a BRAF/MEK inhibitor combo if your melanoma is BRAF positive. 

Treatment strategies using anti-PD1/PD-L1 (anti-PD) and BRAF/MEK inhibitor (BRAFi) therapy: a retrospective study comparing sequential vs. concurrent administration in BRAF-mutated metastatic melanoma (BMMM)Amaria, Trinh, Gu, McIntyre, et al. AACR. April 2018.

Background: It is unclear whether anti-PD and BRAFi therapy should be administered sequentially or concurrently in patients (pts) with BMMM, although clinical trials using varying strategies are ongoing. We performed a retrospective, single-center analysis of BMMM pts who received anti-PD therapy either sequentially or concurrent with BRAFi therapy. 

Methods: A total of 457 metastatic melanoma pts (excluding uveal) were treated with anti-PD therapy at MD Anderson Cancer Center from 11/2009-12/2015. Of those, 148 pts had BMMM and were categorized into 4 treatment groups: BRAFi-naïve treated with anti-PD alone (group 1) N=39 (26%); BRAFi-naive treated with combination therapy (group 2) N=30 (20%); BRAFi-refractory treated with anti-PD alone (group 3) N=45 (31%); and BRAFi-refractory treated with combination therapy (group 4) N=34 (23%). Clinical outcomes were analyzed and tabulated for each group. Pretreatment tissue samples were obtained for correlative biomarker immunohistochemistry (IHC) analyses. 

Results: BMMM pts with elevated LDH are more likely to receive upfront combination therapy. BRAFi-refractory pts have a higher incidence of brain metastases than BRAFi-naïve pts. The clinical outcomes of overall responses, median PFS and OS are provided in the table. Preliminary biomarker IHC analyses in 11 pts showed PD-L1 expression on the tumor cells correlated with median PFS and OS : 15 mo and 22 mo, respectively in 7 pts with PD-L1 greater than 1%, vs. 6.5 mo and 12 mo in 4 pts with PD-L1 less than1%. 

Conclusions: Single-agent anti-PD therapy is an effective strategy in BMMM pts who are either BRAFi-naïve or refractory. Combination therapy of anti-PD and BRAFi in either BRAFi-naïve or refractory BMMM did not appear to improve clinical outcomes. Confirmation data are needed from ongoing prospective randomized clinical trials.

Group 1, BRAFi-naive, anti-PD alone:  (N=39)
LDH greater than normal = 23.7
Prior CNS mets = 23
Prior ipi = 17.9
Number of anti-PD-1 doses = 12.5
Overall responses, CRs +PRs = 30.8 + 25.6 = 56.4
Median PFS = 10 months
Median OS =  21 months

Group 2, BRAFi-naive, combination:  (N=30)
LDH greater than normal = 37.9
Prior CNS mets =  20
Prior ipi =  6.7
Number of anti-PD-1 doses = 10.5
Overall responses, CRs +PRs =   23.3 + 43.3 = 66.6
Median PFS = 8 months
Median OS =  12.5 months

Group 3, BRAFi-refractory, anti-PD alone:  (N=45)
LDH greater than normal = 25
Prior CNS mets =  40
Prior ipi =  73.3
Number of anti-PD-1 doses = 16
Overall responses, CRs +PRs = 37.8 + 17.8 = 55.6
Median PFS = 9 months
Median OS =  25 months

Group 4, BRAFi-refractory, combination:  (N= 34)
LDH greater than normal = 17.6
Prior CNS mets = 44.1
Prior ipi =  72.7
Number of anti-PD-1 doses = 11.5
Overall responses, CRs +PRs = 29.4 + 5.9 = 35.3
Median PFS = 5 months
Median OS = 19 months

For what it's worth.... - c

Sew Chaotically! - The Bristol Dress by Orageuse

It is now safe to say that I love Orageuse Patterns!!  The Berlin Skirt went together fabulously and has been a real fav.  When I saw the  Bristol Dress on their site and on the cute ladies of Mix and Sew, I couldn't wait to try it!   I admit I am spoiled and B prints and puts together my PDF patterns.  So, that is certainly easy for me.  But the instructions on Orageuse "bosses" (as they say in France) are really great and they are drafted so things go together as they should!  So far the EU size 40 has worked great for me with little to no modification.  (I had to take the skirt in a bit at the waist.) The patterns give excellent information and instructions about measurements (your own and the pattern's) with details about how to adjust them in any way that is needed.  They are very clear about how the garment is going to measure at completion and upon what measurements the sizes are based.  Given their in-depth info, I was able to add one inch to the dress at the waist shorten/lengthen line and another inch at hip level to keep the lines of the dress intact yet fit my height as needed.  I did curve out to a 42 at the hips because multiple reviews on-line did mention a tendency of the skirt to ride up on sitting and some tightness in that area generally.  I think it worked out perfectly!  I love the material, a washable 'suiting' fabric from JoAnn's, that comes out of the dryer without a wrinkle!  I plan to make another in something with a small amount of stretch for cooler weather.  I think the details are just lovely!  See what you think....

Oh!  Looking at that cuff detail reminded me.  If you have forearms of any significant size you might double check the circumference as they are a little tight and I don't think I'm a she-hulk or anything!!!  HA!  Looking forward to making Bruges Trousers soon!  Sew chaotically! - les

Sew Chaotically! - Coral Rumi Tank

I loved making and wearing my Rumi Dress by Christine Haynes.  So, with a left over bit from Rosie's Coral Faux Wrap dress I made a Rumi tank!  Once again, it made the perfect piece to wear to Atlanta's Botanical Garden...

Yep!  Keeping cool and shady!!!  This visit, the garden's peeps had out done themselves with amazing topiaries from fairy tales!

Rose and her Jamester, with Roo rocking her Sorbetto top by Colette, made from the tiniest smidge of fabric remaining after this Lisette Liberty  make.

Were those not amazing???  Thanks to B and the kiddos for a great weekend!  Sew Chaotically! - les

Neutrophil-to-lymphocyte ratio and outcomes in melanoma. Yep, AGAIN!!!!!

Y'all know I've been yelling about simple blood tests in melanoma that can help diagnose, evaluate tumor type, progression, and response to therapy for years!!!  Here are just a few zillion posts on the subject:  Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!

Now, there's this:

High baseline neutrophil-to-lymphocyte ratio predicts worse outcome in patients with metastatic BRAF-positive melanoma treated with BRAF and MEK inhibitors. Teterycz, Jagofzinska-Mucha, Cybulska-Stopa, et al. Melanoma Res. 2018 May 18.  

Neutrophil-to-lymphocyte ratio (NLR) has been shown to be prognostic in several solid malignancies. There are limited data regarding its value during novel therapies in patients with melanoma. The aim of the study was to assess the practical utility of this ratio in patients with BRAF-mutant melanoma treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi). We included 215 patients with inoperable or metastatic melanoma who underwent BRAFi/MEKi treatment between October 2015 and June 2017. Baseline NLR and other complete blood count-derived inflammatory markers were tested for association with overall survival and progression-free survival in univariate and multivariate models. On-treatment NLR was also assessed for relationship with these outcomes using the time-dependent Cox's proportional hazard model. Prognostic model based on NLR and lactate dehydrogenase (LDH) levels was also developed. Patients with NLR values more than four had poorer progression-free survival (1-year rates 51.6 vs. 26.7%) and overall survival (1-year rates 77.3 vs. 53.1%). In a multivariate model adjusted for LDH levels, metastatic sites and age baseline NLR ratio and delay in starting MEKi were deemed statistically significant. In a model based on NLR and LDH, 1-year survival rates were 57, 40 and 23%, respectively if zero, one or both factors were elevated. Our results demonstrate the usefulness of NLR and a predictive model based on combinations of NLR and LDH as a prognostic markers during BRAFi/MEKi treatment. Our real-world data confirm the efficacy of BRAFi/MEKi therapy showed in the clinical trials.

So these researchers developed a prognostic model based on NLR (the neutrophil-to-lymphocyte ratio).  They found that melanoma peeps with values greater than 4 had poorer PFS than those with lower ratios (51% vs 26% at one year).  When they adjusted those numbers to also address LDH levels, metastatic sites and age....the melanoma peeps' baseline NLR and a delay starting treatment with a MEK inhibitor were found to be statistically significant.  When all those factors were included, they found that 1 year survival rates were 57% if neither LDH nor NLR were elevated, 40% if only one factor was elevated, and 23% when both were.

I wouldn't bet the farm on this algorithm alone, and most of this is not news, but all the lab values I've been yelling about can contribute meaningful information that can impact treatment decisions for melanoma peeps!  So, docs and researchers, lets make this a routine part of patient care, shall we???? - c

ipi/nivo efficacy in melanoma brain mets, CD8+ T cell actions, and (surprise, surprise!!!) CONCURRENT radiation and immunotherapy is even better in brain mets

I've only said most of this post a zillion times.  Brain mets suck great big hairy green wizard balls!!! We know immunotherapy works in the brain and body.  AND...we KNOW that immunotherapy combined with radiation works even better for brain mets.  But...we begin again...

We'll start with a bit of relatively new information at the cellular level:

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Taggart, Andreou, Scott, et al.  Proc Natl Acad Sci U S A. 2018 Jan 31.

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8⁺ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8⁺T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8⁺ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8⁺ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8⁺ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8⁺ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

OK....so that sounds important and impressive.  Now, there's this, which probably explains a bit of the above:

CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment. Edwards, Wilmott, Madore, et al.Clin Cancer Res. 2018 Mar 29.

Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response.  

We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy.

Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. 

Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

Ok.  That is good to know!  Now...how to we make that happen?????

And of course...no melanoma brain met post is complete unless I'm yelling!!!!  So here are a zillion posts about the benefit of immunotherapy COMBINED with radiation for brain mets:

CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)

And yes...there is this shocking finding!!!  The ipi/nivo combo is better in treating melanoma in the brain than nivo alone!!!  AGAIN!!!  (Just like in the body....sigh....)

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Long, Atknson, Lo, et al.  Lancet Oncol. 2018 Mar 27.

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.

This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.

Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.

Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Why in the world the poor folks in Cohort C had to get the shaft TWICE, I don't know!!  Once in being the poor peeps who had already failed a therapy and/or had symptomatic disease and secondly by being given the less effect treatment....DAMN!  Anyhow, as usual, I digress...  So folks with untreated brain mets with no symptoms were put into two groups.  Group A got ipi/nivo and 46% gained a response.  Group B got nivo alone and attained a 20% response rate.  And as noted, the folks with symptoms and/or had already failed one treatment for their brain mets were put into Group C and given nivo only, where they had only 1 response in their n=16.  So...small numbers here...and to me this serves only as reinforcement for what we already know: YES!!!! Immunotherapy works in the brain!!!!  (BUT....even better WITH SRS or gamma knife radiation therapy....circle back to above!!!!)

For what it's worth... - c

Sew Chaotically! - A coral Basic InstincT

My #basicinstinctshirt by Sasha went together perfectly and works well with any bottom!!!  I decided Roo needed one too.  When I found this super luscious and silky jersey from Mood, I know it would be just the thing!  And it could not have gone better with her wardrobe re-boot....

You may remember the wardrobe review and repair post!

....which included the purple ruched top, along with the Purple Work-out Top and the coral Faux Wrap Dress!

So now...The Sasha Basic InstincT!!!

I can't tell you how nice this pattern is!!!  It is perfectly drafted and so easy to dress up or down!

Again, Roo was a sport, letting me snag a photo before we ran off to our work out!  I know she'll get lots of use out of this top at work and play!

Seriously, y'all!!  You gotta check out Sasha!  Here's a link to her blog:  Secondo Piano  She makes the coolest things and includes lots of inspo on how to hack her very own pattern - Basic InstincT ( a t-shirt pattern).  And crazy woman!  As if that's not enough, the pattern is FREE!!!!!
Thanks, Sasha!  Sew Chaotically!!! - les

Whatever it takes!!!

Melanoma steals so much from so many.  It frightens all of us if we think upon it too long.  It petrifies those newly diagnosed ~ almost beyond bearing.  Still, it has allowed me to meet, and know, and love, REAL heroes whose outlook on life, while forever changed, is nothing short of amazing.  They light my path.  They bring me smiles.  They inspire my efforts.  They give me strength.  I want to be just like them when I grow up!!!  So, for ALL of you there is this ~

(With much credit and appreciation to - Imagine Dragons!!!  Listen to the link, words below.)

Whatever It Takes - Imagine Dragons

Falling too fast to prepare for this
Tripping in the world could be dangerous
Everybody circling is vulturous
Negative, nepotist
Everybody waiting for the fall of man
Everybody praying for the end of times

Everybody hoping they could be the one

I was born to run, I was born for this.

Whip, whip

Run me like a race horse

Pull me like a ripcord

Break me down and build me up

I wanna be the slip, slip

Word upon your lip, lip

Letter that you rip, rip

Break me down and build me up

Whatever it takes

'Cause I love the adrenaline in my veins

I do whatever it takes

'Cause I love how it feels when I break the chains

Whatever it takes

You take me to the top, I'm ready for

Whatever it takes

'Cause I love the adrenaline in my veins

I do what it takes.

Always had a fear of being typical

Looking at my body feeling miserable

Always hanging onto the visual

I wanna be invisible

Looking at my years like a martyrdom

Everybody needs to be a part of 'em

Never be enough, I'm the prodigal son

I was born to run, I was born for this.

Hypocritical, egotistical

Don't wanna be the parenthetical, hypothetical

Working hard on something that I'm proud of, out of the box

An epoxy to the world and the vision we've lost

I'm an apostrophe

I'm just a symbol to remind you that there's more to see

I'm just a product of the system; a catastrophe

And yet a masterpiece, and yet I'm half-diseased

And when I am deceased

At least I'll go down to the grave and die happily

And leave the body and the soul to be a part of thee ~

I do what it takes.

Whatever it takes

'Cause I love the adrenaline in my veins

I do whatever it takes

'Cause I love how it feels when I break the chains

Whatever it takes

You take me to the top, I'm ready for

Whatever it takes

'Cause I love the adrenaline in my veins

I do what it takes.

And so we melanoma peeps do ~ whatever it takes.  At times, merely whatever it takes to make it through an hour, or day.  But, bit by bit, we grow stronger than melanoma.  No matter what that bitch tries to dish out.  Despite forever half diseased, we are a masterpiece!   

With sincere appreciation and remembrance - Artie, Patti, Josh, Juan, Ms. Ituah (and daughter), Bob, Santos, Dfeng, Jamie, Paul, and Rob's Adriana - you are forever part of my heart.

Great thanks to my dear J and F, Jeanne, Eric, and Ed.  You guys rock and are part of the foundation on which I stand. Tammy B, Danita, Ashia, Anita - you stand by me, watch me like mother hens, and put up with NONE of my BS!  It is a blessing.  Roo, your spirit and determination are contagious.  I would not be running or doing those push-ups were it not for you!!  Ruthie, your support and example are more than inspiring.  And B.... you're always there, for whatever it takes! 

And to all of those who think you can't...  Yes, you can!!!  Whatever it takes.

~ love and gratitude, les

In melanoma, if you are worried about your PD-L1 level....DON'T wig out yet!!!!

While a wide variety of folks have been gettin' folks fired up about the presence or absence of PD-L1 expression in relation to response to immunotherapy (checkpoint inhibitors)...there's this:

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.  Morrison, Pabla, Conroy, et al.  J Immunother Cancer. 2018 May 9.  

Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.  

Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8⁺ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

PD-L1 positivity greater than or equal to 1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Immunotherapy works in about 40% of melanoma patients, if you are talking about anti-PD-1 (Nivo/Opdivo or Pembro/Keytruda) and we REALLY need to figure out how to make that response rate better.  Here, researchers from 8 facilities looked at a lot of factors ~ PD-L1 expression, CD8 T cell infiltration, tumor mutational burden and other funky immune factors.  After examination of 231 patients (as best as I can tell), while PD-L1 positivity "correlated with response and OS...but demonstrated limited predictive performance."  "Comprehensive immune profiling demonstrated higher sensitivity (72%) compared to PD-L1 (34%) and tumor mutational burden (32%)."

Clearly, the presence of PD-L1 on your tumor is not the end all be all in determining response to immunotherapy.  Would that it were that simple!  But, y'all know melanoma don't play that way!!  Hang in there ratties!  - c

Sew Chaotically! - Another faux wrap dress, but coral and for Roo!!! M6884

Sew!!!  I plowed through my purple period with this little ruched knit top, M6282 and a cute mesh exercise top, M7610 for Roo!  Now for a coral cornucopia!!


First up is the faux wrap dress, middle left.  I made this one for myself a while back: 

Faux wrap dress - M6884

The pattern is super straight forward and though I had lowered the placement of the "tie" on mine, as it is placed rather high for most reviewers and I am tall, once I had Rose try on mine, I moved it back up almost to where the pattern places it for her.

And since neither of us are all about those bows, after a few wears, I removed them from mine, cutting off some length from the ties and adding snaps to attach them at the side.  Should I make this dress for myself again, I will probably leave the ties off entirely, but Rosie liked them on hers and followed suit with a hidden closure on the left side.

I think it looks so pretty on her!  She was even a good sport and let me snap a quick pic just after she rushed in from work as we were zooming out to our weekly Barre Cardio class!!!  The material is a very soft, lush, almost sweater knit and a little thicker than is comfortable for the season currently.  It will serve her well when school restarts in the fall!!  Part 2 of my coral cornucopia coming soon!  Sew chaotically! - les

X4P-001, an oral CXCR4 inhibitor for melanoma, Phase 1 study examines results when given alone vs with pembro

Early days for this one...but, there's this:

X4P-001, an orally bioavailable CXCR4 antagonist, enhances immune cell infiltration and activation in the tumor microenvironment of melanoma.  Andtbacka, Pierce, Campbell, Yushak, et al. AARC April 2018.

The CXCR4/CXCL12 pathway plays a central role in the trafficking of key immune cells in the tumor microenvironment (TME). X4P-001 is an oral, selective, allosteric CXCR4 inhibitor. We hypothesize that the disruption of CXCR4/CXCL12 signaling by X4P-001 will favor an improved response to checkpoint inhibitors by modulating the immune cell profile within the TME and increasing CD8+ T cell infiltration. A biomarker-driven phase 1b clinical study is being conducted in melanoma patients to test this hypothesis (NCT02823405).

The primary objectives for the study are to evaluate the safety and tolerability of X4P-001 as a single agent and in combination with pembrolizumab in patients (pts) with metastatic melanoma, and to characterize the effects of X4P-001 alone and in combination with pembrolizumab on tumor immune cell infiltrates. Serial biopsies of cutaneous or subcutaneous melanoma lesions, peripheral blood mononuclear cells (PBMCs), and serum samples were collected pre-dose, after 3 weeks of X4P-001 treatment, and after 6 weeks of combination treatment. Biopsies were assessed by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) for multiple markers, including CD3, CD8, FoxP3, PD-L1 and Granzyme B, and by NanoString® analysis for changes in gene expression. PBMCs were analyzed by flow cytometry for both lymphoid and myeloid cells. In addition, multiple serum markers will be assessed using the multi-analyte profile (MAP) platform.

As of September 15, 2017, 13 pts have been enrolled, and 11 have completed the study. The median age was 73 years (range 53-90). Of the evaluable pairs of biopsies, X4P-001 treatment alone increased CD8+ T cells, increased granzyme B signal, increased antigen-presenting machinery such as HLA-DR, and increased IFN-gamma gene expression signature scores in the TME. These biomarker responses were further enhanced when X4P-001 was combined with pembrolizumab. X4P-001 was well tolerated. AEs assessed as related to either X4P-001 or pembrolizumab at any time were diarrhea, maculopapular rash, fatigue, chills, and acute kidney injury. These data, along with additional biomarker measurements, will be presented.

Evidence of enhanced immune cell infiltration and activation is observed in the TME with X4P-001 treatment alone. Increased IFN-gamma gene expression signature scores after single-agent X4P 001 treatment support the use of X4P-001 to increase the likelihood of a response when combined with anti-PD-1 therapy. X4P-001 as a single agent and in combination with pembrolizumab is generally safe and well tolerated. Further in-depth biomarker analysis is ongoing as enrollment nears completion. 

So, real live ratties with metastatic melanoma (though there are only 13 of them, as of this report and only 11 had completed the study) were given X4P-001 alone or with pembro.  Samples of their tumor along with blood tests looking at the immune response were done before the drug, as well as at 3 and 6 weeks into treatment.  Researchers report that they saw increased activation and efforts by the immune system in the tumor microenvironment.  Because of this, they are hopeful that by giving X4P-001 with pembro, the likelihood of a response will be increased.

So...yes.  Early days and few patients examined on this one so far...but, here's hoping!  - c

When there is beauty....

...enjoy.

And when your love and best friend knows just what you need...even better.  Thanks B.  Love and hugs to each of you. - les

Vemurafenib and HSP90 for BRAF positive peeps with unresectable melanoma

Folks have been looking at many meds to add to targeted therapy so that melanoma peeps (who happen to be BRAF positive....about 1/2 of us) will not develop resistance to the positive effects of those drugs.  They have been looking at HSP90 (heat shock protein 90) as well as ricolinostat (an HDAC6 inhibitor) for some time now.  Here are some prior reports:  Heat Shock Protein 

Now, there's this: 

Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma. Eroglu, Chen, Gibney, Weber, et al. Clin Cancer Res. 2018 Apr 19. 

BRAF inhibitors are clinically active in patients with advanced BRAF^V600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.

Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAF^V600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.
Objective responses were observed in 15/20 evaluable patients (75%), with 3 complete and 12 partial responses. Median progression-free and overall survival were 9.2 months (95%) and 34.6 months, respectively. The most common grade 3/4 toxicities were skin toxicities such as rash (n=4, 19%) and cutaneous squamous cell carcinomas (n=3, 14%), along with diarrhea (n=3, 14%). Pharmacodynamic analysis of patients' PBMCs showed increased day 8 HSP70 expression compared to baseline in the three cohorts with XL888 doses greater than/= to45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP-client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.

XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF^V600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF^V600-mutant melanoma.

Thanks, ratties.  We'll have to see if this moves any further along and/or if they will finally combine it with a BRAF/MEK combo which we already know does better than BRAFi alone! - c

Stage III melanoma ~ 3 interesting reports:

When I was diagnosed with Stage III melanoma in 2003, I had affected bits and pieces surgically  removed, but there wasn't much else I could do - nothing that was effective anyway.  Thank goodness, the life of a Stage III melanoma patient is different now that viable, effective adjuvant treatments (Here's just a "few" posts on that topic: Adjuvant treatments in melanoma ) are available!!!  Or....are they?????????

Disparities of Immunotherapy Utilization in Patients with Stage III Cutaneous Melanoma: A National Perspective.  Al-Qurayshi, Crowther, Hamner, et al. Anticancer Res. 2018 May.

Immunotherapy combined with surgery is associated with better survival than surgery alone in patients with advanced melanoma. This study examined the utilization of immunotherapy in relation to population characteristics and the associated survival benefit.  This was a retrospective cohort study utilizing the US National Cancer Database. The study population included 6,165 adult patients (greater than/= to18 years) with stage III cutaneous melanoma (median follow-up=32 months).  A total of 1,854 patients underwent immunotherapy in addition to surgery, which was associated with a survival benefit over surgery alone. Older age, presence of comorbidities, Medicaid/Medicare insurance, and living in a community with lower average education level were associated with less immunotherapy utilization. No statistically significant racial disparity in immunotherapy usage was found.  Compared to other demographic factors, insurance status was associated with the greatest disparities in immunotherapy utilization and mortality for patients who underwent surgery for advanced melanoma.

Does this not explain why I am so pissed off??  Does this clarify my hatred of insurance companies?  Does this not elucidate ONE of the reasons I continue to yell and scream????  Health care is a human right...NOT a privilege!!!!!!!!!!  Okay...slow deep cleansing breaths....

Now, there's this ~

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont, Blank, Mandal, et al. N Engl J Med. 2018 Apr 15. 

The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. 

Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.

At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% vs. 61.0%) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% in the pembrolizumab group and 62.6% in the placebo group). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. 

As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.

THIS is one of THOSE reports!  You know the type.  The ones that take a good deal of time, effort, and money to tell us that:  Obesity is found in children who ingest more calories and get less exercise!  OR:  Teen depression is more frequent in children who have fewer friends!  So, not surprisingly...folks in this study who were given anti-PD-1 (in this instance it was pembrolizumab/Keytruda....we have similar reports for nivolumab/Opdivo...) did better than folks who were given placebo!  Well, duh!!!  Perhaps the most important point made in this study is that folks who were PD-L1 positive had a recurrence free survival at 1 year of 77% when treated with pembro. While the overall RFS at 1 year for those treated with pembro, no matter PD-L1 status, was basically the same at 75%.  This could be better broken down and might actually make the study worthwhile (and maybe it is in the whole article) as the overall pembro responders obviously included both PD-L1 positive and PD-L1 negative patients.  BUT...even with this limited data...it is clear that anti-PD-1 worked in some ratties whose tumors were PD-L1 positive and in some whose tumors were not!!!

Now, this...

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma. Lewin, Sayers, Kee, et al. Ann Oncol. 2018 Apr 12.

As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance.

From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were performed of imaging outcomes.

170 patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56% - 83%. Negative scans had predictive values of 89% - 96% for true non-recurrence (negative predictive values (NPV)) until the next scan. A negative PET at 18 months had NPVs of 80% - 84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median).

Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Sorry, but again, Well, Duh!!!!  Stage III patients who were scanned, had recurrences found early, even when asymptomatic and therefore had "potentially curable disease".  Yet, Stage III patients (and yes...even many of us Stage IV peeps) have to fight tooth and toenail to have needed scans done and paid for by our insurance plans.  Yes, you can bet I've yelled about this as well:  The need for scans and appropriate follow-up!  The first two posts are incredibly pertinent as they include excerpts written by Rev. Carol Clark Taylor, formerly of the blog "Attitude of Gratitude", and now simply "The Queen of Melanoma", to whom we all give unending  thanks...for her grace, fortitude and the incredible advocacy she has maintained for years for all of us!!!  

Despite my current frustrations with problems in the "system" and management of melanoma generally, we have come a LOOOOOONG way, baby!  In 2003, I couldn't even fuss about these things because they didn't exist!!!  Today, THEY DO!!!  Now, we must to work to find even better treatment and follow-up options and make sure they are a reality for ALL of those who need them!!! - love, c