Saturday, June 29, 2013

Continued love and support...Thanks, Peds Care!!!!

On May 6, 2010, not long after experiencing sterotactic radiation for a brain met, followed by a right lung upper lobectomy, a beautiful basket with two lovely lavender hydrangeas arrived from my dear ones at Peds Care.  After enjoying their beauty indoors as long as possible, I planted them outside in a spot I thought they would like.  But, as we all learn, life happens...and in August, a storm brought a tree down on one of the plants.  Yet, as in life, the other continued to thrive and here is its beauty and  It made me smile and I thought I would share it with you all. Enjoy - c

Thursday, June 27, 2013

3 miles....for my girls

I ran today, for my girls; for Kidlet and Rosie, Dania and Kathryn.  There was no PR. It was not particularly beautiful, being overcast and muggy.  It was not pain-free.  But, I did hear a tree fall in the woods. I saw a gold finch feeding on wild thistle on the side of the road.  I scoped out wild crab apples that I may forage later. is done. But...I am not.

I wish I could tell you each day will bring sunshine and roses, with clear skin, good hair, and a number on the scale that will make you smile.  I wish those who, by all that is right, SHOULD love and support you, would never fail to do so.  I wish that your professors and friends, bosses and lovers would always play fair.  I wish all that for you and so much more....but it is unlikely to be so....ALL of the time.  So, you must enjoy those who ARE there and the small but tangible gift that EVERY day brings.  Even if the best you can say of some days is:  It is done.  But, I am not.

And should you ever fail to remember how beautiful and smart, creative and strong you really are?  Carry me in your heart and I will always be there to remind you.  Much love with hugs and kisses - c

Wednesday, June 26, 2013

Melanoma: Long Overall Survival in Patients Receiving Nivolumab

From presentation and interview given by Sznol at ASCO:
Published:  Wednesday, June 05, 2013
Melanoma: Long Overall Survival in Patients Receiving Nivolumab

Favorable One- and Two-Year Survival Rates

A total of 107 patients with metastatic melanoma enrolled in the trial, which was led by

Mario Sznol, MD, Professor of Medical Oncology at Yale Cancer Center. To be eligible, patients had to have had at least one prior therapy but no more than four for advanced disease and no prior treatment with ipilimumab. Patients received intravenous nivolumab every two weeks at a dose of 0.1 to 10 mg/kg.

The patients had a median age of 61.... the group was heavily pretreated, with 66 percent of patients having had at least two prior therapies and 25 percent,  three or more. Additionally, 78 percent of patients had visceral metastases and 36 percent had elevated lactate dehydrogenase, which is associated with a poorer outcome.

The investigators saw no dose limiting toxicities. (With all the usual side effects I've already mentioned.)

"There was no additional safety signal seen with the additional year of follow-up," Sznol said. The overall response rate was 31 percent across all doses, with no apparent dose response. The median duration of response was two years and 45 percent of the responders showed a response at the first tumor assessment at eight weeks, indicating that the responses can be both rapid and durable.

Moreover, 12 of 17 patients who went off drug for reasons other than disease progression continued to respond for at least 16 weeks, and eight of those were continuing response at the time of the data analysis (range of 16 to 56 weeks). "You don't need continued treatment in a subset of patients in order to maintain response," Sznol said.

Pointing to the Kaplan-Meier curve for progression-free survival, he noted that the curve dropped rapidly at first but then flattened out. "Although the median progression-free survival of 3.7 months is not overly impressive, the one- and two-year progression-free survival rates of 36 and 27 percent are," Sznol said.

The median overall survival for the study group is 16.8 months. The one-year estimated overall survival rate is 62 percent and the two-year rate is 43 percent. With a median follow-up of 22 months (range 14 to 51 months), 47 patients remain alive.

[When] asked about the optimal duration of treatment with nivolumab. Sznol said the optimal duration remains unclear, but that his group at Yale have discontinued therapy on two patients with near complete responses, one after three cycles and the other after five cycles. Neither patient has relapsed.

"So at least at complete responders, you probably don't need to continue the drug," he said. "The question is, what do you do in patients with stable disease or partial response. Do you continue to give them drug every two weeks or do you decrease the interval of dosing? I don't think we have an answer to that question."

[When] asked if it was possible to biopsy lesions in responders to see if the lesions really contain residual disease. "I think the rate of complete response here is a little bit underestimated," Sznol responded. "Of the five patients we treated at Yale who are responders, four are complete responders or near-complete responders and the fifth patient, who has a liver nodule, is PET negative.

“So there wasn't much for us to biopsy in our long-term responders. We have biopsied a few patients with progressive disease, but we haven't analyzed that tissue yet."

Brain Metastases?

...Asked about the likelihood that the drug works on brain metastases. Sznol noted that this trial excluded patients with active brain lesions, but accepted patients with previously-treated central nervous system tumors. Therefore the answer to the question remains unknown. "But we have long-term responders who didn't develop any brain metastases, so that suggests that maybe we are controlling disease in the brain," he said.

There are now three ongoing Phase III trials testing nivolumab in patients with metastatic melanoma. A trial testing the drug in patients with brain metastases has been proposed, but Sznol said he did not know if it was approved or would go forward.

For what it's worth....Overall, the response is still very good over 2 years...and if you're a complete responder you may not "ever" need to have any more drug.  While the "brain effect" remains a backwards way...Nivolumab looks like it may have a good effect there as well. group is in a different group all together, because of the volume of disease THIS group was dealing with vs the NED level my group had. Still a lot of unanswered questions:  How long does response REALLY last?  What is the best treatment dose?  What is the best treatment frequency?  What about folks with no prior treatment?  What about folks with brain tumors?  Come on BMS and Merck....risk a little of your bottom line for the ratties.  Let brain tumor patients in a trial.  YOU don't have anything to REALLY do you????  Just say'n - C

Friday, June 21, 2013

Three miles DONE...Take that....

....melanoma, anti-PD1 side effects, and B&B Swindlers!!!  It was slow, but sho, while getting drenched in sunny rain as the Devil was beating his wife!  I'd say those were pretty appropriate conditions for my mood!  My first run since my last infusion, since I've been feeling crappy with arthralgias and mouth ulcers.  (Yes, Virginia.  There IS a Santa Claus.  And, YES, Jeffery!  Side effects ARE cumulative!!!!)  BUT, sometimes you just can't let crappy win!  Besides, The Melanoma Avengers are running in a Half Marathon relay in Johnson City in October and I gotta get ready!!  Bentie is going to be The Hulk.  Rosie - The Black Widow.  Freddo - Iron Man.  And THOR = ces't moi!!!!!  Pissith me off not, or I shall smite thee with my hammer!!!  Rosie has the first leg with 4 miles, Bentie covers the next three, I do the next, and Freddie has to bring it home with a winning time!!  HA!  No pressure, Freddo!!  Rosie is actually planning to run the whole thing, crazy girl!  It should be fun.  It starts at 3PM, so no butt crack of dawn business and there is a Brewfest afterwards.  I think I can be down with that!!!

In other news, driving home yesterday, a mother deer and her three spotted fawns were about to cross the road in front of me.  Herman and Esmeralda were standing in the road.  Geraldine (the mom) and Beatrice were standing on the side.  They quickly stepped back into the bushes as Geraldine called to Herman and Esmeralda to come quickly.  After only a moment's pause, Essie obeyed.  But it wasn't until Geraldine hissed, "Herman, get your spotted little derriere over here RIGHT THIS MINUTE!!", that Herman gave me one more doleful glance and joined the others.  I could here Geraldine fussing as they made their way through the brush...."Just like your father!!!"

Drinking a somewhat nasty protein zone banana chocolate shake at B's behest.  He fears my stomatitis will lead to weight loss and malnutrition.  Hmmmm.  He's just about as bossy as Geraldine. 

Much love to all.  Have a great weekend. - c

Thursday, June 20, 2013

Quack Watch!!! - Jerks who try to take advantage of the word "cancer"!

Yep, folks!!  It's a new technique in the ancient game played by charlatans, hucksters, and snake oil salesmen since time began. Put the word "cancer" in your blog post title and you are likely to have an inane, grammatically incorrect, if not downright incoherent comment posted by Kim Burns.  She's fond of starting them with..."Me and Dr. Fredda Branyon think...."  HOLD up!!!!  Stop right there!!  There are three major problems already.  The obvious one with grammar hits hard from the start.  (I know I shouldn't help you, but, Sweetie...when using "ME and Sam"  vs "Sam and I"....simple rule:  Take "Sam and" out of the sentence and see whether "I" or "ME" makes the most sense!!!!) The fact that either party (if in fact, they are other than one and the same) "thinks" is easily disputed.  And, finally, Fredda Branyon is NOT a doctor!  Here's the story:

On June 10, Ms. Burns decided to put a comment on my May 8 post whose title included the word "cancer".  I guess she's not smart enough to know that melanoma is cancer, too! Anyhow, given her sad excuse for the King's English, while touting the wonders of "Dr. Fredda Branyon", I immediately smelled a rat.  (Check it out...I left her comment up for the world to see!!!)  A cursory google look up of the dear doctor quickly told the sordid tale.  Turns out, she's not a licensed physician at all!!!  Even her own web site confesses to that...though it doesn't stop proclaiming her as one!!  But, more than that, Fredda Branyon is a CRIMINAL!!!!!!!  Fredda Branyon of Scottsdale, Arizona, has made thousands off sick and desperate individuals. Ms. Branyon started buying umbilical cords and cord blood tissue from a Del Rio birthing center in 2009. Then, with no training regarding stem cell development or the legal ability to do so, she manufactured hundreds of vials of "stem cells". She sold 183 vials of "stem cells" for more than $300,000, to Francisco Morales, who worked with the lab she owned, Global Laboratories. Morales, in turn, led his patients to believe he was a doctor (he isn't) and was arrested in Texas for treating people with cancer and multiple sclerosis in "treatments" not approved by the FDA. Branyon pleaded guilty during an investigation by the FDA and FBI in 2011. She was facing 3 years in jail and a $10,000 fine. I hope she is cooling her heels in prison as I write. 

Ruthie, the wonder sleuth, took a different tact. She began a search looking for the Kim Burns + Fredda Branyon combo.  Lo and behold!!!!  Scam revealed!!!  Thus far, we have found her ridiculous comments, with the goal of garnering support and press for her Witch Doctor, on numerous blogs by people she assumes are suffering from cancer and are thereby desperate, gullible, and without recourse. Sad news, sweet cheeks!  You picked on the wrong folks.  We may have cancer or currently be suffering pain from the loss of another of cancer's victims, but we do NOT suffer cheats, connivers, imposters, and frauds quietly.  You picked the wrong girl!!!  I will be following your comments with my own....everywhere I find them!  SURPRISE!!!!

The range of blogs and the real live, breathing, caring, feeling, and at times, hurting, human beings that she has tried to hi-jack is nauseating.  Chris seems like a really sweet guy, trying to do some real good in this world.  Americanloons is a pretty hysterical expose' of some of America's deceivers; a point that Ms. Burns was completely oblivious to when making her comment.  There are a variety of informational blogs, some more scientifically credible than others, that she has tried to horn in on.  Super Mommy gives a pretty funny and realistic look at the life of a mom but managed to be yanked on by Ms. Burns when recounting the touching story of the loss of a dear friend's brother to cancer.  Angela Johnson was smart enough to delete comments Ms. Burns made on her photography blog when she made a heart felt plea for brain cancer awareness in May.  In The Barrs..., a humorous, charming husband, tells his story as his wife battles brain cancer. And, for the manipulation of Andrew's Fight...I could gouge the little Burns/Branyon couple's eyes out with a spoon....and never blink once, as Joe, the blog's writer recounts the struggle his son had with cancer and the pain he still feels acutely after the child's death almost one year ago.  The pain in his words are palpable.  Really, Ms Burns?  Really?

To you courageous bloggers out there:  I hope I have not offended by including your stories here.  I will be more than happy to remove them should you wish it...just leave me a comment if that is what you desire and it will be done.

To the swindler team of Burns and Branyon:  I am watching you.  I have only just begun.  You have been warned!  Want some more free press? - c

Sunday, June 16, 2013

Love Potion...or Patient...#9!!!!!

She jumped down, turned around and gave me a wink.
She said, "I'll mix it up right here in the sink."
It smelled like turpentine and looked like India ink!
I held my nose, I closed my eyes...
I took a drink!

At the end of my visit in Tampa last week, it suddenly hit me.  Which patient had I been?  So, I asked one of the clinical coordinators.  With a little smile, she tilted my chart so I could see the front.  There, in black magic marker:  #9.  However, she noted, a couple patients had passed (I knew of two) and "several" had dropped out or been assigned numbers but for a variety of reasons had not participated. (These patients may have decided against it or had labs/scans that in the end didn't meet criteria.  I knew of one who had been ahead of me, but had to drop out due to progression, but then spontaneously resolved).  "In fact," she continued, "the first patient returning for the 3-month post infusion follow-up is here today."  Wow!  I don't know why it hit me so strangely.  But, when you count it up...I am #9 minus 2 = 7, then minus the one who progressed = 6, minus the one returning that day = 5, minus Lynn Luc = 4, then maybe minus one who didn't make it in due to unfortunate results = probably patient #3!!!!  I felt rather startled!

Cognitively, that was not such a surprise.  I knew I was in the first cohort of the NED arm of the study and there were to be only 10 patients per the start.  I also knew the rough history of anti- PD1....

Once upon a time (2005), in a land far, far away...(Japan), ONO Pharmaceutical generated ONO4538, an anti-PD1 monoclonal antibody, in research collaboration with Medarex (who called the product, MDX1106).  In 2009, the big, getting ever bigger, (? benevolent) King of the World, Bristol-Myers Squibb (BMS) acquired the rights to develop ONO4538/MDX1106/BMS936558  in North America.   In an additional agreement in 2011, BMS attained the rights to the product in the rest of the world...except Japan, Korea, and Taiwan...where ONO retained exclusive development rights and is conducting Phase II studies with ONO4538 in non small cell lung cancer and melanoma and Phase III studies in renal cell carcinoma currently.  However, no results of either of those studies can be found.

Thus began the exploration of BMS 936558 in the Americas!  There was a study by Sznol at Yale (that I can't manage to lay my hands on) that included approximately 15 patients with melanoma.

In 2009:  Phase II experience with MDX1106 (ONO4538) an anti PD1 monoclonal antibody in patients with selected refractory or relapsed malignancies.  Journal of Clinical Oncology, Topalian, et al. John Hopkins.  Where 21 patients, 8 of whom had melanoma, were treated with a 10 mg/kg dose.

In 2010:  Phase I study of single agent anti-programmed death-1 (MDX 1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates.  Journal of Clinical Oncology, Brahmer, Topalian, et al.  39 patients, 10 with melanoma, with data tallied as of January 2010 had been treated with said drug. (Keep in mind this may simply be an extension of the study noted above.)

In 2012:  Safety, Activity, and Immune Correlates of Anti-Pd1 Antibody in Cancer.  New England Journal of Medicine, Hodi, Sznol, McDermott, et al, from a variety of centers. 296 patients were treated. 94 of those had melanoma.  Patients with non-small cell lung cancer, renal cell carcinoma, and melanoma showed some response.

But, back to Patient #9.  As best as I can find and add, apart from the uncountable, unknowable Japanese study, I am actually roughly patient #36 (or perhaps patient #28!!!), since I embarked on this adventure before those in the Hodi study or the growing numbers in the various arms of my current study.  So...knowing all this...why did I feel so discombobulated at hearing I was Patient #9 (or #3) in my study????

I don't really know.  Except, when you go to your doctor every 2 weeks, or every 3 months, being scanned, leukophoresised, poked, prodded, and given more bug juice...a much more apt moniker in my mind than Nivolumab!!!!... and you ask:  "So, how are things going?"  "What is the data looking like?"  "Has anybody else had this rash, done that thing?"  "How are they, anyway?" You somehow, despite KNOWING:  He doesn't know!!!!!...value the few points and details you can glean.  When the real truth is, especially at first, the main response was only, "Hmmm.  This stuff is WEIRD!!!"

I  didn't know if it was day or night.
I started kissing everything in sight.
But, when I kissed a cop at 34th and Vine,
He broke my little bottle of....
Love Potion #9!

WEIRD!!!!!! -c

Saturday, June 15, 2013

Happy Father's the best daddy in the world!!!!!

We have loved you always.  - The Binga Heads

Tuesday, June 11, 2013

Anti-PD1 (Nivolumab)..FINISHED!!! The whole story:

In keeping with the strange routine that has been my life for the past two and a half years, it was time for me to return to Moffitt in Tampa.  It is hard to believe that I have been traveling back and forth, every two weeks for the first 6 months, then every 3 months for the past 2 years!!!  Anyhow, Brent and I took off and here is my story:

"Adriaaaaaaan!  Adriaaaaan!"
"Rocky, I love you!!!!"

Wait....different Adrian, better known as Andrea, actually, but hey!! Yes, I travel to Tampa predominately in inclement weather!  Snow - check!  Ice - check!  Path of a tornado - check!  Horrible thunderstorm with devastating hail - check!!  And now, we fly toward the first hurricane of the season, planning to follow it north when we land in Atlanta the following day!  Awesome!!!!!

So, though cloudy, we drove to Atlanta before the rain set in, with pretty mild traffic and minimal stomping of his imaginary brake...though he did get in trouble a couple of times!!! Bentie.  Got my veggie sandwich from the Atlanta Bread Company while watching bags fly off the carts being pulled by jeep-like vehicles as they zoomed across the tarmac.  Waiting for our flight I was entertained by my fellow travelers; they never disappoint.  As B went off on an explore (don't ask me why!!) I observed a lady wearing a T-shirt of so bright an orange, that only those of us who have been exposed to UT on game day, would fail to be alarmed.  In addition to its vivid color, it bore three crosses in bright white relief with "REPENT" written above in large block letters.  Behind me, a gentleman (?) is yelling loudly at someone on his phone:  "All you want is your G@# D@^m* money!" And..."You didn't leave no damn message...I check my messages!" with lots of "a.k.a"...which I don't think he understood the meaning of, sprinkled throughout.  But, his closing was the best, after all that...."Ok, baby. I love you."  Ruthie has considered that perhaps, certain folks who look as though they are waiting on a flight, are actually paid entertainers. I think it is more like a nurse I work with recently said, "The world is full of crazy people....AND THEY DON'T STAY HOME!!!!"  We boarded our Air Tran flight and were off.  The flight wasn't nearly as bumpy as I had feared, though the landing was a little sketchy as the pilot was having to deal with some very high winds.  Once in Tampa, the rain began in earnest.  Off to Alamo to check out their fluid line up, and discovered that a bright yellow Fiat 500 was an option for our 21 bucks.  (Car rental is an amazing craziness in and of itself.  We have paid over $80.00 at times, for the cheapest possible ride!) But, happy with the price of the day, B indulged my selection, knowing to ask..."Does it smell ok?"  Hee Hee!!! Driving off into rain and pretty high winds in a vehicle, while very cute, was tiny and top heavy, having little pick-up, loose steering, and wheelbarrow tires, was probably not the wisest choice.  But, a girl's gotta have fun.  The wind definitely got my attention as we crossed the bridges and overpasses through Tampa to our hotel and then on to Pho Quyen.  So, yummy!!!

Off to Moffitt the next morning, the skies were mostly clear and the sun was shining.  However, in talking to the locals, Andrea had made her presence known with winds and high water that had caused some residents trouble before we arrived.  IV start and labs accomplished, over for our visit with Dr. Weber.  It was a happy meeting given his recent return from ASCO and my completion of the trial!!  What we learned:

Though no one can state the significance with any certainty, the fact that I remain NED, after 32 months, S/P a brain tumor is pretty remarkable.  The data for my NED arm remains unchanged since I last posted them (See "My Thoughts - posted May 29).  But, the bottom line continues unchanged:  Of 31 patients, 26 remain NED.  For a clinical benefit of 83%!!!  Weber remains in talks with the folks at BMS to try to get a clinical trial started to examine Nivolumab as an adjuvant for folks who are Stage IV NED.  They however, are concerned that there just aren't enough of us to make it profitable.  ASSHOLES!!!!  But, for what it's worth, Dr. Weber believes in it, and is continuing to try to encourage them to pursue it.

Random gleanings:
  • There has been at least one case report of a patient who did recur after having been treated with Nivolumab, who was retreated and responded again.
  • Relapses in treated folks have occurred at the site of resected tumors.  Though, interestingly, "all of the patients with brain mets are alive and free of disease, which is very surprising since those are the highest risk patients".
  • When asked about the effect of Nivolumab in the brain...we were told that it probably does not work particularly well, but after the brain is irradiated, it can definitely prevent tumors from returning because it gives you the absconal effect, in that once an inflammatory environment is created, the drug will work...much like what they are finding out about the use of ipi after SRS for brain mets.
  • Folks in Tampa seem to think that BMS will beat Merck to market with their anti-PD1 product, by a few months, and the wait time will be around 18 months. (I hope it is even sooner!)
  • After hearing, and presenting data at ASCO, folks in Tampa felt that sequential therapy, anti-PD1 followed by ipi, will probably be the most successful sequential strategy in melanoma treatment and that sadly, side effects are likely to be very difficult to deal with when ipi and anti-PD1 are given together, even at dosage levels of 1mg/kg anti-PD1 with 3mg/kg of ipi.
  • There are more check point drugs in the pipeline, like BMS-663513, an agonist of the CD137 immune regulatory protein, for instance.  How they will do is yet to be seen.
  • AND...I have it from Dr. Weber himself:  Peptide vaccines are not going to be used (in their current form at least) in any more trials at Moffitt!  Thank goodness!!!  If we can't implement what we learn from all the ratties, then what is the point????!!!

NEXT STEP:  So, now that I've spent 2 1/2 years doing this business, what's a girl to do?  The new plan for folks in my trial (the protocol is in process of being amended....again!) once we have completed our doses of anti-PD1 as I have, is to have scans and return as usual, 3 months after our last dose, for a final visit and labs with Dr. Weber.  Then, patients can continue to see him, or their local oncologist, on a schedule of every 6 months to a year.  He noted that he would like to continue to receive lab and scan reports from his trial participants via mail, recognizing that costs of continuing to go to Tampa for simple follow-up, in both time and treasure, can be prohibitive.

So after giving Bentie a twirl in the hall, with applause from one of the lab techs, we were off to the airport, where for no extra charge (Are you listening Delta?  NO EXTRA CHARGE!!!) we were allowed to board an earlier flight.  And, yep.  Andrea, or at least her heavy surrounding rains, were in Atlanta, along with rush hour traffic, just waiting on us.  After stop and go in pouring rain, we bailed and landed at the It's OK! restaurant!  It was wonderful.  Could there have been a restaurant better named for our adventure????  I don't think so.  Had me a veggie plate with mac 'n cheese, collards, black eyed peas, and squash casserole.  That's what I'm talkin' about!  Check them out if you're in Atlanta!!

One more nugget, Love Potion #9, to follow soon.  It's OK! - c

Monday, June 10, 2013

Happy Birthday, Freddie Froo! 23 years! Is it true????

The Fred azaleas are blooming!!!!  That can mean only one thing!  Happy birthday, baby. Hope you have a great day tomorrow!!!  Can't wait to give you your birthday hug this weekend!!! Love you.  mommy

Saturday, June 8, 2013

Last dose, Nivolumab (BMS anti-PD1, 936558)... DONE!

Feeling extremely tired this morning, with anti-PD1 aches in my ankles, knees, and toes and road rash on my tongue...but it is done. My scans of last week all remained clear, so we made our usual visit to Tampa. We learned a lot from Dr. Weber who had just returned from ASCO and had our usual small adventures. Will be posting more on all of that soon. But, for now....NEW dimensions in my melanoma world:

118 months - since diagnosed with melanoma
38 months - Stage IV
32 months -NED
30 months - BMS anti-PD1 trial (Nivolumab with peptide vaccines) at Moffit, in Tampa

More details to come. Happy weekend - c

Sunday, June 2, 2013

New data on treatments for Melanoma Brain Mets....My Take

1.  Should you be dealing with brain mets from melanoma, make sure you are seeing a melanoma specialist...not just an oncologist.  Things are constantly changing, updating, and improving (thank goodness!!!!).  You need someone on the cutting edge of this data.

2.  A primary melanoma lesion that is ulcerated is unfortunately a bad prognostic sign for melanoma progression period, as well as for brain mets, as this first report noted.

3.  Re: "high peritumoral T-cell infiltrates are associated with prolonged survival" plain English....if there are a lot of T-cells around the tumor, they are trying to kill it and you are more likely to live.  Now....we just gotta figure out how to make that happen!!!

4.  Treatment with ipi, which has about a 20% response rate in melanoma patients' tumors in their body, is showing the same response rate for melanoma brain mets.  (Back to those T-cells again!!!)

5.  A combination of ipi and stereotactic radiation is looking to be a combo that is more effective than either on their own, with patients having brain mets showing an overall survival of 28.3 months when given both, but only an OS of 6.9 months when treated with SRS alone.  Additionally, the next study shows patients treated with ipi but having had no brain mets had about the same survival as patients with brain mets, when treated with both ipi and SRS.

6.  BRAF inhibitors.  Ok...first you need to be BRAF positive, with the V600E mutation for these to work. (Researchers are working on other treatments for wild types and NRAS.) There are two BRAF inhibitors currently on the market.  The first was Vemurafenib, now named Zelboraf.  The second is Dabrafenib, now named Tafinlar.  A recent study with Vemurafenib showed a 50% CNS (central nervous system) response rate...that means brain.  The last study posted shows that for some reason, when patients were started on the BRAF inhibitor (BRAFi) POST brain tumor, their survival was much increased (to 23.2 months) as opposed to patients who developed a brain met when already on it.  Clearly, we have much to learn.  BRAF inhibitors are known for some pretty sucky side effects and for their limited time of action, as tumors frequently learn to work around them and start to grow again.  Yet, there are those among us who have had great success taking them for years.  (Go Dick_K and JMMM!!!!!!)  [See my post on new ways to use BRAFi on Jan 13, 2013.]

SO....if in need, check with the authors of these papers.  Call them or their institution.  Or, get your doc to do so.  Things are changing rapidly....and it's about time.  Don't miss out on any treatment opportunity that may help you.

Yours, c

Brain mets in Melanoma...the latest from ASCO

 Prospective analysis of predictors of survival in melanoma patients with brain metastases.
Authors:  Zakrzewski, et al.  NY University School of Med, Weill Medical College, Cornell.

Melanoma patients with brain mets have limited survival, and brain mets remain an exclusion criterion in most clinical trials.  Recent retrospective analysis at Sloan Kettering identified 4 clinical variables associated with worse post brain met survival.  This study looked to see if tumor features could improve predictability of post brain met survival and the reproducibility of that study.  89 patients were identified. Median post brain met survival = 5.75 months. Median follow-up = 4.2 months. Ulceration and mitotic index >3 were associated with worse post brain met survival.  Age greater than 65, >3 lesions, presence of neurologic symptoms, and extracranial metastases were also associated with worse survival.  CONCLUSION:  Data suggest that ulceration of the primary melanoma might indicate an adverse biologic behavior that impacts post brain met survival.

Association of high T-cell immune infiltrate and low hemorrhage in melanoma brain metastases with prolonged survival.
Authors:  Krauze, et al. University of Pittsburgh and Beth Israel Medical Center, Boston

Despite the poor prognosis of patients with brain mets, several patients have prolonged survival.  We id'd patients who have undergone craniotomy for melanoma brain mets and examined clinical histories, pathology, and genome expression profiling of archived tissues.  Factors associated with prolonged survival were high immune infiltrate plus low hemorrhage, present melanin, and recursive partitioning analysis class 1.  CONCLUSION: High peritumoral T-cell infiltrates are associated with prolonged survival.  High tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma cells that migrate and invade the brain.

Phase II trial of ipi monotherapy in melanoma patients with brain metastases.
Authors: Lawrence, et al.  Mass General, Boston. The Angeles Clinic, Santa Monica. Beth Israel, Boston. Vanderbilt, Nashville. Yale, New Haven. Loyola, Maywood, IL. Indiana University, Indianapolis. Dana-Farber Boston. Bristol-Meyers Squibb, NJ. University of Washington, Seattle.

Ipilimumab, a human monoclonal antibody that blocks CTLA-4 has activity in advanced melanoma.  This phase II trial attempted to assess ipi safety and activity in melanoma patients with brain mets.  Patients had measurable brain mets with at least one lesion >0.5cm and/or 2 lesions greater than 0.3cm, and none greater than 3cm in diameter.  Prior whole brain or stereotactic radiation to non-index lesions were allowed.  Ipi 10mg/kg was given IV every 3 weeks for 4 doses.  Responding or stable patients could receive maintenance ipi at 10mg/kg every 12 weeks.  Total of 72 patients in two arms...arm B still ongoing.  No association between brain edema or cerebral hemorrhage and objective response.  Of 51 patients in Arm A, at week 12: 4/51 had a partial response, 5/51 had stable disease, with additional unconfirmed responses.  Duration of responses ranged from 3 to 12+ months and duration of stable disease ranged from 1-7 months.  CONCLUSION:  Ipi has a similar level of activity in brain and non-CNS lesions.  Analyses are ongoing and final data will be presented.

Outcome with stereotactic radiosurgery (SRS) and ipilimumab (ipi) for malignant melanoma brain metastases.
Authors: Shoukat, et al.  Emory, Atlanta, GA.

Retrospective analysis to determine if this combination is safe and improves overall survival.  Patients with melanoma brain mets who underwent SRS b/w 1998-2010 (n=124) were compared to those who additionally got ipi (n=11).  Median overall survival for the entire cohort was 6.9 months.  Patients in the ipi group had an improved median overall survival of 28.3 months.  CONCLUSION:  Uses of SRS with ipi appears to be safe and associated with an impressive increase in median overall survival.

Survival of melanoma patients with brain metastases treated with ipilimumab combined with stereotactic radiosurgery.
Authors:  Tazi, et al. Medical University of South Carolina, Charleston.

Retrospective record review, we report the outcome of patients with stage IV melanoma with brain mets treated with ipi and SRS.  Twelve of 30 patients treated with ipi had brain mets. Median age = 66 years. Group A = no brain mets.  Group B = brain mets.  33% of both groups died as of last f/u. Median survivals from date of Stage IV for Group A = 29.1 months and for Group B = 32.9 months.  Estimated 2 year survival rates from date of cycle 1 ipi administration for A = 58% and for B = 55%.  CONCLUSION:  Survival of patients with melanoma brain mets treated with ipi combined with SRS may be comparable to patients without brain mets.

Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Dzienis, et al.  Princess Alexandra Hospital Brisbane, Australia.

Responses to dabrafenib have already been reported in over 50% of patients.  We aimed at assessing response rate to vemurafenib.  Patients with BRAF positive melanoma and asymptomatic brain mets were included.  Conclusion:  Vemurafenib resulted in 50% CNS response rate.  Prospective comparison to dabrafenib may be warranted.

Survival patterns following brain metastases for patients with melanoma in the targeted therapy era.
Authors:  Wattson, et al.  Mass General Hosp, Dpt of Radiation Oncology and Cancer Center, Harvard.

Survival from metastatic melanoma has been significantly prolonged by molecularly targeted therapy, specifically BRAF inhibitors (BRAFi) for patients with V600E mutation.  This is a retrospective review of 191 patients with metastatic melanoma.  Of 98 patients who developed brain mets, median f/u after first one was 7.7 months (15.5 mo for the 25 living patients) and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months, which preceded brain mets in 30%, was concurrent in 18%, and followed first brain met in 52%.  Ipi or anti-PD1/PD-L1 was given to 58% of patients who got BRAFi and 95% of those who did not.  CONCLUSION:  Survival for patients with brain mets from BRAF mutant melanoma can significantly exceed the often anticipated 4-6 months, particularly if a BRAFi is initiated after brain mets arise.

 TABLE:                                         Median survival, months            N                  
BRAF mutant, with BRAFi                           13.2                             33
BRAFi started pre brain                                5.6                              16
BRAFi started post brain met             23.2                          17
BRAF mutant, no BRAFi                               6.7                               7
BRAF wild type                                              8.0                              34
BRAF unknown                                              6.5                              24

To those in need, hope this helps.  All their words, not mine!!!  My  Peace - c

Saturday, June 1, 2013

For Melanoma: Ipi and Nivolumab (the BMS anti-PD1 drug)....better together!!!! Safe too!!!

Safety and clinical activity of nivolumab (anti-PD1, BMS-936558) in combination with ipilimumab in patients with advanced melanoma.
Authors:  Wolchok, Sznol, et al.  From:  Memorial Sloan-Kettering, Yale School of Medicine, Bristol-Meyers Squibb, NJ and CA.
J Clin Oncol, 31, 2013 (abstr 9012) for ASCO Meeting

CTLA-4 and PD-1 are critical immune checkpoint receptors. In melanoma patients, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (ant-PD1) produced an objective response rate of 31% in a phase I trial.  PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced anti-tumor activity in [mouse] models.  Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy.

Method:  Melanoma patients with greater or equal to 3 prior therapies received IV nivolumab and ipi concurrently, every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for four more doses.  At week 24, combined treatment was continued every 12 weeks for 8 cycles in patients with disease control and no dose limiting toxicities.  In 2 sequenced-regimen cohorts, patients with prior standard ipi therapy were treated with nivolumab every 2 weeks for 48 cycles.

Results:  Per Dec. 6, 2012:  69 patients were treated.  Data on 37 patients with concurrent therapy in completed cohorts 1-3:  Overall objective response rate (ORR) = 38%.  In cohort 1:  ORR = 21%.  In cohort 2: ORR = 47%, and 41% of patients had greater or equal to 80% tumor reduction at 12 week mark, with some patients showing rapid responses, prompt symptom resolution, and durable complete responses. Related adverse events for concurrent therapy were similar in nature with some higher frequency than those seen typically for monotherapies and were generally manageable using immunosuppressants.  Cohort 3:  ORR = 50%, BUT exceeded the maximum tolerated dose (MTD) [which happened to be ipi at 3mg/kg and nivolumab at 3mg/kg]. [NOTE:  Cohort 1 was treated with ipi at 3mg/kg and nivolumab at 0.3mg/kg.  Cohort 2 = ipi at 3mg/kg and nivolumab =1mg/kg]  At the MTD, grade 3/4 adverse events occurred in 59% of patients and included  uveitis/choroiditis, colitis, and reversible lab abnormalities.

Conclusion:  The combined therapy had a manageable safety profile.  Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (80% tumor reduction at 12 wk) in 30% (11/37) of patients.  A phase III trial is planned to compare concurrent combination dosing with each monotherapy.

Table of data:

Cohort          Ipi (mg/kg) plus        N       Complete         Partial             Overall         >/= 80% tumor  

                    antiPDI (mg/kg)                  Response         Response        Response      reduction at 12 wk
      1                3 + 0.3                     14            1                      2                    21%                  4/14 (29%)
      2                3 + 1                        17             3                      5                    47%                  7/17 (41%)
      3                3 + 3                        6              0                      3                    50%                   0/6   (0%)
      2a              1 + 3                        12            ongoing
      6                Prior + 1                  14            ongoing
      7                Prior + 3                  6              ongoing

ASCO 2013:  Phase I Trial Suggests Ipilimumab and PD1 Drug Nivolumab May Be Better Together than Alone for Advanced Melanoma
By:  The ASCO Post
Posted: 5/17/2013

Key Points:
  • In a phase I trial, patients with inoperable stage III or IV melanoma who had undergone up to three prior therapies received combination therapy with ipi and nivolumab.
  • In the three completed treatment arms, tumor shrinkage rates were 21%, 53%, and 50% with the highest rates seen in patients treated with the highest dose of both drugs.
  • While the data are still preliminary, it appears that even patients who initially had little benefit from ipi, had significant tumor shrinkage after subsequent treatment with nivolumab.
Results from a phase I study with combined ipi (yervoy) and investigational drug nivolumab (BMS anti-PD1) led to lasting tumor shrinkage in approximately half of patients with aggressive, advanced melanoma.

"The complete and near-complete response rates we're seeing are unprecedented for an immunotherapy in melanoma, " said Jedd Wolchok, MD, PhD, a medical oncologist at Memorial Sloan Kettering.

Phase I trial:  In this trial, patients with inoperable stage III and stage IV (metastatic) melanoma who had undergone up to 3 prior therapies were assigned to 6 different treatment arms. The current results are based on 52 patients in 3 completed arms, in which patients received concurrent treatment with the two drugs.

In those three arms, tumor shrinkage rates were 21%, 53%, and 50%, with the highest rates seen in patients treated with the highest dose of both drugs.  The responses to therapy were rapid for an immunotherapy.  Three out of 4 patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipi. Thirty-one percent of patients (16 out of 52) experienced significant tumor shrinkage of more than 80%.

Two of the remaining three arms enrolled patients who had undergone prior ipi treatment. Those patients received only nivolumab on this study.  While the data are still preliminary, it appears that even patients who initially had little benefit from ipi had significant tumor shrinkage after subsequent treatment with nivolumab. 

Side effects have been manageable in the trial and did not impact the positive therapeutic activity for the majority of the patients in this analysis.  A randomized phase III trial of the nivolumab/ipi combination as first-line therapy for patients with advanced melanoma scheduled to begin in June 2013.

  • All of the commentary, report, and table above are direct quotes from the two articles.
  • Were patients with brain mets admitted?
  • What time frame are we using for "durable"?
  • While this is good news and I do believe that concurrent or sequential therapies will offer improved outcomes for many melanoma patients....I find it very strange and even suspect that headlines report the "big" numbers of "SUCCESS" on very SMALL numbers of patients and in the fine print admit that...Yes, the best results came from the group with the highest doses of meds, but we can't actually use that dose, because there were way too many side effects...but we're still going to use those numbers to sing our praises although we can't really give that to anybody!!!!  Look carefully at the table.  Especially at cohort number 3.  There were only 6 patients.  NONE of them had a complete response and only 3 had a partial response. NONE had the "80% tumor reduction at 12 weeks".  Yet, they are touting a 50% overall response.  Yes...that is the math.  But, I'm not sure it has real meaning with real patients and they state that that cohort had "dose limiting toxicities".  So....we'll see.
  • The OVERALL objective response 38%. We'll see what the final report at ASCO has to say.
  • FYI:  I am being treated with this same anti-PD1 drug at 1mg/kg.
  • Thanks to every rattie who went there for the rest of us.  Bless you every one. - c