For Mat: CDK4/6 inhibitors, PLX8394, or copper chelation?????

Thought about you all day my friend.  Between planting 9 million iris bulbs and repairing a brick wall (mortar mix is an amazing desiccant from which my hands may never recover) at my daughter's "new" house, while shouting curse words (in my head) on your behalf, that even my most tolerant blog audience may find cringe worthy...this is what I (and a brain far better than mine) came up with:

For those unaware of Amazing Mat...I am thinking of a CURE for someone already experienced in BRAF/MEK, ipi, and Keytruda with a brain met near the optic nerve.

Here goes: 

CDK4/6 inhibitors:  
90% of melanoma patients are positive for CDK4/6.
The inhibitor has been proven to cross the blood brain barrier.
Sosman at Vanderbilt has been working with this under the name of LEE011 for some time.
Clinical Trial - NCT01777776: LEE011 and LGX818  is noted to be "active, but not recruiting".
Check out this post from ASCO 2015 (second abstract) where one version (P1446A-05 [voruciclib]) is combined with vermurafenib:  ASCO 2015 new BRAF inhibitor combos
Several other trials with the drug are also noted to be "suspended".  On researching them, the suspension does not appear to be due to patient problems, rather they are due to decisions made by BIG Pharma.
Another CDK4/6 inhibitor:  Palbociclib (PD-0332991) demonstrated "stability" in 27% of patients with melanoma and other cancers.  In another study, a partial response was found in 1 of 31 patients and stability in 29%.
When LEE011 and Binimetinib were combined:  Folks with NRAS mutant melanoma (which may be precluded by your BRAF + status, Mat....but you never know) demonstrated a partial response of 43% as well as stable disease in 43%....per report in Jan 2015.
It's a long shot....but I would call Sosman.  What the heck?  All he can say is no.

A more effective, new generation, BRAF inhibitor - PLX8394?!!!
PLX8394  treats wild and mutated BRAF status melanoma.
May be more effective in BRAF mutated tumors not responsive to other BRAF inhibitors.
Clinical trial #:  NCT02428712 - A study of PLX8394
You have to be refractory to BRAF/MEK, ipi and/or pembro (CHECK!!!).
Do have to have stable brain mets for one month, but sounds pretty flexible and can even be stable on prednisone.
Currently recruiting in Texas, Michigan, Arizona and Utah.

Copper chelation:
Apparently copper is an important co-factor for BRAF mutant melanoma and there is some animal evidence that reducing body levels of copper may inhibit melanoma cells.  Copper chelation for BRAF mutated disease
What's the easiest way to do this?  Duke has been looking at this with an already available drug used to treat copper overload:  Trietine combined with vemurafenib.   Copper starvation could be a promising treatment for some cancers
Clinical trial #:  NCT02068079  Copper chelation and Duke Study
Unfortunately, this study is also "active, but not recruiting".
I would still call.   But, I'm like that.

Much love and warm wishes.  Still thinking. - c

Nivo/Opdivo effective no matter BRAF!!!!

Efficacy and safety of Nivolumab in patients with BRAF V600 Mutant and BRAF Wild-type advanced melanoma:  A pooled analysis of 4 clincal trials.  Larkin, Lao, Urba, Wolchok et al.  JAMA Oncol.  2015 July 1.

The anti-PD1 antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma.  The activity of nivo in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset.  This is an analysis of data pooled from 4 clinical trials of nivo in 440 patents with unresectable stage III of stage IV melanoma who had been tested for BRAF mutational status.  Nivo was given IV at doses of 0.1, 0.3, 1.0, 3.0 or 10.0 mg/kg every 2 weeks until disease progression, discontinuation due to adverse effects, withdrawal, or end of study.  Most patients (83%) were given 3 mg/kg.

Of the 440 patients from 4 clinical trials, 334 were BRAF wild-type and 106 were positive for the BRAF V600 mutation.  In patients evaluable for response, the objective response rates were 34.6% for the 217 patients with wild-type BRAF status and 29.7% for the 74 with mutant BRAF status.  The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipi therapy, or PD-L1 status of the tumor.  The median duration of objective response was 14.8 months for wild-type BRAF and 11.2 months for mutant BRAF.  Median time to objective response was 2.2 months in both patients groups.  Incidence of adverse events were 68% in the wild-type BRAF group and 58% in the mutant BRAF group.  

The results of this retrospective analysis suggest that nivo has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAFi or ipi treatment.

1.  Suspect that my trial ratties were reviewed given the dosages.
2.  A little surprised that there were so few mutant BRAF patients as the breakdown is about 50/50 BRAF positive vs BRAF wild-type in melanoma patients.  Wonder if trial requirements played a role.
3.  Still getting conflicting info of whether prior ipi and PD-L1 status affect response rates.  Hope that will clear up soon.
4.  Good info for lots of patients!!!  This was reported at ASCO 2014:  Nivo/opdivo effectiveness in melanoma

Hang in there my friends! - c

A really good review of treatment data for Melanoma Brain Mets!!!

Clinical Management of Multiple Melanoma Brain Metastases:  A Systematic Review
Goyal, Silk, Tian, et al.  JAMA Oncol.  2015 May 21.

Treatment of brain mets from melanoma is controversial and includes surgical resection, SRS, and WBRT.  Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival.  Given this, brain met management in melanoma is continually evolving.  A PubMed database search for related terms...published from Jan 1995 - Jan 2015....was reviewed.  Of 2243 articles initially id'd, 110 were selected for full review.  Of these, 73 were included here.  

Level 1 evidence supports use of SRS alone, WBRT, and SRS with WBRT.  Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes.  Cytotoxic chemo has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials.  Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT.

A much better review of data regarding the treatment of melanoma brain mets incorporating the new systemic therapies.  And, YES!!!!  We certainly need studies looking at the results of anti-PD1, ipi, and BRAFi when combined with SRS.  These treatments were withheld from folks with brain mets for far too long!  Hopefully that tide has turned!!!

Sad that all this is taking so long given this data out of ASCO 2013!!!  Brain Mets in melanoma the latest from ASCO 2013

Info from ASCO 2015 re: Pembro/Keytruda and an ongoing brain met study:  ASCO 2015 pembrolizumab/keytruda

Also out of ASCO 2015....ongoing study with Nivo/Opdivo and ipi/Yervoy for brain mets:  ASCO 2015 new nivo/ipi trial for melanoma brain mets

Discussion of brain met patients in clinical trials from 2014:  Should melanoma brain met patients be allowed in clinical trials?

More data that ipi and anti-PD1 work in the brain:  Anti-pd1 and ipi and t cells in the brain

Vemurafenib works in the brain:  Vemurafenib really does work on brain mets!

Thanks, ratties!  - c

Things that make me ridiculously HAPPY!!!

Blueberry banana muffins from Ruthie's recipe (see below)!

Blueberries from MY bushes!

Delicious fresh eggs from Julia!

Fried to perfection by Bentie, with a double yolk!!!

Silly dog with floppy ears (and, yes he could fit in his bed if he weren't a goof ball!!!)!

Special blue surprise from dear Kay!

More blue from Trina and B!  Not to mention B's Mojito!  YUM!

A house with a blue door!

A hike to Gregory Bald, in June, with blooming flame azaleas, EVERYWHERE, with B!

Ruthie's Blueberry Buttermilk Bread

3/4 cup low fat buttermilk            none - 1/2 cup packed brown sugar (depending on taste)
1/4 cup cannola oil                        2 large eggs             1 cup mashed bananas
1 1/4 cup whole wheat flour         1 cup all-purpose flour
1 1/2 teaspoon baking powder      1/2 teaspoon baking soda
1/2 teaspoon salt                           1 teaspoon cinnamon
1/4 teaspoon ground nutmeg        1 1/4 cups blueberries, fresh or frozen

Preheat oven to 375 for loaf, 400 for muffins.  Coat 5X7 loaf pan or muffin tin with cooking spray.  Whisk buttermilk, eggs, brown sugar and oil in large bowl.  Add mashed bananas.  Whisk together dry ingredients.  Fold dry into wet ingredients, til just combined.  Fold in blueberries.  Place batter in pan.  Bake til golden and wooden skewer inserted in center comes out clean...about 50-60 minutes for loaf, 20-25 minutes for muffins.  Enjoy!!    Thanks, Ruthie.

What makes you ridiculously happy????? - c

Brain mets in melanoma...a relatively irrelevant retrospective!

Malignant melanoma brain metastases:  Treatment results and prognostic factors - a single-center retrospective study. Ostheimer, Bormann, Fiedler, et al.  Int J Oncol.  April 20, 2015.

Brain is a frequent site of melanoma mets.  Study aimed to ID prognostic factors for overall survival (OS) and local tumor control (LC).  Patients were dx'd with brain mets from 1992 - 2011.  N=100.  53 patients has 1-2 brain mets, 47% had greater than 2, and 71% presented with additional extracranial mets.  Primary treatment included systemic therapy alone (temozolomide/fotemustine, 14%), local therapy (surg and/or SRS, 25%), whole brain radiation (WBR, 10%), combined WBRT and systemic therapy (18%), local therapy plus WBR (5%), and combo of local and systemic therapy (8%).  3% had local, WBR, and systemic therapy.  17% refused treatment.  Median f/u in surviving pts was 32 months.  Median OS in all pts = 3.9 months.  Local therapy, systemic therapy, # of brain mets, and primary therapy including local therapy were significantly associated with OS.  In the subgroup with multiple brain mets (n=35), a trend for improved OS after initial treatment with WBR plus systemic therapy was noted and use of these two modalities over the course of the disease was significantly associated with OS.  The best LC per single lesion (n=37) could be achieved by combo of local with systemic therapy.  Number of brain mets, extracranial mets and use of local therapy are independent prognostic factors in melanoma metastatic to the brain.

I don't really don't see much value in this report on patients with brain mets from 1992-2011.  Despite its recent publication it is dealing with a set of very old data...esp in melanoma world.  Ipi and the first BRAFi weren't FDA approved until 2011 and folks with brain mets weren't treated with those drugs initially.  It is very clear from more recent data that those drugs along with anti-PD1 products are far superior in eradicating melanoma tumors EVERYWHERE compared to the drugs used in these patients.  However, combo's still reigned supreme and folks with the most tumor burden (no matter if just multiple brain mets or brain mets along with mets elsewhere in the body) have the most difficulty.  For what it's worth.  We've come a long way baby!!!

Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases.  Liu, Alexander, Chen, Horvath, et al.  J Neurooncol.  Jun 25, 2015.

Patients with limited brain mets are often candidates for SRS or WBRT.  Among pts who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear.  Study examined rates of salvage WBRT or SRS among 180 pts with 1-4 newly dx'd brain mets who received index SRS from 2008-2013.  Patients had NSCLC (53%), melanoma (23%), breast (10%), renal (6%), and other (8%) cancers.  Patients had SRS to 1 (60%), 2 (21%), 3 (13%), 4 (7%) brain mets.  Median survival after SRS was 9.7 months.  No further brain directed radiotherapy was delivered after index SRS in 55% pts.  27% of patients ever received salvage WBRT, and 30% ever received salvage SRS. 12% received both salvage WBRT and salvage SRS.  Median time to salvage WBRT and salvage SRS were 5.6 and 6.1 months respectively.  Age greater than 60 years and controlled/absent extracranial disease were associated with shorter time to salvage WBRT.  Isolated brain progression caused death in only 11% of decedents.  In summary, most patients with 1-4 brain mets receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months.

Wow.  Guess I've sure out lived my shelf-life!  Again, these patients were not in receipt of radiation combined with more effective systemic therapies.  So, hopefully, a study looking back on us...say from 2010-2015...would paint a very different picture of duration of treatment effect.  I do find it strange that this study found that "controlled/absent extracranial disease were associated with a SHORTER time to WBRT."  You'd think that controlled or absent disease in the body would prolong the time before additional problems.   Hmmm....

Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases.  Patel, Shoukat, Oliver, et al.  Am J Clin Oncol.  May 16, 2015.

Compared safety and efficacy of ipi and SRS to SRS alone for newly dx'd brain mets.  Reviewed records from 2009-2013.  54 consecutive melanoma brain met pts were id'd with 20 receiving ipi within 4 months of SRS.  Ipi treated pts had similar baseline characteristics.  No difference between symptomatic radiation necrosis or hemorrhage was id'd between cohorts.  Compared with pts in the non-ipi group, 1 year local control 71.4% vs 92.3% and intracranial control 12.7% vs 29% were also statistically similar.  The ipi cohort also had no difference in 1 year OS (37% vs 38%).  Patients given ipi within 14 days of SRS had higher 1 year (42.9%) and 2 year OS (42.9%) relative to ipi delivered more than 14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these differences were not statistically significant.  

Again, a retrospective tally of patients from 2009-2013. The numbers (esp for those treated with ipi) are rather small.  I suspect that has something to do with the lack of statistical significance.  Looking at the numbers, I'd rather be in the ipi/SRS combo group!  Especially when the ipi is administered less than 14 days after SRS!!!  Take home message:  GET YOUR IPI SOONER RATHER THAN LATER AFTER SRS!!!!  Here's a post with more recent data:  Radiation for melanoma: better combined with immunotherapy!

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era.  Wattson, Sulllivan. Neimierko, Flaherty, et al.  April 12, 2015.

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi).  Among pts with brain mets, however, the clinical course of MAPKi-treated pts is not well described  We analyzed 106 pts who developed brain mets between 2007 and 2013.  Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease which preceded BM in 49%.  Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi.  With a median f/u of 8 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7 months).  This survival advantage was driven by the 16.6 month median survival of pts who initiated MAPKi after BM were dx'd, vs 5.6 months if initiated prior to BM development.  Median survival from the onset of any systemic mets was 22 months regardless of the timing of MAPKi relative to BM appearance.  Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement.  These findings are consistent with potential MAPKi activity in intracranial melanoma.

Before you get confused...MAP-kinase inhibitors = MEK inhibitors.  It is not clear which ones were used here or if they were combined with BRAFi as they almost always are today, thereby increasing effectiveness, while decreasing side effects and tumor work around. MEK inhibitors include:  trametinib, selumetinib, Binimetinib, PD325901, and cobimetinib.  So..another review of folks with brain mets from 2007-2013.  Use of MEKi prolonged survival in BRAF positive patients with brain mets from 7 months to 14 months.  However, if you took the MEKi before your brain met appeared median survival was only 5.6 months.  If you took it AFTER your brain met, median survival increased to 16.6 months.  Pts got 22 months on average before the appearance of mets elsewhere in the body, not matter when MEKi was started relative to brain mets.  So, yes, Virginia.  MEKi work in the brain.  

Don't feel that this was the most helpful bunch of gibberish I've ever plowed through.  But, I guess it is a pretty dismal synopsis of life with brain mets circa 1992 - 2013.  What a difference the past 5 years has made.  May we keep moving forward....QUICKLY!!!!  Best - c

Lame, lazy PhD student!

Found this posted on my blog...twice:  

"Greetings, My name is Dr. Dana Hansen, Assistant Professor of Nursing at Kent State University. You can learn more about me by visiting my faculty web page at http://www.kent.edu/nursing/facstaff/bio/~dhansen1/ We are contacting you because you are listed as the contact person of the blog. My research team and I are interested in learning about the family caregiver’s experience with reading their loved one’s illness blog. A family caregiver is someone who provides emotional, spiritual, or physical care or support to a loved one. I was inspired to conduct this research during my sister-in-law’s journey through breast cancer. After interacting on her blog, I began to wonder what it was like for her husband (family caregiver) to read her blog. The family caregiver of the person who is writing the illness blog can find out more about our study by going to our study website: https://nursing.kent.edu/caretaker. There is a screen for you to share your contact information if you are"

On the surface, that all seems a worthy process, innocuous at best, if poorly written.  I have had the incredibly horrible, beautiful, emotional experience of helping families allow their children to die.  It was difficult for me and other staff.  I cannot begin to imagine how dreadful and heart rending it was for the families...even though I was there, watching, working, and supporting patient and family as best I could.  When you add that to my own life experiences, I am more than aware of the the need for nurses and other providers to know what the family and patients truly need and feel during those difficult times.  Yet, something about this chick's approach and the description of her own work...at odds with what is posted in her message....rankled!  So....I wrote her this!!!

Dear Dana,

So, let me get this straight:  You are working on your PhD.  And in your own words:  "The purpose of my research is to explore family interactions and relationships at the end life.  Often, families are uncertain of what to say or how to interact with their dying loved one during this difficult and stressful time.  Ultimately, I hope to discover important and unique aspects of family relationships at the end of life that will improve care of both the patient and family."  

 So, it would seem like you would bother to read at least a bit of the blog you are posting your lazy (no actual links to your addresses, exactly the same blurb used repeatedly) message on, to ascertain if there is really someone DYING (more rapidly than you are, for instance) on the blog in question!!!  But, no.  You didn't.  I am heartened only by the fact that looking at your bio, you don't appear to provide patient care.  That is a really good thing.  Sadly, if you actually attain your PhD you may have access to nursing students and curriculum development.  That would be a shame indeed.  However, I will be reaching out to your professors at Kent State.  If their motto is "Excellence in Action" this is it's antithesis!

And in case you are wondering who I am, since I am certain you haven't bothered to keep a record of the blogs you have left your message on, or the number of times you left that message, I am Celeste Morris, RN, MSN C-PNP.  I have taught nursing students how to provide complete, thoughtful, compassionate care with integrity.  I also provide pediatric care daily utilizing basic nursing skills, the knowledge of development and disease in children, and 30 plus years of experience, never failing to remain cognizant of my responsibility to respect the LIVES of my patients and their families, rather than assuming they are at the END of theirs, no matter what their diagnosis may be.  And, yes, I have Stage IV melanoma.

Your work could be valuable.  Your approach is lame and lazy.  You have a typo in your consent form and eligibility criteria as well as a missing word in your mission statement. Sad.  Perhaps this will jog your memory of who I am and teach you something about how great a nurse can really be, especially to a person with Stage IV disease.

My blog and a real nurse

Perhaps your PhD work will prove a learning experience after all.  C

SO!  Ruthie, Rosie, Freddo and B!! Sign up. Go for it.  https://nursing.kent.edu/caretaker/consent 
Get your 50 bucks!!!  You've certainly wasted plenty of time reading my crap!!!  You have my blessing alive and well, but I'll be dead someday...so make the big ones while you can.  Any other peeps out there who can meet this criteria????????

Eligibility: You are eligible for the study if you meet the following criteria: 

• Your and your loved one are 18 years or older; 
• The blogger must have a diagnosis of cancer, congestive heart failure (CHF), chronic obstructive lung disease (COPD), or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS);
• The blogs must be written in English with a minimum of 1 posting per month;
• The family caregiver must participate in the blog by responding to the blog or reading the blog.

Make fifty bucks!  I am serious as a heart attack in an AID's patient having trouble breathing while dying of cancer!!!!  Good thing I view most of life as funny as hell!!  Hope I made you laugh.  Lord knows, we all need to.  So, thanks, "Dr." Dana!  I'll be in touch!!! - c

Spring/Summer Sewing! Lisette Passport and the Morris Blazer!!!

This is the story of the Lisette Passport dress and jacket, beautiful material that Ruthie gave me for my 50th birthday, and the Morris Blazer!!!!!

This T-shirt dress, blogged about before, is made from the same birthday stash.  The beautiful panel print gave me heart palpitations to cut into...but I lived and am very proud of the dress for it's matched sides, print placement, etc!!!  The matching jacket was somewhat of a coincidence, apart from my love of those particular colors!  It was to be a "muslin" of a jacket I would later make from additional amazing fabric Ruthie gave me.  It is the jacket from the PassPort pattern above.  On researching the pattern, folks said the pattern ran small. In retail world, I wear a 4-6 depending on brand.  In pattern world, I am generally a 10.  Given the internet sewists' advice I made a straight 12.  It fit perfectly! 

This dress is from the PassPort pattern as well. I looked the pattern over and made another straight 12. The pleats (that don't show up very well in this photo) are really awesome.  However, the side seams were tricky.  A quarter inch seam would have been perfect and easy enough, except for having to incorporate a side zip!! YIKES!!!  But, dealt with.  Not terribly noticeable here, but the flowers on top have a little green center that matches the jacket perfectly!

Next rendition:  Got a bit wiser and cut an ever so slightly wider side seam so that normal 5/8th's stitching and the side zip could be accommodated easily.  Perfect!

But, got to thinking.  The jacket above, which I will certainly make again (came together perfectly, fits great) has two pieces on each front side and three in the back.  Not an easy plan for a busy Ikat print (example jacket on the pattern sleeve not withstanding!!!)!  Then, Ruthie, to the rescue.  Just as my feeble brain was coming to grips with this reality...she emailed me a blip about the Morris Blazer!!!  How simple!  My esthetic!!  Fewer pieces!  The NAME!!!  PERFECTION!  And.....it is. I made this one as a muslin.  Despite matching my new purple dress and having a lovely hand...the fabric proved persnickety...prone to raveling and pulls.  The pattern went together very easily, as advertised by various sewists.  However, as someone with zero spatial relations skills, I had to go on faith that the pieces would actually form a blazer!  BUT!!!  They did!  And...I didn't have any trouble with step #15, placing the hem facing, etc.  Possibly because of warnings from sewist world or...because I'm awesome!  Hee hee!  At any rate, Morris Blazer = good. Though the jacket called for 2 pieces for the back, I cut one piece on the fold here as a test case for my upcoming print.  It worked perfectly and I see no reason to look back!

 Ta-dah!!!  The MORRIS Blazer in my special, celebrating 50 big ones, Ikat print!!!  Awesome, no?  Cutting the print made me nervous.  But, the results made me proud!  FYI:  Just to keep things super confusing...I made a straight size 8 in this pattern after peering nervously at pattern pieces on my mannequin and since that matched my measurements.  It worked!

And because I had more fabric than I realized.  A cute swingy top (McCall's 6960) that went together very well and had a neat way of approaching the inner facings that worked perfectly.

Happy sewing...or whatever you enjoy!!  Purple wardrobe, anyone??? - c

PD-L1 positive? Which immunotherapy is best? Same song, second verse...

Differential activity Nivolumab, Pembrolizumab, and MPDL3280A according to the tumor expression of Programmed Death-Ligand (PD-L1):  Sensitivity Analysis of trials in melanoma, lung, and genitourinary cancers.  Carbognin, Pilotto, Milella, et al.  PLos One.  June 18, 2015.

The potential predictive role of PD-L1 expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research.  ORR was extracted from Phase I-III trials investigating nivolumab, pembrolizumab, MPDL3280A [an anti-PD-L1 product] for advanced melanoma, NSCLC, and genitourinary cancer...  Interaction test according to tumor PD-L1 was accomplished, and analysis performed.  Twenty trials (1,475 patients) were used.  A significant interaction per tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% in the PD-L1 positive and 19.9% in the PD-L1 negative population.  ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivo and pembro, with an absolute difference of 16.4% and 19.5% respectively.  A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLS, respectively with no difference for gu cancer.  Overall, 3 antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells.  The predictive value of PD-L1 on tumor cells seems more robust for anti-PD-1 antibody (nivo and pembro) and in the context of melanoma and NSCLC.

Thoughts:
1.  Background info on MPDL3280A:  Anti-PD-L1 for melanoma phase 1 trial
2.  Note that you can still respond, even if PD-L1 negative.  Is that true?  Does that reflect action of the medication?  Or, is the current test for PD-L1 not terribly accurate?
3.  Let's standardize testing tumors for the presence of PD-L1 and make it available to all melanoma and NSCLC patients so treatments can be chosen more wisely!!!  NOW!!!  Prior rant on my tumor testing for PD-L1:  Info on test for PD-L1 from 2012!
4.  I think we ratties have given you enough intel over many years.  Researchers and FDA weirdo's...get with it!  Make this happen, TODAY!!!

Don't make me come back there!  c

Combo's looking good....but if PD-L1 positive...just do nivo!!??

What's new in melanoma?  Combination!  Ascierto, Marincola, Atkins.  J Transl Med.  Jul 4 2015.

Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma. Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone and 6.9 months with nivolumab alone. Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies. Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy. However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing. Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib. Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use. In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.

Thoughts:
1.  What I've been saying....COMBO's!!!!
2.  But, which one???
3.  If you are BRAFV600 positive and are ready for BRAFi...these combo's are doing very well:  vemurafenib with combimetinib, dabrafenib with trametinib, and encorafenib plus binimetinib.
4.  Combo immunotherapy:  CheckMate 067 showed us PFS of 11.5 months on the ipi/nivo combo vs 2.9 months on ipi alone and 6.9 months on nivo alone.  BUT!!!!!  In PD-L1 positive patients PFS was 14 months on just nivo vs 3.9 months for ipi.  In PD-L1 negative patients the ipi/nivo combo was better than either monotherapy.  SO!  Since the ipi/nivo combo has more side effects but gives you no better results if you are PD-L1 positive....it probably makes more sense to just do nivo alone!
5.  T-VEC with ipi and yet another anti-PD1 product (MEDI4736/durvolumab) with dabrafenib plus trametinib seem promising as well.
6.  Here's hoping that markers and combo's become more clarified and APPROVED very soon.
7.  Thanks, ratties!!!
c

BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.  Massi, Brusa, Merelli, et al. Ann Oncol, June 2, 2015. 

BRAF inhibitors improve survival in metastatic melanoma patients but the duration of clinical benefit is limited by development of drug resistance.  Here, we investigated whether the expression of Programmed Death-Ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated melanoma patients. 
PD-L1 expression (cut-off - 5%) and TIMC were analyzed...from 80 consecutive melanoma patients treated with BRAFi at a single institution.  46 and 34 patients received vemurafenib and dabrafenib, respectively.  Membraneous expression of PD-L1 was detected in 35% of patients.  After analysis:  ABSENCE of tumoral PD-L1 staining and the presence of TIMC were associated with a better response to treatment.  Median PFS and OS were 10 and 15 months respectively.  Additionally, analysis demonstrated, PD-L1 expression and absence of TIMC correlated with SHORTER PFS.  Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 expression and density of immune cell infiltration of BRAF V600 mutated melanoma treated with BRAFi.

Thoughts:
1.  The study used a 5% cut-off for PD-L1 expression, while many studies use 1%, not sure that matters.
2. According to this study, patients treated with BRAF inhibitors did better if their tumors were negative for PD-L1 and loaded with TIMC.
3.  Now...these results can't (yet) be determined to mean that BRAFi was undermined by the presence of PD-L1 or facilitated by the presence of TIMC.  It is just one more study that demonstrates the presence of PD-L1 and absence of TIMC are bad prognostic indicators...unless...at least in the case of the PD-L1...you are taking anti-PD1 drugs.
4.  Notice...one more time...PD-L1 was present in 35% of patients.
5.  Clearly, we have lots to learn.

Complete remission of metastatic melanoma upon BRAF inhibitor treatment - what happens after discontinuation?  Tolk, Stzger, Mohr, et al.  Melanoma Res. June 8, 2015.

Treatments with BRAFi leads to complete remission in 3-6% of patients with BRAF mutant melanoma.  In cases of complete remission, it is unclear whether BRAFi therapy should be continued.  We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving CR.  In 12 patients, CR of melanoma was diagnosed after a median BRAFi treatment duration of 13 (0.3-32 months) months.  Reasons for d/c were side effects in 7 and patient demand in 5.  Six patients are still in CR after a median 17 months (2-26 months) after discontinuation of BRAF inhibition.  Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy.  Subsequently, these patients were again treated with a BRAFi, which resulted in 3 CR, one stable disease, and one progressive disease, and one patient who could not be assessed.  Melanoma patients achieving CR during BRAFi therapy represent a heterogenous group.  Discontinuation of BRAFi therapy after CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse.

Thoughts:
1.  While BRAFi provides a beneficial response in approximately 70-80% of BRAF positive patients, apparently only 3-6% of those gain complete remission.
2.  But, if you do....it seems that half of those will maintain remission (for at least 17 months...so far) after discontinuation of BRAFi.
3.  The half who do recur after stopping BRAFi, appear to have a 50% chance of regaining complete remission on retreatment. 
4.  These are very small numbers...but something to think about.

Health-related quality of life impact in a randomized phase III study of the combination of dabrafenib and trametinib vs dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.  Schadendorf, Amonkar, Stroyakovskiy, et al.  Eur J Cancer, March 17, 2015.

The COMBI-d trial that combined dabrafenib and trametinib vs dabrafenib monotherapy showed that patients taking the combo experienced significantly prolonged progression-free survival.  These same patients were evaluated regarding quality of life using an established questionnaire.  Questionnaire completion rates were more than 95% at baseline, less than 85% to week 40 and less than 70% at disease progression.  Baseline scores across both arms were comparable for all dimensions.  Global health dimension scores were significantly better at weeks 8, 16, and 24 for patients receiving the combo during treatment and at progression.  Pain scores were improved and meaningful in patients receiving the combo for all follow-up assessments vs those receiving monotherapy.  For other symptoms (nausea, vomiting, diarrhea, dyspnea, constipation) scores trended in favor of monotherapy.  This analysis demonstrates that the combo of dabrafenib and trametinib provides better preservation of quality of life measures and pain improvements vs dabrafenib monotherapy, while delaying progression.

Thoughts:
Given the better results and decreased side effects noted in the COMBI-d study when dabrafenib was combined with trametinib...improved quality of life is not really a surprise, but still nice to know.  For a refresher regarding BRAFi:  BRAFi for melanoma - dabrafenib, vemurafenib, and the dabrafenib/trametinib combo  For more info:  Data on BRAFi combo's

Wishing you all my best. - c