Friday, May 26, 2017

Sew Chaotically! - Button, button...who's got the button? Sorbetto, that's who!

Sew.....I needed some buttons for two shirts I have in the works.  B was sweet enough to accompany me to our ONLY fabric shopping option in our town....JoAnn's.  To my dismay, their limited button supply was cut by half as they appeared to be in process of turning that area into a different set of supplies altogether.  I found some buttons that I thought would do and was heading toward the checkout...when I suddenly let out a shriek and turned on my heel, to head in the opposite direction! B was not as surprised or panic stricken as you might imagine!  Sadly, the man is used to such events. He was a bit confused.  But, the light of recognition dawned!  I had spied two baskets of "clearance buttons"!!!  The "wall" that once was a button display was now relegated to baskets labeled "75 cents per card"!!!!  Now....they were in an unholy mess, but my B gamely helped me search through them until we were satisfied that we had found the best of the lot.  A mere couple of hours!!!  What better way to spend your time, right?????  So...with all these random buttons in my possession, what's a girl to do????????
Inspo sent by Ruthie..after seeing ALLLLLLL the buttons!!!

With that, you remember a bit of white linen and what could be better than your 5th
 Colette's Sorbetto??!!!

Need to make a cute summer top work appropriate while you survive overactive air conditioning?  Add 1 of your 4 Grainline Studio's Morris Blazers!!! works with your latest skirt!!  Win, win, win!!!
Sew and shop and live - chaotically!!! - love, c

Thursday, May 25, 2017

Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS

Since it was double skirt day....I decided to go ahead and make it a double post day!!!!
To continue the subject of BRAFi -

From The coBRIM trial - August 2016 we learned - that when cobinmetinib and vemurafinib were combined, the median overall survival (OS) was 22.3 months and the median progression free survival (PFS) was 12.3 months.

From this discussion of BRAF/MEK and immunotherapy (Nov 2016)  we learned = that generally treatment that was a combination of a BRAF inhibitor and a MEK inhibitor could illicit a response rate of 48-59%, even as much as 70% with some combo's and PFS of 11-12 months.

Now there's this (I've included most of the report, you may read it yourself via the link at the bottom, my comments are in red!):

Update Confirms Benefit of Encorafenib/Binimetinib Combo in Melanoma  Jason Broderick – Thursday, May 11, 2017 From OncLive
The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib reduced the risk of disease progression or death by 23% compared with single-agent encorafenib for patients with BRAF-mutant melanoma, according to findings from part 2 of the phase III COLUMBUS trial.  The median progression-free survival (PFS) for patients treated with the combination was 12.9 months compared with 9.2 months for patients receiving encorafenib alone.  Based on these data, along with previously reported findings from part 1 of the COLUMBUS trial, the developer of the combination, Array BioPharma, anticipates filing a new drug application with the FDA in June or July.

The COLUMBUS trial included 921 patients with locally advanced, unresectable, or metastatic 
-mutant melanoma. Prior treatment with immunotherapy was allowed. Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial. [Why the hell not???? You could put them in their own separate group, so as not to sully your results Array CEO person!!! And still give them access to the drug!]

In part 1 of the study, 577 patients were randomized in a 1:1:1 ratio to receive encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone. In the combination arm, encorafenib was administered at 450 mg daily and binimetinib was administered at 45 mg twice daily. Single-agent encorafenib was given at 300 mg daily. Vemurafenib was administered at 960 mg twice daily.  Part 2 of the study randomized 344 patients in a 3:1 ratio to receive encorafenib plus binimetinib at 45 mg twice daily or encorafenib alone. Encorafenib was given at 300 mg daily.  “Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300 mg in the combination arm to allow for a comparison of equal doses across arms,” Array wrote in a press release.
In Part 1 of the study, the median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for vemurafenib alone. The improvement in PFS represented a 46% reduction in the risk of progression or death. [That's good, but of course we have learned never to give vemurafenib, a BRAF inhibitor without a MEK inhibitor!!! So that's a bit of a false comparison!]
When single-agent encorafenib was compared with the combination arm the difference between the groups did not reach statistical significance. However, median PFS with encorafenib was statistically superior to vemurafenib. Findings for overall survival (OS) were not yet available. [hmmmmmm.....]

The objective response rate (ORR) with the combination was 63% versus 40% with vemurafenib. [Again...not comparing apples to apples...we KNOW that response rates are better with a BRAF/MEK combo!!!] With single-agent encorafenib, the ORR was 51%. [This fact can at least be compared to single agent vemurafenib response rate of 40%.]The complete response rate was 8% with the combination versus 5% and 6% with encorafenib and vemurafenib, respectively. The median duration of response was 16.6 months with the combination versus 14.9 months with encorafenib and 12.5 months with vemurafenib.

By local review, median PFS with the combination was 14.8 versus 7.3 months with vemurafenib. The ORRs by local review were 75% for the combination versus 49% and 58% for vemurafenib and encorafenib monotherapy, respectively.  In this assessment, the combination was superior to single-agent encorafenib. The median PFS with encorafenib was 9.2 months, which was also superior to single-agent vemurafenib.

All-grade AEs with the most variability between the two arms for the combination, single-agent encorafenib, and vemurafenib, respectively, were arthralgia (26%, 44%, 45%), pyrexia (18%, 15%, 28%), alopecia (14%, 56%, 37%), hyperkeratosis (14%, 38%, 29%), dry skin (14%, 30%, 23%), rash (14%, 21%, 29%), palmoplantar keratoderma (9%, 26%, 16%), and palmar-plantar erythrodysesthesia syndrome (7%, 51%, 14%). All-grade AEs of special interest with the combination included rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%), and photosensitivity (5%).

Grade 3/4 AEs were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. [As previously demonstrated, side effects were DECREASED with a BRAF/MEK combo.]  The most common grade 3/4 AEs with the combination were gamma-glutamyltransferase, increased blood creatine phosphokinase, and hypertension. Time to first grade 3/4 AE was long with the combination, at 2.5 months versus 0.4 months for encorafenib and 1.3 months for vemurafenib.

In March, Array withdrew its FDA new drug application for single-agent binimetinib as a treatment for patients with NRAS
-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting.  [So I gather they are going to market this only for BRAF positive folks, rather than NRAS mutant.]  The application for binimetinib was based on data from the phase III NEMO study, which was presented at the 2016 ASCO Annual Meeting. In the open-label study, PFS with binimetinib was 2.8 versus 1.5 months with dacarbazine, representing a 38% reduction in the risk of progression or death; however, OS was not improved with the MEK inhibitor. [Pretty sad if you can't beat dacarbazine!]

Okay.  My synopsis is this:  Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS.  This combo showed a PFS of 14.9 months.  Objective response rate was 63% with the comb0.  There was an ORR of 51% to encorafenib alone.  Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending.  OS data for encorafenib/binimetinib has not yet been reported.  OS in most other BRAF/MEK combo's is around 2 years.  The combo discussed here demonstrated fewer side effects than when the BRAFi component was used alone....which is consistent with other reports using a BRAF/MEK combo vs BRAFi alone.

PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.  Hang tough ratties.  You will save us all. - c

Sew Chaotically! - Double Decker Skirt Day!!!

Double decker skirt day indeed!!!  I got this thick, almost scuba, knit from Metro Textiles and the infamous Kashi during Our New York Fabric Shopping!!
The fabric can look a little funky in the photos here's a shot that's accurate.

I decided it would be perfect for this flippy little skirt (View C) for Miss Roo!!!

I think I was right!!!

I can't wait to give it to her!!!  I hope it fits her well!!!

And because, waste not want not...and I love pencil skirts....I made this one for me.

Poor Mannie!  Her bootie is a little sad!  But, the skirt is pretty cute on a human posterior!!!
It was a fun day of sewing.  And since I made two skirts to wear in the month of Me Made May...this has gotta be worth quadruple points!!!  Sew Chaotically!!! - love, c

Wednesday, May 24, 2017

Management of Adverse Events with Targeted Therapy (BRAF/MEKi)

BRAF inhibitors combined with MEK inhibitors have been an amazing targeted treatment option for BRAF positive melanoma patients (about half of us).  They rarely have durable responses, though occasionally they can remain effective therapy for years, but are incredibly useful in our treatment arsenal.

Here is a post that gives a basic primer on BRAF and targeted therapy:  BRAF inhibitors for melanoma

Here is a post on several BRAF/MEK combo's  The coBRIM trial with links to other reports

And of course....there are always side effects.  Here is a report from Weber and Agarwala:  Side effects and how to manage them

Now there is this with specific plans re management of adverse events.....

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma. Daud, Tsai. The Oncologist. May 18, 2017.

Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600–mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients. Because the goal of treatment is to prolong survival with minimal impairment of quality of life, drug-related adverse events (AEs) require prompt management to ensure that patients derive the best possible benefit from therapy. Proper management depends on an understanding of which AEs are most likely BRAF or MEK inhibitor associated, thus providing a rationale for dose modification of the appropriate drug. Additionally, the unique safety profile of the chosen regimen may influence patient selection and monitoring. This review discusses the toxicity profiles of these agents, with a focus on the most commonly reported and serious AEs. Here, we offer practical guidance derived from our clinical experience for the optimal management of key drug-related AEs.  

Recommended dosage adjustments....
LATE NOTE:  Thanks to the sharp eyes of Mike Brooks and a note he left me....I think he is correct in having found a typo in the dose reduction chart above regarding the trametinib dose.  It appears they have simply copied the dose reduction for vemurafenib....which comes in 240 mg tabs and is usually dosed at 960 mg taken twice a day.  However, trametinib (Mekinist) comes in 0.5, 1 and 2 mg tabs and is usually dosed at 2 mg once a day, either alone or in combination with a BRAFi. Therefore, Mike is probably right that a dose reduction regimen is likely to be something along the lines of:  2 mg, to 1.5 mg, to 1 mg, to 0.5 mg. It takes a village!!!
Management of fever...

Management of rash....

Management of cardiac side effects....
Again, as I noted in my last post, I hope this is information for which you will find no need...but here it is....if you do. - c

Monday, May 22, 2017

Neurologic side effects to immunotherapy with treatment algorithm

I have been posting individual articles as well as collections of abstracts regarding possible side effect of immunotherapy for years.  I figure...forewarned is forearmed.  Here is the latest post with a link to prior:  The mice told us so...cardiotoxicity - with links to more articles related to the possible side effects of immunotherapy

Additionally, I've reported on what the experts tell us in regard to dealing with these side effects:
Here in a discussion:  Side effects and how to manage them - Weber and Agarwala

And this report that includes multiple charts with algorithms for treatments of GI, endocrine, pulmonary and hepatic side effects:  How to deal with side effects from anti-PD-1

Now there's this:

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis.  Larkin, Chmielowski ... Hodi ...Weber, et al. The Oncologist. May 11, 2017.  

Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment related encephalitis, and provide practical guidance on diagnosis and management. Methods. We searched a Global Pharmaco-vigilance and Epidemiology database for neurologic irAEs reported over an 8- year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. Results. In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n 5 22), noninfective meningitis (n 5 5), encephalitis (n 5 6), neuromuscular disorders (n 5 3), and nonspecific adverse events (n 5 7). Study drug was discontinued (n 5 20), interrupted (n 5 8), or unchanged (n 5 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1–170) and to resolution was 32 days (2–8091). Median time to onset of encephalitis was 55.5 days (range 18–297); four cases resolved and one was fatal. Conclusion. Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.

[with this algorithm]

I hope this is information you will never need....but if you do....I hope it helps. - c

Sunday, May 21, 2017

Sew Chaotically! - Me Made May - Week 3

Me Made May!!! Week 3 ~

Pretty cool skirt pattern actually - Simplicity 2451

Just knowing how I acquired this fabric...and the folks who said, upon seeing the fabric [that I proudly had in my possession!!!], "You would never wear that!!!"  (Check out The best helper (in all things!!!) a girl could ever have!!! ) - makes me laugh!!!

'Cause,"YES, I  WOULD!!!" and do!  Modified version of this A-line skirt
Some days you don't have a lot of photog skillz!  Another me made McCall's 7093!
The happiest days are when you get a visit from your bestie!!!  AND she brings presents!!!  #sisters #colette #sorbetto  #ruthiemakesthebestmemadesever  Check out her newly minted (Hee hee!!) embroidered lawn (?) she got in NY from Mood and made into a sweet little summer dress!

Such a fun visit to the Atlanta Botanical Gardens. #rumi #christinehaynespatterns  How cool is Ruthie's maxi skirt in a fab Liberty of London print???!!!

Didn't get a pic on this day!  However, wore this little vogue dress, minus the shirt, to the DeKalb Farmer's Market.  We were too busy with our adventure and eating ALL the food!!!!

When your bestie has to go home...but you look cute anyway in the t shirt dress  you made with great fabric she sent you!!  And isn't that the cutest little Ruthie-made sundress in a panel print?????
Such a great way to end my week getting to play!!  Thanks for indulging us, Bent and Frankie!!  Sew and live chaotically!! - love, les

Thursday, May 18, 2017

Proof of concept. CAR-T and Immunotherapy + mice and research = "containment" and "cure" for ratties!!!

Not exactly news....but sometimes it is nice to recognize how far we've come...

Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies.  Hegde, Mukherji. Cancer Immunol Immunother. 2017 May 11.
Adoptive cell therapies with chimeric antigen receptor (CAR) engineered T cells (CAR-T) and immune checkpoint inhibition (ICI)-based cancer immunotherapies have lately shown remarkable success in certain tumor types. CAR-T cell-based therapies targeting CD19 can now induce durable remissions as well as prolong disease-free survival of patients with CD19 positive treatment refractory B cell malignancies and ICI-based therapies with humanized monoclonal antibodies against the T cell inhibitory receptors CTLA-4 and PD-1 as well as against the PD-1 ligand, PD-L1, can now achieve durable remissions as well as prolongation of life of a sizeable fraction of patients with melanoma and Hodgkin's lymphoma and non-small cell cancers. Most importantly, these immuno-therapeutic treatment modalities have raised the possibility of achieving long-term "containment" as well as "cures" for certain types of cancer. While this represents major advances in cancer immunotherapy, both modalities come with considerable toxicities, including fatalities. Although more work will be needed to bring CAR-T cell-based therapies to the bedside for most major cancers and a good deal more will be needed to make ICI-alone or in combination with other treatment modalities-work more consistently and across most major cancers, these two treatment modalities stand out as superb examples of successful translation of bench research to the bedside as well as represent real progress in the field of cancer immunotherapy.

We've come a long way, baby!  Thanks to the mice....AND the ratties!  Take care. - c