Friday, June 30, 2017

Outcomes for melanoma patients ~ clinical trials vs standard of care

I thought this was an interesting outcome to look at:

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care. Goldman, Tchack, Robinson...Pavick, et al.  Oncology. 2017 Jun 10.

Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population.
182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed
Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS, irrespective of stratification by trial status or therapy.
Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit. this report it is noted that folks who were NOT in a clinical trial, no matter if they were being treated with immunotherapy OR targeted therapy, did less well.  The researchers acknowledge that it is likely that folks who were in poorer health were the peeps who made up more of the population in the standard of care group.  Heaven knows....I have yelled and yelled about the exclusions that are so very often baked into clinical trials...and my firm belief that Big Pharma's (and even some researcher's) desire to make their outcomes look good drives much of this.  For far too long, folks who are in dire straits with significant tumor burden, prior treatments, and certainly CNS disease have been automatically excluded from clinical trials.  Consequently, when those folks finally get treatment from their local doc, outside of a clinical trial, they do less well when compared to the cream of the crop patients that the trials deign to include.

However, I feel there may be one other component relevant to this outcome ~ expertise. Participating in a clinical trial comes with some significant risks, expense, chaos and craziness inherent to the process. But, much of the time, it also comes with state of the art facilities, research labs, and renowned experts in the field in question who are at the top of their game and on top of the latest data and intel.  I fear that local oncs are not always well versed and experienced in the treatments they are providing.  They may fail to recognize symptoms of both progression and side effects as rapidly as a more expert clinician would.  Equally importantly, they may not allow the time needed for a response when dealing with immunotherapy, leading to the abandonment of a potentially good treatment outcome before the patient can attain the response needed, thus causing an unnecessary bad outcome.

As the article notes, these therapies have now been on the market, and therefore in the arsenal of melanoma treatments available for use by local oncologists, for 6 years.  Hopefully, local learning curves have been climbed and trial requirements will soon be adjusted in ways that make standard of care what it really should be for all melanoma patients. - c

Wednesday, June 28, 2017

Sew Chaotically! - Hollyburn skirt

I have loved Provençal fabrics, food, colors, the people, the place since we visited France, driving from Nice to Antibes, in 2006. Such a lovely trip.  So when I saw this fabric in Paris last year, I knew EXACTLY what I wanted to do with it!!!  A full, but shaped skirt!  Yes, this print and fabric is more commonly used for tablecloths and other household linens...but....that's just how I roll!!!

The Hollyburn skirt from Sewaholic has gotten rave reviews by many sewists and its shape was perfect for what I envisioned.  But, some had mentioned the need to contour the waistband and having had that experience on a pair of pants I made, I bit the bullet and did it!  I was taught every step in this amazing Tutorial by A Fashionable Stitch 

While the waistband may not lay perfectly on mannie.....

It's a great fit on me!!!
I finished the back with a button and embroidered loop.

The construction of this pattern is perfect and the pockets are awesome!!!

While I purchased this fabric and created a skirt with it on a bit of a whim, I think it will end up being more flexible, utilized in more styles and through more seasons than I had even hoped! Sew Chaotically! - les

Sunday, June 25, 2017

Sew Chaotically! - Jean Jacket B5616 - May's Magnum Opus!!!

Though it has been finished for a bit, this jacket was certainly my magnum opus of Me Made May...if not my entire sewing career!!!  I began this project in May and it was slow going...on purpose!  I looked at tons of sew-a-longs  Like Alina's for her Hampton Jean Jacket  and found them very helpful.  I ended up using B5616, cropped with a mandarin collar.  For fabric, I used a stretch, but substantial denim from JoAnn's.  I considered distressing along the seams...but in the end, left it as it was.  It will wear, with wear. 53 it may be wiser to keep things classic!!!  I considered doing a double row of top stitching...and did on the side seams...but for the most part, I kept that clean and super simple as well.

BUT!!!!!  I did go nutters in one area!!!  The buttons!  (I know.  It seems to be a thing with me lately!!!) I got the buttons (minus one) visible in this picture when we visited Maiwa in Vancouver, having no idea about what I would do with them!  Once I decided they would be perfect on this jacket...I didn't have enough!  No worries. B sent them a pic of the buttons in question and ordered some more right up with help from a super sweet and tolerant lady!!!! 

I worked slowly, finishing every seam.  Pinning and pressing and basting and pressing AGAIN all the flat felled seams before top stitching with a thicker classic thread used with denim....which Bernie was not terribly fond of having in his bobbin!!!  (Since then, I've learned that lots of sewists keep a more normal thread in the bobbin and just use the thicker thread on top...but...then my insides wouldn't have been quite as fab!  Though Bernie may have been a bit happier!)  Yes, there was threading and re-threading the machine!!!  And..when you are going to that much trouble....those basted, top stitched seams better match up.  But not per the rule of life (and sewing) - the first sleeve went in like a charm, matching the back yoke seam perfectly....ON THE FIRST TRY!!!!  The next sleeve - 4!....FOUR!!!!....F@#king tries later...and all was right with the world!

NO puckers, baby!!  Not one!!!

Yes.  I am inordinately proud of that back yoke!!!  Hee hee!

Since I was going for a jean jacket with a classic, crazy button twist....I used two buttons to both sleeves, creating a Faux French cuff!  How cute are these buttons????

No ugly insides!!!

And I mean ~ NONE!!!!  The pattern, oddly, didn't include a facing to the back yoke...but it was easy peasy.  I just used a bit of left over chambray for the job.

It even got a label B had made special for me...using my mantra and his dragonfly pic!!!

I am Scott-Boy-Stoked about this one!!!  I really enjoyed taking my time and doing it right.  (Though I did have to interject a super fast Silly button Sorbetto and a  quick and flirty double knit skirt  as well as a crazy chair recovery project in order to continue to feel I was being true to my chaotic self!!!!)
Just to prove how much I love it....

It's style...

...and shape...

...makes anything look good!  (Even when your ancient dog is leaving you behind!)

In spite of having no idea what your photog is wanting you to do....

...a jacket like this goes with anything and keeps you looking GOOD!
Sew chaotically! - les

Saturday, June 24, 2017

ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!

I do NOT believe in blaming the patient (their diet, stress, attitude, etc., etc.) for the development of their disease process...much less death!!!! I do believe in hope.  I believe in finding joy in every thing we can and living every minute of life to the fullest.  Play hard. Work hard.  Love and laugh even harder.  Those were my abiding principles before melanoma and they continue to be so now. However, as I've noted before, my belief that you can emote yourself out of cancer falls more along these lines:

I wrote this in 2012 ~ As much as we would like to truly believe that positivity can overcome anything and some studies demonstrate a beneficial effect from the "laughter is the best medicine" sort of thing.  Many books and studies out there prove otherwise. David Rakoff,  the incredibly funny, journalist and writer (1964-2012) talks about many of them in his book "Half Empty".  He experienced 18 months of chemo and radiation at the age of 22 when diagnosed with Hodgkin's disease, only to have a tumor that eventually took his life recur in his shoulder and metastasize.  Perhaps, he said it best in an interview with John Stewart.  "There was a study that showed that the long term mortality of people with lousy attitudes is no different from people with great attitudes.  So, you can be the worst bastard on the ward and you will not die at any greater rate than the other people.  People will simply be gladder when you do!"

On the other hand...going it alone in life is never easy.  And a cancer diagnosis can be extremely isolating.  There are scans and procedures which you must endure alone...even if there is someone who really wants to be by your side.  There are dark thoughts that are very difficult to share. And, some folks just can't (won't!) stand alongside to help you handle it.  I have found incredible solace and support in many of my dear ones, but I have also lost some I would have previously bet on to be my greatest advocates.  It hurts. And it happens...fairly often.

Now, there is this:

The effect of loneliness on cancer mortality.
ASCO 2017. J Clin Oncol 35, 2017. Dilppolito, Ambrosini, Shams, et al.

Background: Convergent findings indicate the need of broadening the vision of cancer beyond known prognostic factors, as many variables of different nature equally affect the course of disease. Loneliness has been found to be associated with various health outcomes, but its relationship with cancer remains unclear. Here we aimed to investigate the specific effect of loneliness and other demographic, psychological, and clinical variables on cancer mortality and to validate the Italian UCLA Loneliness Scale in cancer patients. Methods: This descriptive and correlational study was conducted at the Veneto Institute of Oncology in Padua. 400 patients undergoing chemotherapy from 01/2014 to 06/2015 were enrolled. The sample was stratified by sex and age (4 groups, 40-80 y). We collected demographic, clinical (site and stage of cancer, type of chemotherapy, death date), and psychosocial [self-esteem (RSE), perceived social support (MSPSS), social interaction anxiety (SIAS), personality (EPQR), and depression (BDI)] data. Results: GLM analyses: loneliness was higher in women than men and it linearly increased with age. Loneliness was also influenced by marital status, cohabitant offspring, and educational level, but not by clinical variables. Correlation analyses: loneliness was inversely related to RSE, MSPSS, and extroversion, and directly related to SIAS, neuroticism, and BDI. More importantly, a hierarchical binomial logistic regression revealed that patients’ mortality was reliably predicted by gender, stage of cancer at diagnosis, time from diagnosis to UCLA collection, BDI, and UCLA. In particular, high BDI predicted higher mortality; surprisingly, after controlling for BDI and other effects, high loneliness predicted lower mortality. Conclusions: Our results replicate prior research and reveal a surprising association between loneliness and mortality risk after partialling out the impact of, especially, depression. This suggests the role of loneliness on cancer course as an important health concern.

In this study, 400 peeps on chemo were evaluated utilizing demographic date (age, sex, marital status, well as stage of cancer) along with psychological data that scored them re:  self esteem, perceived social support, anxiety in social settings, personality type, depression and loneliness. Loneliness was higher in women, increased with age...was also influenced by marriage, children living in the same home, education (I presume folks with those things were less lonely, but that is not specifically stated), but NOT by clinical variables.  Folks who were extroverts with higher self esteem and greater social support were less lonely while those with anxiety, neuroses, and depression were more so.  No surprise there.  However, mortality was reliably predicted by gender, cancer stage, depression and loneliness.  Of course, if you were very ill physically, it would be hard NOT to be depressed!!  In fact, when the researchers controlled for other effects and just looked at loneliness vs depression...depressed folks still had a higher rate of mortality, while those reporting loneliness did not.

So....what does all this realistically mean?  Being ill is hard, lonely, and depressing.  The person affected doesn't feel good, faces a barrage of treatments that at best are: confusing, time consuming, expensive, often miserable and painful - while simultaneously losing personal relationships and status they held prior to being ill at home, at work, and socially!  The folks around them don't know what to do exactly and necessarily, must go on with their lives.  They are often forced to deal with holes created by the affected person's illness:  child care, household chores, salary that is now diminished... not to mention help meet the basic needs of the cancer friend with doctor's appointments, self-care, and on and on. Hard stuff...all the way around.

While no one can make another person happy and illness is depressing - no two ways around it - the role of caregiver is probably the most difficult thing about cancer, yet the biggest gift EVER to those of us with it.  I absolutely KNOW that I would not be here today were it not for my B, my kids, my sweet sister Ruthie, dear friends and my crazy nurse peeps.  Would. Not. Be. Here.  So...if you ever think your role as caregiver is insurmountable, I don't blame you.  But, I can assure you, you are giving the best gift in the whole world to your cancer person.

Additionally, cancer peeps are stubborn.  Well...some of them are....
I actually came across this note just this week!  All I can say is:  A) I did give it to B.  B) He is a sentimental nut.  C) Some cancer peeps do not obey or take direction well.  {I don't happen to know any personally, but....}
All this to say, if you feel you need help with depression, feeling down, coping with all the shit that a cancer diagnosis throws at you - as a cancer patient or caregiver - seek help!!!  You caregivers out there....try to get your cancer friend to seek help if you think they are in need.  Call their provider if you think it is warranted.  Perhaps, your cancer friend will be more amenable to suggestion than the one B and my nurses had to deal with...

Everyone is different, but if you are at a loss as to what to do or say for your cancer friend, there are many good sites out there to give you suggestions:
How to be a friend to someone with cancer - The American Cancer Society
Supporting a friend who has cancer - Cancer net
Ten tips for supporting a friend with cancer - Sloan Kettering
What to say and do....and NOT!!...for a cancer FRIEND (not patient)! - from me!!!

A thumb's up, while on the potty pic, may not be the way to make YOUR cancer friend's day, but Tammy B knew it was a great way to make mine.  I have a collection!!!  They still make me smile - No. Matter. What.
I wish I could offer more, but here is a bouquet of beauty, love, and warm wishes to each of you.
Take care.  Seek help when you need it. - much love, les

Friday, June 23, 2017

ASCO 2017: Circulating DNA to measure response in melanoma

Wouldn't it be great if we could do a simple lab draw to determine the type of tumor, as well as tumor burden a patient has??  With such a test we could minimize use of painful biopsies, decrease repeated exposure to radiation via scans, and could much more rapidly determine whether a patient's tumor burden is decreasing in a positive response to a given therapy....or not!

I've been posting studies addressing these possibilities for a while...
From 2014:  With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

From 2015:  PCR testing for melanoma

PCR testing for circulating melanoma mo one!!

Circulating Tumor they may eventually impact melanoma diagnosis and response to therapy

From 2016:  Here, I actually broke down all the various biomarkers, what they are and what they mean ~ Biomarkers - blood components, circulating tumor cells AND of the tumor itself

Then there were these:  BRAF testing via blood rather than tumor tissue

Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma!

From 2017:  Circulating DNA predicts response to anti-PD-1

Circulating tumor DNA provide valid way to monitor response to anti-PD-1 therapy for melanoma....AGAIN!!!

Now...there's this:

Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.
ASCO 2017. J Clin Oncol 35, 2017. Braune, Buboff, Follo, et al.

Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS. A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS. Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 and LDH. Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. 

Here, using a blood test to check for bits of circulating tumor DNA for BRAF V600E and wild type, the researchers looked at 89 previously drawn blood samples from 32 patients along with 158 blood samples from 12 patients in this trial.  These samples were collected at baseline, and in roughly 1 week, 1 month and then q 3 months for up to 2 years.  Examination of the previously drawn samples showed that 23 of the 31 Stage IV patients were positive for BRAF V600E circulating tumor cells in their blood at least once (74%).  The presence of circulating DNA from tumor cells at baseline was a poor indicator for PFS (progression free survival), while decreasing levels of same was a favorable prognostic factor for PFS.  Patients that still had circulating DNA from tumor cells in their blood "early after a change or institution of treatment predicted tumor progression at first clinical response assessment".  If the test changed from being positive for the ctDNA to negative for it, or if there was a decrease in the level measured, the patients had a more favorable course.

Makes sense, right?  If you have a lot of circulating tumor DNA in your blood...that's not good.  If you still have ctDNA floating around after you have started a new doesn't bode well for you to respond well to that treatment.  However, if you have little ctDNA period, or if the amount you have is decreasing with your is likely that you will do well!!!  Think how much more quickly we could get a patient on the treatment that works for them with a tool like this!!!  I think we've beat around this bush for long enough!!!  Let's make peripheral blood sample testing for circulating tumor DNA a reality!! - c

Thursday, June 22, 2017

ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

I've been posting about our intestinal flora and its possible interaction with immunotherapy for some time.  This is from 2015: Cooties in our gut keep us skinny, smart and cure cancer!????? where bifidobacterium is thought to enhance efficacy of anti-PD-1.  There was this in 2016: Intestinal bacteria as a way to determine risk for ipi induced colitis!  in which it was suggested that the presence of "bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis" in patients taking ipi.  And this year, I posted Antibiotic use MAY decrease effectiveness of immunotherapy????? which, if the prior studies are accurate, would make sense as antibiotics drastically change the microbes in our intestines.

"Right there I had it, and right here I lost it"... cause, now ~ there's this:

Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.
ASCO 2017. J Clin Oncol 35, 2017. Wargo, Gopalakrishnan, Spencer, et al.

Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR. Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome. Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity and abundance of specific bacteria in R was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.

Okay - oral and gut microbiome samples were taken from 221 folks with metastatic melanoma who were treated with anti-PD-1 and those patients were classified as responders (R) or non-responders (NR).  Per this study, responders had an abundance of clostidiales and non-responders had mostly bacteroidales in their respective flora. Also, "Diversity and abundance of specific bacteria in R was associated with improved progression free survival to anti-PD-1 therapy."  Well, hmmm....  Not too specific here about exactly WHAT bacteria and how one is to attain them in our gut in order to improve our chances.  A little googling told me that "Clostridiales" (the cooties we want) are of the genus "Firmicutes" and the class "Clostridia".  (I'm glad there is a cuteness quotient cause the "clostridia" class is not sounding cute at all!)  From wikipedia there is this:  
"The Clostridia are a highly polyphyletic class of Firmicutes, including Clostridium and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them. Species of the genus Clostridium are often but not always Gram-positive (see Halanaerobium hydrogenoformans) and have the ability to form spores.  Studies show they are not a monophyletic group, and their relationships are not entirely certain. Currently, most are placed in a single order called Clostridiales, but this is not a natural group and is likely to be redefined in the future.
Most species of the genus Clostridium are saprophytic organisms found in many places in the environment, most notably the soil. However, the genus does contain some human pathogens (outlined below). The toxins produced by certain members of the Clostridium genus are among the most dangerous known. Examples are tetanus toxin (known as tetanospasmin) produced by C. tetani and botulinum toxin produced by C. botulinum. Some species have been isolated from women with bacterial vaginosis.
Notable species of this class include:

Heliobacteria and Christensenella are also members of the class Clostridia."
Okay...that's weird.  Cause some of those cooties are really bad shit!  (Sorry, sometimes I can't help myself!)  

So...what are the Bacteroidales?  Well, wiki ain't touching this one with a ten foot pole.
However, this article: Genomic characterization of the uncultured Bacteroidales family S24-7 inhabiting the guts of homeothermic animals.  Ormerod, Wood, Lachner, et al.  Microbiome 2016.

Provided this insight:  "Our view of host-associated microbiota remains incomplete due to the presence of as yet uncultured constituents. The Bacteroidales family S24-7 is a prominent example of one of these groups. Marker gene surveys indicate that members of this family are highly localized to the gastrointestinal tracts of homeothermic animals and are increasingly being recognized as a numerically predominant member of the gut microbiota; however, little is known about the nature of their interactions with the host.  Here, we provide the first whole genome exploration of this family, for which we propose the name “Candidatus Homeothermaceae,” using 30 population genomes extracted from fecal samples of four different animal hosts: human, mouse, koala, and guinea pig. We infer the core metabolism of “Ca. Homeothermaceae” to be that of fermentative or nanaerobic bacteria, resembling that of related Bacteroidales families. In addition, we describe three trophic guilds within the family, plant glycan (hemicellulose and pectin), host glycan, and α-glucan, each broadly defined by increased abundance of enzymes involved in the degradation of particular carbohydrates. "Ca. Homeothermaceae” representatives constitute a substantial component of the murine gut microbiota, as well as being present within the human gut, and this study provides important first insights into the nature of their residency. The presence of trophic guilds within the family indicates the potential for niche partitioning and specific roles for each guild in gut health and dysbiosis."

For those of you who think I know stuff....I'm pretty floundered on this one!!!  Have to say I've never seen a study where the ratties included were:  peeps, mice, koalas, AND guinea pigs....all together!! (Koalas?  Really??? I mean...there's their cuddly appearance, their life exclusively down under...and most germane to this discussion, as I understand it, they feed exclusively on eucalyptus plants!!!  I would assume the intestinal microbiome needed to digest this food source would be one more in keeping with that found in a termite than a human!!!!!)
But, back to the ASCO study, have to say that it makes me feel a little sick to my stomach thinking that if I am to be a responder to anti-PD-1 clostridium difficile, tetanus, and botulinum cooties need to be part of my make up.  Maybe it just means that if we can survive with that crap in the old poop shoot, melanoma doesn't stand a chance?  I wonder if the asbstract has a typo and mixed up the names of the organisms associated with R and NR.  Oh, well...

Don't really know where this line of investigation is going!  I think I'll just keep eating my sauerkraut, kimchi, yogurt, and kefir!  In case you are interested in more handy dandy, readily available, and delectable cures for melanoma....I've been keeping up with the data on all that jazz for years, too. Here's the last post on that front:  Everything Cures Melanoma: Installment #6

Hang tough ratties - it's a pretty toxic world without and within....apparently!!! - les

PS ~ Not sure many of you grew up reading the folktales of Richard Chase, but if you did, I'm sure you recognized, "Right there I had it.  Right here I lost it!" as the refrain the main character used in his story:  Soap, soap, soap!  If you want a trip down memory lane or have never heard is an abbreviated, 'cleaned up' version...and after all that may be just what we need:  Soap, soap, soap. Revised by: Eldrbarry

Wednesday, June 21, 2017

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

It goes without saying that over the years I have posted a zillion reports about all things immunotherapy:  anti-PD-1 ~ Pembrolizumab (also referred to as Pembro and Keytruda) as well as Nivolumab (also called nivo and Opdivo) both of which have very similar side effect profiles and a roughly 40% response rate when used alone; anti-CTLA-4 ~ ipilimumab (also called ipi and Yervoy) which has similar side effects but with greater frequency and intensity than the anti-PD-1 products {though many tolerate it well} with about a 15% response rate when used alone; as well as the ipi/nivo combo which has a response rate of 50+%. (Here's a link:  ASCO 2016: Checkmate 069 - ipi/nivo combo in Stage IV melanoma demonstrated a 68% ORR)  Consistently, treatment naive patients have responded best to all of the above, responses are the most durable we have ever had in any melanoma treatments, many folks continue to respond even if they have to stop treatment due to side effects.  We have also learned that side effects need to be treated as soon as possible, often with steroids, so as to save lives and prevent greater damage than has already occurred, AND the use of steroids, if needed, DOES NOT IMPEDE RESPONSE!!!!  Feel free to use the blog's search bubble to find more info and data on all of this.  Now researchers are looking at:

Pembro plus ipi:

Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.
ASCO 2017. J Clin Oncl, 35, 2017. Carlino, Atkinson, Cebon, et al.

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received greater than/= to 1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61%; the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

Here 153 Stage IV melanoma patients (no brain mets) but some with increased LDH were given Pembro 2mg/kg and ipi at only 1mg/kg, together every three weeks for 4 doses and then pembro alone q 2 wks.  There were no treatment related deaths, though ALL patients had side effects, but were grade 3/4 in only 45%.  The way the data was examined ~ with one near endpoint and another 7 months later...proved...AGAIN...that responses can occur late....and as per Weber and Agarwala, when it comes to immunotherapy, "Give the patient time!" ~ for an ultimate ORR of 61% and CR of 15%.  So....these responses are no better than those demonstrated in the ipi/nivo combo.  But...what is interesting is that ipi was dosed at only 1mg/kg whereas in the ipi/nivo combo it is used at 3mg/kg. (AGAIN!!!  Why can't researchers [and Big Pharma!!!!] construct trials so that you can REALLY compare results!!!) At any rate, this tidbit of data may prove important in decreased side effects and it would be important/interesting to see if nivo with ipi at only 1m/kg would continue to do as well as the combo does currently.  I'm betting it would....but that's just me.

While the next couple of articles did not come out of ASCO this year...they pertain to the topic at I've included them here.

Here, researchers looked at the response to ipi after patients have progressed on pembro:

Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma  KEYNOTE-006 Poster Spotlight: G. Long (Australia).  European Cancer Conference, Jan 2017.

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti–PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab.
Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported.
Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAFV600-mutant tumors at baseline. Best response to pembrolizumab was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks, and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks. Median duration of ipilimumab was 8 weeks. The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received greater/= to 1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months.
Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.

So in 97 patients, most of whom had taken pembro for about 18 weeks with a PR in 16% and SD in 12%, PD in 62% (clearly, these were folks who were not responding to pembro as well as the usual data) were, in about 5 weeks placed on ipi at 3mg/kg, with most folks taking it for 8 weeks.  At that point, the ORR to ipi was 14% (which is what responses to ipi usually run at).  Additional data showed:  CR in 3%, PR in 11%, SD in 33%, PD in 33%.  While not great, this certainly shows that if you are not a responder to pembro....switching ASAP to ipi can gain a response of about 15%.  A similar response was attained in the last abstract noted in this post from ASCO 2015:  ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Here researchers looked at how tumors, and subsequently the patients!!!, responded to pembro:

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Nishino, Giobbie-Hurder, Manos, et al. Clin Cancer Res. 2017 June 7.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.

Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained less than 20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with less than 20% tumor burden increase from baseline had longer OS than patients with greater than/= to 20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with less than 20% tumor burden increase during therapy had significantly reduced hazards of death.  Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of less than 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention.

Here 96 patients with measureable disease were given pembro.  ORR was the expected 44%.  Folks whose tumor burden increased less than 20% from their baseline, once therapy was started, did best, and this was 55% of the peeps in the study.  They ended up with a longer OS than those whose known tumor burden increased more than 20% from baseline while on pembro.  Of course!  If your tumors mostly just shrink while on do better!!!   BUT!  The pseudoprogression thing is real for some...albeit in small numbers...3 patients had target lesions increase in size but went on to gain a response and 1 patient that didn't have measureable disease when they started treatment developed a new lesion that then regressed.

Well, there you have it.  Things remain about as clear as mud if you are a melanoma patient who is progressing on immunotherapy as to trying to decide what to do next!!! is clear...that there is hope.  Love and luck to all the ratties - c

Sunday, June 18, 2017

ASCO 2017: All things intralesional/intratumoral

I have long been a fan of intralesional (intratumoral...pick your nomenclature) therapy's potential. These are medications that are injected directly into superficial lesions...which researchers have found can make the injected tumors, as well as distant ones, GO AWAY!!! Additionally, it has long been supposed that if they were combined with systemic immunotherapy they would work even better.

In 2014 I wrote:  "Intralesional melanoma therapy (A procedure in which the "treatment" is directly injected into superficial tumors and in theory, not only does that tumor die, but "by stander" tumors at more distant sites die too!!!) was first recorded back in 1975.  A 75 year old male with 64 melanoma mets just below the skin, as well as junk in his lungs, had 17 superficial lesions injected with Bacille Calmette-Guerin over a period of 8 months. (BCG is a vaccine against some strains of tuberculosis, but does contain a weakened version of the bacteria itself within it.) In the end, all 17 tumors injected resolved and his pulmonary mets diminished by more than 50%!  However, enthusiasm for BCG as a melanoma treatment waned as patients in subsequent trials experienced anaphylactic reactions and death due to disseminated BCG, and randomized trials failed to replicate significant clinical benefit.

Later, intralesional therapy was tried using all sorts of things.  More recently Allovectin-7, OncoVEX, and PV-10 have demonstrated positive results, killing melanoma at the injected site and systemically.  

Today, three years later.... we now know that, unfortunately, Allovectin-7 (velimogen aliplasmid) did not work out and trials were ended by its manufacturer, Vical. However, we do have an additional intralesional: CAVATAK, derived from the Coxsackievirus (a frequent cause of the common cold) produced by Virolytics.   OncoVEX now also called Talimogene Laherparepvec (or T-vec, brand name Imlygic) engineered using the herpes virus and GM-CSF, developed originally by BioVex and now produced by Amgen who bought them out, is still in process. There is also PV-10 generated from Rose Bengal made by Provectus.  It has shown promise in studies I have previously posted and there is this blurb from Fortune magazine in 2016:

"Final results from an ongoing 225-patient melanoma trial of the experimental drug compared to chemotherapy are expected in early 2018. The hope is that the drug, known as PV-10, will prevent melanoma from progressing beyond Stage III, in which the disease has spread but not yet to other organs, and allow patients with more advanced cancer to live longer." 

From a 2016 study that paired PV-10 with radiation there was this:   "15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months.  Size of metastases (less than 10mm) predicted potential for lesion complete response. "

For whatever reason, perhaps due to the immaturity of the data, (In addition to the study referenced above, a study was started in 2016 combining PV-10 with pembro.) PV-10 did not make it to an ASCO presentation this year...not at least any I found. Here is a link to prior posts:  All things PV-10


CAVATAK has been talked up for a while now.  Here are links to many posts:  All things CAVATAK  In a 2016 report where CAVATAK was used alone, this was reported:  "Responders on the CALM study (16/57 pts, 28.1%) displayed reductions in both injected and non-injected lesions, suggesting the generation of significant host anti-tumor responses. A comparable ORR was observed in pts administered prior immunotherapy, 29.0% (9/31) vs other tx 27.0% (7/26). Interestingly, 26.7% (4/15) and 40% (2/5) of pts previously treated with ipilimumab and talimogene laherparepvec, respectively, developed confirmed responses."

Here, CAVATAK is combined with ipi:

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.
ASCO 2017. J Clin Oncol 35, 2017. Curti, Richards, Hallmeyer, Faries, Andbacka, et al.

Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. 

Here 26 patients (Stage III and IV) - 13 with prior anti-PD-1, had lesions injected with CAVATAK and ipi (3mg/kg) was given 4 times IV.  Best ORR = 38% with a total response rate of 88% when complete response, partial response and stable disease were combined.


ASCO 2016 began to report the results of T-VEC combined with Pembro, reporting:  "Of the 21 pts enrolled from Dec 2014 – Mar 2015, 48% had IIIB-IVM1a, 52% IVM1b/c, 76% HSV-1+, and 19% BRAFmut+. Median follow-up at data cut was 33 w. All pts received at least one dose of T-VEC+pembro. Tx-related AEs occurred in all pts: 33% G3/4, and no G5. Most common AEs were fatigue (62%), pyrexia (52%), and chills (48%). Per irRC, in 21 pts, confirmed/not yet confirmed objective response rate (ORR) was 48%/57%CR rate was 14%/24%. Median time to response was 17 wks."

Here is a report from a study using T-VEC alone:  "In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients."
Here is a link to posts that are:  All things T-VEC

Here T-VEC plus ipi was compared to ipi alone:

Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.
ASCO 2017. J Clin Oncol 35, 2017. Chesney, Puzanov, Ross, et al.

Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab [ipi/Yervoy] that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The primary endpoint was ORR by immune-related response criteria. Key secondary endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr greater than/ = to 3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. 

Here patients were Stage III/IV, some had had prior treatment, some not.  98 were given T-VEC and ipi, 100 got only ipi.  ORR to combo = 38.8%.  Ipi alone ORR = 18%.  


Here is a study using HF-10, another HSV based intralesional, produced by Japanese company TaKaRa combined with ipi:

Final results of a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic virus, and ipilimumab combination treatment in patients with stage IIIB-IV unresectable or metastatic melanoma.
ASCO 2017. J Clin Onco 35, 2017. Andtbacka, Ross, Agarwala, ...Grossmann.

Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age greater than/= to 18 yrs, ECOG less than/= to 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as greater than/= to G3 non-hematologic/hematologic toxicity, greater than/= G2 neurologic toxicity, or allergic event occurring within 1st 3wks of therapy. Results: Of 46 pts enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with greater than/= to 1 prior cancer therapy for unresectable/metastatic melanoma. Most HF10-related AEs were less than/= to G2, similar to HF10 monotherapy. No DLTs were reported. 37% had greater than/= to G3 AEs, the majority due to ipi. HF10-related greater than/= to G3 AEs (n=3) were embolism, lymphedema, diarrhea, hypoglycemia, and groin pain. Of the 44 efficacy evaluable pts per irRC, BORR at 24 weeks was 41%; disease stability rate was 68%. As of Feb 06, 2017, median PFS was 19 months and median overall survival was 21.8 months. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in pts with stage IIIB, IIIC, or IV unresectable or metastatic melanoma. this HF-10/ipi study - there were 46 patients, 63% of whom were Stage III and 37% Stage IV. About 1/2 were treatment naive and half had had at least one melanoma treatment.  Best ORR was 41%.  SD was attained in 68%.


Here, SD-101, a different type of intralesional entirely, a TLR9 agonist from Dynavax, is paired with Pembro:

Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve and experienced metastatic melanoma patients.
ASCO 2017. J Clin Onco 35, 2017. Leung, Kummar, Agarwala, etal.

Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH greater than 1 ULN 27%, greater than/= to 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (greater than/= to 20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade greater than/ = to3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. 

Patients were Stage III/IV (14 and 86% respectively).  Of the 22, 9 were anti-PD-1 naive and 13 had already taken it.  SD-101 was injected into a single lesion and patients were also given pembro.  No matter the SD-101 dose, patients who had never had anti-PD1 before, all had a response in injected and non-injected lesions for an ORR of 66.7%, CR of 22%, PR of 44%, SD of 11%.  In patients who had had anti-PD-1 previously, there was a partial response in almost 8% and stable disease in 38%.
This is a very small sample.  

Okay.  Why in the world we cannot have studies constructed in ways that make sense is beyond me!!! We KNOW the results of ipi alone...a 15-18% response rate is typical and that was borne out here. Why we cannot have a very simple study directly comparing T-VEC to CAVATAK to PV-10 and whatever other intralesionals there are on the market is nutters!  I have been calling for it for years....but clearly no one listens to me!  However, it seems that no matter the intralesional presented here....they all can kill the melanoma tumor they are injected into and other lesions hanging about the body elsewhere.  When used alone, CAVATAK and T-VEC studies report about a 28% ORR, while PV-10 has studies reporting a 50% ORR.  I don't have data on HF-10 and SD-101 when used alone. When used with ipi, HF-10, T-VEC, and CAVATAK boosted ipi's usual response rate of about 15% to about 40%. When SD-101 was paired with pembro (anti-PD-1), pembro's usual response rate of about 40% was boosted to 66%.  Why we are pairing these drugs with ipi is another huge question for me! Let's see....ipi has lower response rates and higher side effect risks than anti-PD-1....but I digress. As we have already learned in many other studies...treatment naive patients did better...but even those who had already been through the wringer did have a chance of a response. I still feel that intralesionals, whose side effects are pretty much limited to local redness and irritation at the injection site with some fever and fatigue, have a lot of promise and their effectiveness in getting rid of lesions that were NOT EVEN INJECTED should be able to teach us a great deal about how melanoma works and hides.  Pairing intralesionals with anti-PD-1 as well as radiation appears to be a treatment methodology that could clearly benefit many.

Hang in there ratties....and...thanks.  - c