CheckMate 172 - nivo used after progression on ipi - report on those with acral,ocular and mucosal melanoma

As difficult as it is to treat cutaneous melanoma, folks with mucosal melanoma and other subtypes face even greater challenges.  Here are some previous reports:  Mucosal Melanoma 
Now, there's this:

Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172).  Nathan, Ascierto, Haanen, et al. Eur J Cancer. 2019 Aug 21.

Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab.

CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade greater than/= to 3, treatment-related select adverse events (AEs).

Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade greater than/= to 3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively.

The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival.

Not the numbers we wish for...but it is something!  Let's make them better for everyone SOON!!! - c

A few of my favorite things...

...when the treatment bites, and cancer stings, and I feel so sad ~ I simply remember my favorite things ~ and then I don't feel so bad!!!

This week a year ago, I was discharged after what was basically a 3 week hospital stay that included innumerable miseries, two surgeries, and a new cancer diagnosis of Stage II, ex-goblet cell adenocarcinoma of the appendix (GCC) to add to my existing Stage IV melanoma.  Once home, recovery was slow and followed by 3 months of adjuvant CAPOX chemotherapy treatment which created its own special hell.  It may seem strange having survived 16 years with melanoma, post brain and lung mets, along with a 2 1/2 year immunotherapy trial, to say that this year's insults have been the hardest to rally from. But it is so.  It has been physically exhausting; mentally demoralizing. Still, I am here.  I continue to work to gain strength and normalcy in my life and will be giving you updates on all of that very soon.  Though much in this year has been incredibly hard, I have also been blessed with love and beauty!!! As summer turns to fall, here are a few of what have been my favorite things...

Friends and loved ones near and far have made all the difference.  Hugs and laughter.  Amazing care packages of all stripes.  The best buttons and butt creams.  Bungee jumping workouts.  Calls, notes and emails - of encouragement, shared fears, and plain silliness have seen me through.

This guy!!!  (Seriously.  THIS GUY!!!)

Fun plans and laughs with this crew who never failed to make time to cheer me on no matter their personal challenges, work schedules, and all around busy lives!

Smiles and stories are never better than when shared with this boy!

Who knew his initials "FBM" would end up standing for Frederick Buttermilk Morris????

My personal perennial flower girl!  Bringing love, light and eternal blooms to life for all of us.

Belly laughs are seriously good for the soul!

Enthusiasm and love from friends like my dear Kay is worth more than any gold or medical potion.

My 55th birthday happened!  A surprise event in and of itself, was celebrated in the best ways...

Let them eat cake!!  Bentie hooked me up with apple pie and ice cream!  Yay, for 'warm fruit', right Char????  Plus the coolest little "note" book with a Sherlock motif!  Referencing another summer joy, along with the innumerable times I waxed enthusiastically about it to B, reading the complete collection by Arthur Conan Doyle ~ a literary work I had somehow missed all my life!  Should you indulge, which I highly recommend you do, know that I discovered I am very much aligned with Sherlock in my way of thinking.  Who knew?

I was blessed with surprise cards from many and this one from folks unknown!  Whoever you are, dear sender ~ know that you made my day!!!  Thank you!

Most folks would agree that I am a pretty great gift giver.  I know ALL would agree that I am a HORRIBLE gift wrapper!!!  Sometimes the paper is just too small and the bottom must go unwrapped!  I mean, how does one deal with that???  Ruthie, on the other hand is perfection on BOTH sides of the gift giving conundrum!  When the HAND DECORATED paper is this pretty, does there really need to be anything IN the package????????? 

You guessed it!  A perfect gift was wrapped within that amazing paper!!!  Look how her lovely dragonflies complete my porch!!!  Hope flies on dragonfly wings

Sewing and the sewing community, along with B's indulgence and participation in my efforts, have certainly been a huge part of my recovery this year.

My sewing space is just part of the sanctuary that is my sewing.

My inspiration board lifts my spirit - with cards and tokens from dear ones, my sweet little Granny's pin cushion, and yes, there's a little sewing inspo, too!!  It recently got a re-do!  Check that awesome background paper!

It's a bird!!  It's a plane!!!!  It's an incredible act of kindness!!!!!!

I cannot tell you how touched I was to learn that dear melanoma peep, Laurie, made a donation in my honor to Stand Up To Cancer and in so doing put my name on a plane!!!  Seriously, how cool is that?

And there WERE birds!!!!  As I sat looking out onto our back porch throughout my convalescence, B made sure I was medicated, fed, assisted, ensconced or uncovered with cozy blankets per my whim. Battery powered slippers were available to warm my feet (shaped like fierce dragons no less).  I was catered to in every way imaginable.  In the midst of all of that, he took care of the house, all the daily chores that life requires, AND made sure I had plenty of birds to watch.  He fed and called them daily.  (To the point that today, when he steps out on the porch and whistles, you see them gather in the branches of nearby trees!!!)  He rigged feeders and houses positioned just so, allowing me to watch them easily.  Look what happened...

We watched multiple sets of blue birds build their nests and hatch their chicks!  We even got to see this adventurous little one take his fledgling flight!!!

The poor parents were the hardest workers ever.  Sorry for the slightly sad photos.  Best I could do on my phone.  B's birds played a huge role in my recovery and have certainly been one of my favorite things.  Thanks, B!!

As I got stronger, I found relief and peace working in our garden.  Though a consistent comfort to me, gardening doesn't always turn out as you hope!  Initial enthusiasm for our gooseberries has been a bit dashed and one is even missing!!!  The birds I love ate more of our blueberries than we did and took pecks out of every tomato they could get to.  Whistle pigs pull any plant to the ground and chomp on it whenever they like.  Deer have given my beans and even some azaleas nice trim haircuts!  Still, my efforts to work with nature in all its forms soothed my jangled nerves and provided some successes of which I am inordinately proud.

Having planted my blackberry lilies in too much shade initially, not to mention in the chomping grounds of moles or voles, they were in serious danger of extinction!  Moving them to two sunnier locations this spring has reaped beautiful benefits!  Isn't the bloom lovely?  Glossy seed pods that look much like fat purple black berries are already forming.

But these coleus have been my most surprising favorite gardening thing!  Two bags of bulbs, purchased for a couple of bucks on a whim while in Wally World, then recklessly tossed into a dark spot of the garden under a dogwood, have provided bobbing light and color to what would have been dull shadows of the yard as well as the foggy, dim corners of my spirit.

These silly leaves have made me smile and been a balm to my wounded soul.

Sometimes the smallest gifts, the least effort, can provide the largest benefit to those in need.

There you have it my dear ones.  Know that all of you helped me find me ~ again.  You are always and forever, a few of my favorite things.  Much love, les

Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

We melanoma patients all want to know!  Should I opt for targeted or immunotherapy?  What happens to me during treatment?  What happens after?  While there are no absolutes, here are some reports that attempt to provide a few answers.

TARGETED THERAPY:

The first addresses outcomes in Stage III/IV patients treated with the targeted therapy combo, Dabrafenib plus trametinib:

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.  Robert, Grob, Stroyakovskiy, et al.  N Engl J Med. 2019 Jun 4. 

Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.

A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (17 to 24) at 4 years and 19% (15 to 22) at 5 years. The overall survival rates were 37% (33 to 42) at 4 years and 34% (30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (62 to 79) at 5 years.

First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Here are some links to earlier posts on the subject:
2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

2015:  BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?

2016:  Factors predictive of response, progression and OS with dabrafenib and trametinib

Also from 2016:  ASCO 2016 - Cobimetinib and Vermurafenib - coBRIM study

IMMUNOTHERAPY:

For comparison to the targeted therapy outcomes above, here's a report on immunotherapy from the dark ages of 2014:  Review of immunotherapy and durable benefit in melanoma!!!

This report documents the 4 year outcomes for ipi/nivo vs nivo alone for melanoma patients from December 2018:  CheckMate 067 - 4 year outcomes for nivo/ipi combo vs nivo alone in melanoma patients 

2019:  IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma

LOS DOS:

Here is a report from this year (with many links within) on combining targeted and immunotherapy:
Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

HOW RATTIES REPORT THEY WERE AFFECTED BY EITHER TREATMENT:

Here are the results of a survey of 105 melanoma patients treated with either immunotherapy or BRAF/MEK who had an "objective response or stable disease" and were asked about the impact of said treatment on their lives:

The survivorship experience for patients with metastatic melanoma on immune checkpoint and BRAF-MEK inhibitors.  Lai-Kwaon, Khoo,Lo, et al.  J Cancer Surviv. 2019 Jun 4. 

Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi.

Patients with MM, aged greater than/equal to 18 years old, greater than/= to 6 months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports.

One hundred and five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5 years (1.3-8.5) for ICI and 3.1 years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/ BMi 25, 69%), arthralgias (ICI 30, 58%/ BMi 23, 64%) and fatigue (ICI 62, 90%/ BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/ BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/ BMi 31, 86%) or death (ICI 44, 64%/ BMi 26, 72%).

MM survivors experience chronic treatment toxicities and frequently report psychological concerns.  Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports

WHAT TREATMENT TO CHOOSE:

If you are lucky enough to be a BRAF positive melanoma patient (about 1/2 of us) you have the option of targeted therapy or immunotherapy.  But picking which therapy to utilize is really tough for melanoma patients.

Here is some advice from some Melanoma Big Dogs in 2015:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Some advice on sequencing from 2018:  ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

This post includes a report on what ratties have to consider re immunotherapy:  Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy?

Here is advice and thoughts from Weber and Allison this year:  Progress in the Treatment of Advanced Melanoma: Where We Are Now, and Why the Future Is So Promising 

Melanoma gives us no easy answers. Yet, we continue to learn more about the disease and more about how to survive it!!  Hang tough, ratties.  Hang tough. - c

Sew Chaotically! ~ ANOTHER Tate top and Flint pant!

This is my third make for each of these!  Somehow, I never got around to posting my first Flints (Megan Nielsen).  Made of a lovely grey crepe - full length initially - then cropped as they were "too fancy" for much wear at that length.  Currently, they are lovely to dress up or down and I suspect you will be seeing them soon!  My second pair was a knee length version out of a remnant that are fun for bumping around in.  The fabric is not great so they won't last that long, but they've gotten some good use already.  BUT!  My most recent pair is PERFECTION!!  More on that in a minute.

Then this summer, there has been my new found love of TATE!!  It really is a perfect pattern for hot days or fall layering.  AND it's FREE (from Workroom Social)!!  What more can I say?

Heading into fall ~ the perfect combo!!  Tate plus Flint!!  Great together.  Fab as separates!!

Being made of delicious Brussels Washer Linen from Fabric.com aids in their perfection!!

I may be a little obsessed!!!  Wishing a great week to each of you!  Sew and live chaotically! ~ les

Sew Chaotically! ~ Kalle Shirtdress in a crazy print!

I really enjoyed making, and have loved wearing, my bright Kalle Shirt!  So when something works ~ why not rev up the bright in a Kalle Shirtdress?  Making deets:  Lengthened the dress and smoothed out the high low hem just a bit. (See changes to Kalle Shirt in link above, then lengthened by 7 inches.) Used the collar stand piece as collar since I wanted a taller look than the band collar included provided.  Chose the inverted pleat to the back again.  Fabric used was listed as an African Wax print at Fine Fabrics in Norcross, GA.  And while I like it, I don't think that is the case!  It was coated with "something" when purchased, but I planned on washing it all along.  It is now a sort of stiffer gauzy/linen like like piece.  I used the "wrong" side in making.  (If you think THIS side is bright, you should see the other one!!!  HA!)  I have enjoyed it belted and un.  Am looking forward to using it as a "duster" and layering piece with jeans in the fall.  Overall, quite happy with how it turned out!  Thanks, Closet Case Patterns for a great make!

Happy Sewing! Sew and live chaotically!! ~ les

Melanoma peeps with durable benefit from anti-PD-1 even after stopping due to adverse events ~

In June, I posted:  Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment which includes links to multiple reports addressing how melanoma patients treated with anti-PD-1 have fared.  My synopsis of an ASCO 2018 report on outcomes for melanoma peeps after stopping anti-PD-1 follows ~  41 of them stopping after completing 2 years and 34 stopping due to side effects.  I noted: 

So - 580 melanoma patients were given anti-PD-1.  41 patients stopped after 2 years or at doc's discretion (characterized as MCB in study [maximal clinical benefit]).  34 stopped due to side effects.  I presume the rest of the peeps are still on treatment.  Overall, 56% of patients had a complete response, 35% had a partial response, and 9% had stable disease.  These responses were similar across the 2 groups with a response rate of 93% in the MCB group and 88% in the toxicity group.  Complete responses were higher in the MCB group (76% vs 32%).  Median time on drug = 19.5 months for MBC and 6.5 months for the toxicity group.  Median time to response was about 3 months (this has been demonstrated repeatedly in studies looking at anti-PD-1).  Median time to complete response was 7.3 months.  At f/u 16 months after stopping anti-PD-1, 89% were disease free, 93% were alive, 6 had died (NONE due to disease progression), but three deaths were due to complications from anti-PD-1.  8 patients progressed (3 in the MCB group and 5 in the toxicity group).  2 of the MCB group were rechallenged and 1 gained a complete response and the other a partial.

Now, researchers who examined how melanoma peeps forced to stop anti-PD-1 as a single agent due to adverse events have fared, with a median f/u of 30.3 months, found:

Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events.  Swami, Monga, Bossler, et al. J Oncol. 2019 Jul 25.

Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes.

Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin and Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS).

Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause).

Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.

So ~ when the researchers drilled down on this, we are dealing with a rather small sample set of 16 patients who had to stop nivo (1) or pembro (15) as single agents due to side effects.  Average length of treatment was about 5 months (6.5 in the study above).  Median f/u was just over 30 months (16 in the study above).  Median PFS = 24.6 months.  Median OS was not reached. At the time of the report, about 30 months in, 8 (of 16) patients had progressed and 4 had died, though apparently that number includes causes in addition to melanoma. (In the study above, 5 (of 34) patients had progressed at 16 months in.)

As ever, studies annoy me by not looking at results in the same way!  But, it looks as though, much like what we have learned in folks who have to stop the ipi/nivo combo due to side effects, yet still gain a response and have a PFS that is not that much different from those who complete the recommended duration off therapy, melanoma peeps who have to stop anti-PD-1 as a single agent can still attain durable benefits.

For what it's worth ~ c

"Baby, how you feel'n?"

"Feel'n good as Hell!"  Gotta love Lizzo!! 

There are certainly days and circumstances in life that prevent such an answer!!!  Still, perspective seems to be the largest part of what is required to feel good.  I've known healthy peeps of all ages who wallowed in every small misery (physical and social) they experienced daily.  I've been blessed to meet incredible individuals, children to octogenarians, who - despite dealing with physical pain from cancer and other maladies, broken families, personal loss, daily struggles of all kinds - were resilient with a ready smile and forward looking approach to the crazy life threw at them.  These astonishing souls weren't in denial or "faking it" either!!!  If asked, they would frankly and honestly share their difficult experiences without batting an eyelash!  But, that was not their focus.  Living, learning, sharing a laugh and real connection, the wonder of it all - was.  These folks didn't ignore the difficulties of others either!!  Some were the most amazing activists, working daily to make the world a better place for all of us.

Like them, I too have the choice.  I can realize the difficulties the world faces and choose to hide, become depressed, or act! I can focus on my negatives, my pain, my worries.  Or - I can choose the light.

"I do my hair toss.  Check my nails.  Baby, how you feel'n?  Feel'n good as Hell!!!"

Thanks, Lizzo. - les

Blessed!

Life is often hard.  Folks can be unfeeling, even horrifyingly monstrous to the point of gunning down their brothers and sisters.  Mother Nature cries as fires burn, tides rise, hurricanes roar and man disregards our duty to preserve Mother Earth.  Diseases are cruel.

But...

Each day is simultaneously filled with beauty.  Flowers bloom.  Humans show super human strength and power as they work together to save one another - to save someone OTHER than themselves.  Children take action to save our planet.  Heroes walk among us.

And I?  I have been incredibly blessed to experience it all.  No less so yesterday, as I spent a precious day with some of my babies!!!

We had several missions!!!   Bridal attire. Check!  Bridal planning and decor.  Check!!  Share love and laughs with one another!!  CHECK! CHECK!! CHECK!!!

And at home, I get to play with the sweetest boy....

With a sneak peek of a soon to be shared Kalle Shirtdress!!!

More beauty and adventures to come.  Thanks to all of you for sharing your hearts with me.  May you enjoy your days and feel blessed! ~ les

Thanks, Walmart!!

I think this picture says it all:

It is very strange, but more and more I am depending on big business for hope.  They may or may not be charitable, but THEY - unlike a large number of our political "leaders" - can see where most of America stands.  And they respect that!!  Adverts show mixed race and LGBT couples shopping for groceries and insurance.  Hispanic families buy cars and use medicines.  It's not enough, but it's something.  Dick's Sporting Goods led the way and this week Walmart followed by stopping the sell of ammunition for assault rifles and discouraging participation in "open carry" in their stores located in states that allow it.  Again, it is not enough, but it is something.

Hope flies on dragonfly wings.  ~ les

NKTR- 214 (bempegaldesleukin) with Opdivo - PERHAPS the results from the PIVOT trial for melanoma patients were LOWER than they should have been? Meaning if the company who makes it (Nektar) gets its act together patients may demonstrate an even better response????

I've been reporting on NKTR-214 (bempegaldesleukin) since 2013, the PIVOT trial in particular.  The drug was also discussed at ASCO this year, with my report on that (with links to prior reports) here:  New Stuff!! Treatment options and current trials for melanoma patients! The first installment of this year's ASCO review.

Here's most of what I wrote from ASCO:

I first reported on NKTR in 2013.  Click here for that report as well as abstracts and analysis from 2018.  After examining the Phase 1 and Phase 2 reports of the PIVOT trial I wrote:

"...back to NKTR-214 combined with nivo.  Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising.  Phase II results were a little less so.  Responses as noted in the article were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients".  We have already determined that treatment naive patients tend to have the best responses.  But even so, 50% beats 40%.  Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone.  So....

I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold.  BUT!  Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical.  We have to deal with the real live results that are happening for real.  Today.  To us."

That's how I look at melanoma research!!!!   ALWAYS! Now....this from ASCO:

CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).  2019 ASCO.  Nikhil, Khushalani, Diab, .... Sznol, Long.  J Clin Oncol 37, 2019 (suppl; abstr TPS9601)

Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors.Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: Thisphase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983).Eligible pts are greater that/= to 2 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS less that/= to 1 or Lansky PS greater than/= to 80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983

So, this is an open and recruiting trial.  It is randomized.  Some folks will be getting the NKTR-214 drug with nivo, some will get nivo only.  Prior ORR of 53% is better than the usual of about 40% to anti-PD-1 products given alone, but about equal to the ipi/nivo combo.  If the side effects of this combo is less than those caused by ipi/nivo, that could be a good thing.  Lots of the usual melanoma peeps are excluded.  But, there you go.  

So that's where I thought I'd left bempegaldesleukin and nivo.  Seriously, who names this shit???  Anyhow ~ there's more, and it seriously falls in a GOOD NEWS/BAD NEWS category.  Here's a link to the report:  

From FiercePharma, August 2019: Faulty manufacturing trips up Nektar's Bristol-partnered cancer drug in crucial trial  

Which states in part:   

Could a manufacturing mix-up be as detrimental as the fact that a drug simply doesn’t work? Nektar learned the answer the hard way with its Bristol-Myers Squibb-partnered experimental cancer therapy. On Thursday, Nektar CEO Howard Robin went to great lengths to explain why response rates dropped in the second stage of a clinical trial testing NKTR-214 (bempegaldesleukin) in tandem with Bristol's Opdivo.  But in a nutshell, some patients received substandard batches of the Nektar drug, he told analysts during a conference call. And unsurprisingly, those bad batches didn't work as well.

According to Robin, Nektar ran an analysis of all 22 lots of bempeg it had produced and found that two lots—lots 2 and 5—were out of specification, though they had passed release controls under old assays. The team noted correlations between patients who started treatment with the two problematic lots and a lower response rate during the PIVOT-02 trial as compared with the other two lots used in the study.  Specifically, newly diagnosed melanoma patients who started with lots 2 and 5 saw 36% of their tumors respond to the treatment at best, with a complete response rate of 27%. The others posted response rates at 75% and 44%, respectively, Nektar’s R&D chief Stephen Doberstein said during the call. In the trial's first-line urothelial cancer cohort and first-line renal cell carcinoma cohort, similar differences were observed.  Management attributed the mess-up to a single suboptimal batch of intermediate that was used to produce only lots 2 and 5. The company found that bad batch using new quality control assays, Robin said.  And Robin promised that Nektar now has the problem under control.  “As a result of this discovery, we have developed a comprehensive control strategy to limit variances in raw materials, intermediates and the final product in our manufacturing, and this is being validated for commercial-scale manufacturing,” he said, adding that the company has also shaken up its CMC leadership.

The BAD NEWS:  Seriously, Nektar and Mr. Robin CEO man???????  We didn't ask you to change a light fixture or install brakes in our car.  We didn't count on you to do brain surgery, cook us a meal, teach our children to read, repair a computer or put a satellite into space.  We EXPECTED you to do what you SAID you knew how to do.  Make a specific drug, that you eff'n named bempegaldesleukin, they way you said you would, in the strength you said it would be, in a consistent and safe manner for use in HUMAN BEINGS!!!!!!!!!!!!!  We didn't FORCE you to do that job!  YOU SIGNED UP FOR IT!!!!!!!!!!! Good grief!  WTF??????????????!!!!!!!!!!!!!!

On the GOOD NEWS side, perhaps ~ if Mr. Robin CEO man can get his Nektar shit together, and actually make NKTR-214 as it should be - in a safe, consistent, reproducible manner - response rates in melanoma and renal cell carcinoma patients may be much improved on the nivo combo.  To the tune of:   "Newly diagnosed melanoma patients who started with lots 2 and 5 saw 36% of their tumors respond to the treatment at best, with a complete response rate of 27%. The others posted response rates at 75% and 44%, respectively" per the report above.

It is one crazy world.  Being sick should be enough - but no!!!  Hang in there ratties.  You are the best and we thank you. - c