Monday, July 21, 2014

BRAF/MEK combo ~ vemurafenib with cobimetinib

Combination of vemurafenib and cobimetinib in patients with advanced BRAF (V600)-mutated melanoma: a phase 1b study.
Ribas, et al.  Lacet Oncol 2014, July 15 [epub ahead of print]

My synopsis:
The addition of a MEK inhibitor to a BRAF inhibitor has been found to enhance effects on tumors, delay resistance, and provide fewer side effects in patients. (As demonstrated in the CombiDT studies where the BRAFi dabrafinib was combined with the MEK inhibitor trametinib.)  Here researchers combined the BRAFi vemurafenib with the MEK inhibitor cobimetinib, the roche/genentech MEKi.

Patients had advanced melanoma, were positive for the BRAF (V600) mutation, and had either recently progressed on vermurafenib (n=66) or had never been given a BRAF inhibitor (n=63).  They were given vemurafenib 720mg or 960mg twice daily and cobimetinib 60, 80, or 100mg once a day for either 14 days on and 14 days off, 21 days on and 7 days off, or continuously.  Trial number:  NCT01271803.

129 patients were treated at ten dosing regimens. Dose limiting effects arose in 4 patients.  All were on a 960mg bid dose with differing cobimetinib doses. AEs = Grade 3 fatigue, Grade 3 prolonged QT (a heart problem), Grade 3 stomatitis, arthralgia and myalgia.  Maximum tolerated dose turned out to be:  vemurafenib 960mg twice a day with cobimetinib 60mg (21/7)  Across all doses side effects = diarrhea (64%), acne like rash (60%), liver enzyme abnormalities (50%), fatigue (48%), nausea (45%), photosensitivity (40%).  The most common Grade 3 reactions were:  squamous cell carcinoma (9%), increased alkaline phosphatase (9%), and anemia (7%).

Confirmed objective responses were recorded in 10 (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2.8 months.  Confirmed objective responses were recorded in 55 (87%) of 63 patients who had never received BRAFi, including 6 (10%) who had a complete response, median progression free survival was 13.7 months.

My thoughts:
  • The combination of vemurafenib with cobimetinib did better than results of prior studies in which vemurafenib was given alone.
  • Patients who were naive to vemurafenib responded better than those who had failed on it.
  • Both of these facts are being demonstrated with other meds (like the immunmodulators) in other studies.
  • Meaning, studies are showing that treatment naive patients respond better than patients who have already taken the drug...though some patients can still get a response.   And, when meds are combined (like in the ipi/nivo trials) there is a greater response, but also greater side effects.
  • It seems to me the researcher in my LAG3 post is really onto something when he talks about the issues surrounding getting the immune system to "RE-fire" once it has already mounted a response.
  • Also...though this may be premature....according to this data, the vemurafenib/cobimetinib combo did better, with a median progression free survival of 13.7 months, when compared to the dabrafenib/trametinib combo, with a progression free survival of only 9.3 months.  Perhaps they did not have as many BRAF naive patients, I'm not sure.  See slide and prior posts below:


Jan 2014 dabrafenib/trametinib combo FDA approved

Feb 2014 BRAF info and results from CombiDT

June 2014 BRAF studies from ASCO

Good luck to all my ratties!!! - c


Saturday, July 19, 2014

Word Crimes!

My children and some friends know what a weirdo I am about grammar, punctuation, contractions and being a Babylonian (a person who babbles on and on and on)!!! Your (as in something that belongs to you) in place of you're (as in something you ARE going to do) is like nails on a chalk board.  Peeps who protest "I could care less!" drive me nuts!!  Because, if you COULD care less, well, that says it all doesn't it?  You COULD care less, so that is not impressive!!  However, if you COULDN'T care less, that means you are maxed out and there is nothing more you could give.  Folks who pontificate on 'Brent and I' versus 'Brent and me', then use the wrong form anyway...give me chills.  By the way, easy rule!  When deciding whether to use one or the other:  Drop the other guy and see if you should be saying 'I' or 'me'.
"I went to the movies," or "Me went to the movies"?
It's easy.  "Brent and I went to the movies."
Would you say, "He went to the movies," or "Him went to the movies"?
Exactly! So, if you both go, you will say, "He and I went to the movies."  Arrangement makes no difference.  "I and he went to the movies" is correct, even though it sounds weird.
Another example:  This basket is for she and I, or she and me, or her and I?
Same thing.  Focus on one person.  "The basket is for me."  If you share it, it is for....?  Yep!  Her!
So, "This basket is for her and me."

 While all that is dull and boring...this is funny!!!  And...true!!  And...awesome!!!

Word Crimes and Weird Al

Are you listening, Miley?  This opens me up to all sorts of grammatical criticism!  So, bring it on!!  It'll be fun. Love, c

Thursday, July 17, 2014

Beware of sharks!!!!!

OK!  Between posts about T cells, the effects of anti-PD1 on them, subsequent effects in the brain, LAG3, and all the recent updates regarding Pembro, Nivo (Opdivo for heaven's sake!!), and the ipi/nivo combo....my brain is tired!!!  So....I just couldn't resist!  Check it out...






Not only do they bite....they might have melanoma!!!

Melanoma in the skin of a nurse shark.  Waldoch, Burke, et al.  Indianapolis Zoo

A female nurse shark, aged 27 years, had a 5.5 year history of a 6 cm black, raised, nodular skin lesion on the right side of her tail. The lesion was biopsied and diagnosed as a slow-growing melanoma.  The shark was euthanized due to systemic illness 4.5 months after the diagnosis.  No evidence of metastasis was found on evaluation.

Hmmm....I'm thinking sun exposure was not involved.  Who knew?  Be careful with fun in the sun...for LOTS of reasons!   - c

Monday, July 14, 2014

There's no place like home!!!!!

Isn't that right, J????  I'm gonna hook you up!  That way you can just click your heels, should there ever be a need!

           "There's no place like home! There's no place like home!"

Much love and hugs my friend!!!!  - c

Sunday, July 13, 2014

Nivo/ipi combo, Nivo vs Pembro, PD-L1: SugarCone and 2014 ASCO data


B found two posts from SugarCone Biotech Blog, June 12, 2014. The author was apparently at ASCO scoping things out; taking screen shots from the presentations.  Good stuff.  My synopsis:

...PD-1 appears to be a central control point for curtailing T cell responses...similar to the role CTLA4 plays in regulating initial T cell activation...Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed that the PD-1 pathway was used by tumor cells as a shield against immune system attack.  It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers.  Less clear is...why certain patients respond or don't, what biomarkers might predict response, how to increase response..., how to..measure response, and how to safely combine anti-PD-1 with other therapies.

This table lists PD-1 therapies in development, for various tumor types [side highlight...not mine]:

 This table defines response parameters and their abbreviations:


Background note:  The very first trials of [anti] PD-1 began with...Nivolumab in metastatic melanoma.  [For comparison] ipilimumab (Yervoy) an anti-CTLA1 antibody...is approved for treatment of metastatic melanoma....In a Phase 3 trial....of Stage IV melanoma patients who had failed prior therapy (chemo), the trial compared ipi to a tumor vaccine targeting the melanoma antigen gp100.  Ipi treatment = OS of 10 months vs 6 months with vaccine.  1 year survival = 45%.  ORR was only 10%.  AEs (adverse events) were autoimmune issues (colitis, pituitary inflammation) and 2% of patients had treatment related deaths.  In separate study of treatment naive Stage IV mel patients:  Ipi = OS of 11.2 months, 1 year survival = 47%, falling to 21% by year 3.  Patients were given ipi or placebo plus dacarbazine, then moved to ipi or placebo alone if there was a response measured or if the initial therapy caused toxicity.  AEs went up, with 38% of patients experiencing Grade 3/4 SAEs (severe AEs).

Nivolumab (Anti-PD1 by BMS)...provides median OS of 17 months, 1 and 2 year survival rates of 62% and 43%.  ORR = 33%.  AEs less significant than ipi.  Immune-related events occurred in 54% of patients (skin, GI, endocrine problems), but only 5% of patients had Grade 3/4 events and there were no drug related deaths.

So....when you combine ipi and Nivo:  At ASCO last year....trial data reported 4 cohorts of patients given different doses of nivo and ipi in combination.  ORR across cohorts = 40% and 1 year survival was 82%.  Median OS had not been reached.  SAE across cohorts = 53%.  Slide describing cohorts:


In trial update by Sznol this year (Table below)...at optimal dose rates of 1+3 and 3+1. ORR = 43-53%.  "Aggregate Clinical Activity Rate" = 81-83% in cohorts 3 and 4. (Note that Cohort 4 was the maximum tolerated dose due to SAEs and will no longer be used.) The percent of patients whose tumor burden was reduced by more than or equal to 80% at 36 weeks was 42% across the cohorts.  In patients who responded the median DOR in cohorts 1-3 and cohort 8 has not yet been reached.  In cohorts 2-3 the 1 year OS = 94%, 2 year OS = 88%.  Median OS in cohorts 1-3 = 40 months.


These data are best-in-class for treating advanced melanoma....one outstanding issue remains that of toxicity...23% of patients had to discontinue therapy due to toxicity, and one died of complications of treatment....Sznol...pointed out that...toxicities are controlled by standard intervention...but that includes cessation of therapy.  We have already learned from ipi...that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1-2 doses....time may not be kind.

....The activity of pembrolizumab, formerly MK-3475 (Merck's anti-PD1) in melanoma is very similar to that of nivo...and closely resembles nivo except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating.  Slide comparing pembro and nivo:


...the pembro data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma...Merck...made a strategic decision to stratify patients by prior exposure to ipi...This gave [Merck] a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients.  Due...to the toxicity profile of ipi, there are a lot of these patients....  If we focus on the ipi-naive ORR and 1 year survival data...we have to conclude that these drugs are pretty comparable...To differentiate these...data will have to come from longer duration...ongoing trials....In the nivo trial...half of the responding patients stopped therapy for reasons other than disease progression, most likely...due to AEs.  [Though] 3/4 of nivo patients stopping therapy maintained a response, some for extended periods.  In pembro...the SAE rate was 12% but only 4% of patients discontinued therapy.  The catch is that in order to move ORR higher than 40%, combination therapy may be needed.  But..the ipi/nivo combo comes with much higher toxicity and drop-out rates.

Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway...PD-L1 is also important in...predicting response to therapy...the utility of this marker...was subject of considerable discussion.  When ORR is 40% it is helpful to select patients prospectively.  In a study of responsiveness to pembro, Kefford, used an analysis of PD-L1 expression to demonstrate a remarkable difference in...response between patients with greater or = 1% PD-L1 expression vs patients who were PD-L1 negative.  Biopsy 2 months before pembro determined PD-L1 expression.  Patients were given Pembro at either 10mg/kg q2wk, 10mg/kg q3wk, or 2mg/kg q 3 wk with median treatment of 23 weeks and 13 month follow-up.  ORR = 41%.  Median PFS = 31 weeks and median OS was not reached.  1 year survival = 81%.  So this was a terrific cohort within the larger pembro study, likely due to the higher dose used.  PD-L1 expression was associated with improved ORR by 51% vs 6%, PFS = median 12 vs 3 months, and 1 year survival = 84% vs 69%.  No treatment related deaths, 14% experienced SAEs, again reflecting the aggressive dosing schedule.

In the larger trial of ipi naive patients treated with Nivo, PD-L1 tumor staining was associated with ORR, but only weakly with PFS and OS.  Why the data are less robust than the Kefford study is unclear.  What is abundantly clear however is that there were profound responses in patients scored as PD-P1 negative, as shown in the screen grab from Dr. Weber's review:


Not exactly new information from posts I made in June 2013 or within more recent ones...but some interesting view points and nice access to slides.  You can check out the posts themselves via the link below.  Best - c

PS...I couldn't get the address to work as a link...but if you copy/paste the address below and then search....the information will come up.  C



Saturday, July 12, 2014

Beauty...John Legend...Nobody in the World...he got it right!

One of John Legend's latest songs is beautiful.  The lyrics abandon all self preservation. They are a testament to his complete adoration, love, and conviction that "his love" is the most beautiful woman in the world.  Melodically lovely.  Still, it is similar to ballads by wonderful artists attached below.

"...guess you don't know that you're beautiful...you were fine in my eyes, a half hour ago...and if your mirror won't, make it any clearer, I'll be the one to let you know - out of all of the girls - you're my one and only girl - ain't nobody in the world tonight.  All  of the stars - you make them shine like they are ours ain't nobody in the world but you and I..."

Where his differs (surpasses!)...and I can't believe I'm saying this...is in the video.  IT IS AMAZING!  I am not sure if the director was female...it is hard to believe otherwise.  But, as Rosie noted, if it was a man...that's even better.  Never have I seen ALL the beautiful aspects of a woman's heart and soul captured...completely.  Age, weight, pregnancy, Down's, baldness, breast reconstruction, VITILIGO!!!, every color, every culture, all rites of passage...BEAUTIFUL...you'll see...

Nobody in the world...

And, yes, I have used a parked car's mirror to check my makeup and hair.  It takes skillz, y'all!!!  I always smile when I recall the first time B saw me put on lipstick with the help of the reflection of a car window in San Fran....sooooo many years ago!

So, running today, with the song and vision in my head...I kept thinking...what is beauty? Physical beauty is very simple....actually.  A bazillion scientific studies have been done.  It  is not a skin tone.  It is not an ethnic/racial bit of perfection. It is.........................symmetry!  That's all.  Yep.  I could even given you the dimensions!  They're published.  But, I won't!  Don't want you running to the mirror with a tape measure!  But, for all the studies and scientific data...that doesn't capture it REALLY...does it?  When you think about it....I'm sure you can think of physical specimens...humans you know...that in the completely aesthetic sense may be more appealing than those who hold your heart, who have your back, who make you laugh.  And that's just it, isn't it?  Beauty is appearance.  But, ever so much more.  It is a color. Cobalt blue.  It is a sound. Oh, so many.  A child's laugh.  A perfect trumpet.  A jazz sax.  A lover's voice. Laughter of the serious, with complete abandon.  It is a verse.  Mr. Cummings...the world does not often experience your like:


"(i do not know what it is about you that closes
and opens;only something in me understands
the voice of your eyes is deeper than all roses)
nobody,not even the rain,has such small hands "
 
It is a touch.  The sticky fingers of a child.  The knowing pressure to the shoulders or arm from a friend.  The slobbery 'kiss' from a baby.  A slobbery kiss from a silly man.  The sensual, pressured kiss from a lover.  It is nature.  Fairy moss with a perfect mushroom.  The most beautiful rose.  The simplest violet.  The smell of a woodland glade.  The smell of the sea...a child asleep...your lover's breath.  It is anger.  In defiance of abuse, lack of justice, unwarranted power.  Anger that will explode in order to tell others....looking back with disgust, repeatedly, on  a plane...."It's not contagious!  You don't have to worry!  It's cancer!  Okay?"  It is a light from those willing to spread knowledge.  It is a special combo...within the special person...who holds your key.


Probably one of the most perfect love songs...by a man who could not see...
Jeff Healey Band, Angel Eyes

Chris De Burgh, Lady in Red

Look at the man in this video.  Is he "beautiful"?  Oh my goodness, listen....yes...he is!!!
Eric Clapton, Wonderful Tonight

Beauty is so much more than what we see.  We have to remember that.  Love and beauty - c

Friday, July 11, 2014

Expanded Access for ipi/Nivo combo and Nivo/Opdivo Licensing Application????


Yesterday was a big day for BMS.  We learned that Opdivo, the anti-PD1 product we know as Nivolumab, was approved in Japan.

AND....

BMS opened an expanded access program for the IPI and Nivo combo for Stage IV or unresectable Stage III melanoma patients.  No locations are known as yet...typical for these EAP's.  Mucosal melanoma and melanoma patients with treated brain mets that have been stable via MRI for 2 weeks before start of therapy ARE allowed. (That's a big improvement over the usual 8 week stability requirement!)  However, patients must be ipi and Nivo naive and never have been even in the control arm of a trial with same. (This I find RIDICULOUS!!!)  "Prior systemic therapy is permitted if it was completed at least 4 weeks prior to first dose..."  (Which means that prior treatment with IL2, interferon, BRAFi, etc. ARE allowed, but not required.)  No ocular melanoma.  No autoimmune disease. No patient requiring steroids within 14 days prior to treatment.  No HIV, Hep B, or Hep C.   Scuttlebutt says that because ipi is an approved drug patients will have to provide payment for that, via insurance or some source, but the Nivo will be "free"!  Hmmmm....  Bet that leaves a lot of wiggle room for all sorts of administration fees and hospital charges.  Oh well....at least it will provide more options for many.
Here's the link:  ipi and nivo combo expanded access at clinicaltrials.gov

Here's the data from the combo per Weber in his chat with Ribas after the ASCO presentations in June of this year:
"Ipi-Nivo Combo  - ...highlight was...the abstract...presented by Sznol...an update of the concurrent ipi/nivo study in 2013...response rate about 45% in an updated expanded cohort of those with nivo at 1mg/kg and ipi at 3mg/kg...for as long as 96 weeks.  The response rate was in the mid-40% range, but of greater importance, the 2-year survival was in the high-70% range..an important landmark in melanoma. ....must be balanced against a 62% rate of grade 3/4 immune-related adverse events, many of which were easily reversible...only about half required an interruption of treatment...Whenever the rate of side effects at grade 3/4 exceeds the response rate, you have to sit up and take notice.  Nonetheless, a 70% plus survival rate at 2 years is outstanding in melanoma."  
Link to synopsis of the original article from June 2013:  Ipi and nivolumab, better together???

AND...

BMS is planning "a third quarter submission of a Biologics Licensing Application for Opdivo (Nivolumab) for previously treated advanced melanoma."  Stipulations seem to include patients with unresectable or metastatic melanoma who have been previously treated with ipi and, if BRAF positive, with a BRAF inhibitor.  Though none of that is absolute at this point.  See article:
BMS submission of Biologics License for Nivo

Sadly, if these are the requirements....they echo my fears from May when BMS first announced their Expanded Access Program for Nivolumab along with those requirements:
EAP for BMS anti-PD1

Big day for BMS.  I hope sites and provision of meds for real patients in need happens soon!  They deserve a big day too!!

ONO4538 ~ MDX1106 ~ BMS936550 ~ Nivolumab ~ Opdivo????  Seriously??   OMG!  867-5309!!!  LOL!  WTF is wrong with you people!?????  

Hang in there, peeps!  It's gonna be a bumpy ride!  -  c

PS   Anybody get my joke???  Hee hee hee!  I crack myself up!!! ;>)
I think there's something wrong with my brain!