Saturday, August 1, 2015

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


Pembrolizumab cutaneous adverse events and their association with disease progression.  Sanlorenzo, Vujic, Daud, Algazi, et al.  JAMA Dermatol.  2015 Jul 29.

While immunomodulatory anticancer drugs, like anti-PD1 are promising....little is known about cutaneous adverse events caused..and their possible correlation with treatment response.  Single institution, retrospective medical record review, March 1, 2011 - May 28, 2014.  83 patients from 2 clinical trials...who had at least 1 dose of pembro and at least 1 f/u visit.  43 patients had 10mg/kg q 3 wks, 24 had 10mg/kg q 2 wks, and 16 had 2mg/kg q 3 weeks.  66 were melanoma pts, 15 were lung, 1 prostate cancer and another was treated for Merkel cell carcinoma.  

35 patients (42%) developed cutaneous AE's.  Most common = papular eruption (24[29%]), itching (10[12%]), hypopigmentation {vitiligo} (7[8%]).  All 7 pts who developed hypopigmentation were being treated for melanoma.  Survival analyses showed that patients who developed cutaneous AE's had significantly longer progression-free intervals in all 3 treatment dosage groups, compared to patients who did not develop cutaneous AE's.

CONCLUSION:  Pembro was associated with side effects related to the skin in 42% of patients.  The development of these cutaneous AE's, especially hypopigmentation in patients with melanoma, could point toward better treatment response.


Link to post describing general side effects from anti-PD-1 and why we get them:  Side effects of anti-PD1 (Nivo in this case, though data is very similar for Pembro)

Link to post from ASCO 2015:  How Nivo side effects are associated with survival

Link with info from 2015 with article demonstrating positive link between vitiligo and remission of melanoma, back ground info, and white patches:  Vitiligo a good prognostic indicator for melanoma

Pretty much what we've been hearing (and seeing!!) already.  There has got to be something going on between the CD8 T cells, dendritic cells and melanoma, especially since only the melanoma patients in the study developed vitiligo.  B's been screaming about this for years!!!  It is clear that a link between these things exists...but we don't yet know how to ELICIT the vitiligo response so that more melanoma patients GET a response!  Come on researchers!!!  We've got a vaccine for ebola, a reliable treatment for Hep C...let's do this!!!!! - c

Sunday, July 26, 2015

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

Wednesday, July 22, 2015

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

Sunday, July 19, 2015

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

Wednesday, July 15, 2015

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

Sunday, July 12, 2015

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

Saturday, July 11, 2015

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