Monday, September 16, 2019

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

Sunday, September 15, 2019

"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

Sunday, September 8, 2019

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.  Disease 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

Wednesday, September 4, 2019

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

Sunday, September 1, 2019

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

Saturday, August 31, 2019

NEO = Treatment with targeted or immunotherapy BEFORE tumor removal - wave of the future for melanoma?


In the past couple of years, research into the use of targeted and immunotherapies BEFORE the removal of melanoma lesions has been evaluated by researchers and are showing promise. Here are prior reports:  Neoadjuvant treatments for melanoma

Now, there are these:
Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection.  Fujimura, Kambayashi, Sato, et al.  Front Med (Lausanne). 2019 Jun 26.  

Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented. In addition, CD8+ T cells increased among the tumor-infiltrating lymphocytes that were surrounding melanoma cells and caspase 3+ cells. The present case suggests that pre-surgical administration of nivolumab with ipilimumab could be the optimal therapy for the treatment of unresectable advanced melanoma.

Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium.  Amaris, Menzies, Burton ... Antdbacka ...Daud, Faries...Flaherty ...Hamid...Postow ...Sondak...Taube...Davies...Ascierto...Long, et al.  Lancet Oncol. 2019 Jul;20.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAFV600mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Long, Saw, Lo, et al.   Lancet Oncol. 2019 Jun 3.

Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.

NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged greater than/ = to 18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.govNCT01972347, and follow-up of patients is ongoing.

Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%) patients had a complete pathological response and 18 (51%) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.

Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.

Hang tough ratties.  You give us hope! - c

Wednesday, August 28, 2019

Sew Chaotically! ~ Tate 2!


In case you haven't noticed, swingy high necked tops are having a moment.  Check out Everlane's Japanese GoWeave High-neck top here ~

If you like this look, Workroom Social's FREE pattern, the Tate Top, is perfect!!!

I have LOVED my original Tate Top  made as prescribed by the pattern!  In this light as air handkerchief linen it has been the perfect care free summer top.


But, for fewer bra strap worries and multi-setting appropriate wear, I thought widening the shoulders a bit could help create a versatile piece from the same pattern.

This fabric, picked up from a shop in the Walthamstow Market a couple of years ago, was a BEAST to work with, but turned out perfectly in this top!

Here's my adjusted pattern, where I basically added 1 inch around the entire armscye.



As much as I love this top, I am Scott Boy Stoked about these PANTS!!!!!  Using this 90's Simplicity 6544 pattern I made view 2 in a fabulous piece of Japanese Denim B found at Gail K Fabrics in Atlanta.  I would do the zip insert a little differently if I were to make them again, but otherwise they have a neat construction and go together well.  This denim is perfection with a lovely hand and drape.  Being black it was hard to photograph, but here are more than enough shots to feel the love!!!









Thanks for the photos Bentie - and for being the best fabric shopper ever!  - les

Tuesday, August 27, 2019

GET YOUR FLU SHOT!!! Even if you are on immunotherapy!!!!


We're heading into that season!!!  Now, there's this:


Safety of Inactivated Influenza Vaccine in Cancer Patients Receiving Immune Checkpoint Inhibitors (ICI).  Chong, Park, Cohen, Postow, Wolchok, et al.  Clin Infect Dis.  2019 Mar 15.

Cancer patients are at a higher risk for developing influenza (flu) related complications. It is unclear if the flu vaccine exacerbates immune events in patients treated with ICIs.

We conducted an IRB-approved retrospective review of advanced cancer patients on ICIs who received the flu vaccine during three consecutive seasons; 2014-15, 15-16, and 16-17. The primary outcome assessed was any "new onset" immune-related adverse event (IRAE). A subset analysis of vaccinated patients newly treated with anti PD-1 agents (nivolumab or pembrolizumab) was conducted to assess overall IRAE rates for comparison with published clinical trials.

During the three seasons, 370 patients met criteria for ICI and vaccination within ~ two months (65 days). The most common underlying cancers were lung (46%) and melanoma (19%); 61% of patients received anti PD-1 agent only. In the entire cohort, 20% experienced an IRAE (any grade); incidence of grade 3 or 4 toxicity was 8%. No grade 5 events occurred. In the subset of 170 patients newly treated with anti PD-1 agents, overall IRAE rate was 18%, grade 3/4 events occurred in 7.6%. Influenza was diagnosed in 2 patients.

No increase in incidence or severity of IRAE was detected in patients on ICIs who received the inactivated influenza vaccine within ~ 2 months of ICI. For newly treated patients on anti-PDI agents, IRAE rates were comparable to published clinical trials and did not vary with order of administration. Routine seasonal flu vaccination is encouraged in patients on ICIs.

Nuff said!  Get your flu shot!!! - c

Monday, August 26, 2019

31 years with my best friend....


...it doesn't get much better than that.

I love you, Bentie!
You ARE my dragonfly.
...les

Tuesday, August 20, 2019

Sew Chaotically! ~ On the Kalle band wagon...


I've liked so many versions of the Kalle Shirt and Shirt dress by Closet Case Patterns floating around on sewing blogs and IG that I finally made my own!  It's a straight size 10 with the back lengthened by 1 inch and the front by 2 inches, side seams blended to match, and finished with bias binding.

I rounded the collar inspired by and using Lauren's tips from her blog at Guthrie and Ghani
As is true with most patterns, the appearance of the Kalle is much influenced by the material used.  I knew this stiffer cotton would lend the garment a boxy shape, which was the goal for this one.  However, I plan to make up another in a more fluid crepe for a completely different look!
I like it with my newly altered white jeans for now...but it should layer nicely in cooler weather!


Definitely fun to make and wear!  Happy Tuesday, Y'all!!! - les

Monday, August 19, 2019

Antibiotics, gut microbiome and heavier is better in relation to melanoma?????


I've been writing about the cooties in our guts - our microbiome - since 2015.  This post from 2018 includes lots of links to prior articles and reports:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

In June of this year, out of ASCO, the mircobiome was also addressed. I included a report on a couple of their articles here:  The first installment of this year's ASCO review.  That post included:

#6:  The "microbiome" craze is not exactly 'new' as it has taken over the universe! BUT!!!  How much is hype?  How much is real?  How can we drill down on the details?  How can we harness what we know to impact treatments such that patients benefit?  The next 3 posts address this topic.  Now, there's this:

A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.  2019 ASCO.  Shubham, Imke, Amishi, et al. J Clin Oncol 37, 2019 (suppl; abstr TPS2670) 

Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803

Here, researchers are going to give the first 12 patients with solid tumors who have progressed on anti-PD-1, Pembro every 3 weeks along with a capsule of MRx0518, a "live biotherapeutic", taken by mouth, twice a day for one 21 day cycle.  In part b, the plan is that 30 patients could be given the same for up to 35 cycles or until disease progression.  My only concern here would be the fact that we've found that folks who took probiotics from a bottle did not do so well, while those that got their cooties from foods like Kefir, kimchi, yogurt, sauerkraut, etc. - did better.  If I were to consider participation in this study, I'd be asking my doc about that.

#7:  As I noted above, these last two reports are more along the lines of ~ "What once was old is new again!" I've been talking about the Cooties in our Gut since 2015, putting it all together in this post from 2018:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!  Still, there is much we don't understand about how all this works.  Now, there's this:

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5-/- mice.  Li, Tinoco, Elmen, et al.  Nat Commun. 2019 Apr 2.

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

So, a lot of fancy words to say that mice with a certain microbiome component (less UPR expression) responded better to immunotherapy.  Further, when those mice lived with mice whose gut initially did not possess those properties, researchers found that they too developed an altered gut flora and a greater ability to restrict the growth of melanoma.  Bottom line:  Live with somebody who has the right cooties!  (If you can figure out who exactly that is!!!)

#8:  Given the fact that a certain "microbiome" aids our responses to immunotherapy while a different one does not, it makes sense that antibiotics, which kill off bacteria that are trying to do us harm as well as those who may do a body good, could be problematic when trying to foster cooties that improve our response to immunotherapy.  Here are some earlier articles and explanations:

This from 2017:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

And this from April of this year:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!  In that study it was noted that, despite - "Small numbers. ..the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months." 

Now, there's this:

Effect of antibiotic exposure in patients with metastatic melanoma treated with PD-1 inhibitor or CTLA-4 inhibitor or a combination of both.  2019 ASCO. Kapoor, Runnels, Boyce, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14141)

Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed aretrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up.  Results: Out of 108 patients, 66 were men, with a mean age 64.6 ± 15.1 years. 46 patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days] was shorter as compared to abx(-) group [322 days].Patients in abx(-) group had a 68% reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles . Median OS in ab(+) group [294 days] was shorter as compared to abx(-) group [573 days]. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% in abx(-) group as compared to 8.7% ab(+) group. Patients in abx(-) group had a 52% reduced risk of death adjusting for sex, age and number of immunotherapy cycles. Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.

In this retrospective study of 108 melanoma patients treated with immunotherapy, it was noted that 46 were given antibiotics at some point between 6 months prior and 1 month after starting their immunotherapy treatment.  PFS was 88 days in those who took antibiotics and 322 days in the group who didn't.  OS was 294 days in the antibiotic group - 573 days in the non-antibiotic group.  Response rate was 8.7% in the group that had taken antibiotics vs 12.9% in the group that had not been exposed to antibiotics.  As I wrote in the post I put up in April:  "So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways."

Now, there's this:

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer.  Tinsley, Zhou, Tan, et al.  Oncologist. 2019 Jul 10. 

With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI).

This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated.

Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months). Progression-free survival times were similarly affected.

This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics.

Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.

Granted none of the patients in this study had melanoma.  And, as I noted above, if you need antibiotics, they can be essential and life saving.  But - if they are not required - they may cause us more harm than good.

And, finally - this:

Modifiable Host Factors in Melanoma: Emerging Evidence for Obesity, Diet, Exercise, and the Microbiome.  Warner and McQuade. Curr Oncol Rep. 2019 Jul 1.

We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.  Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies. Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.

NO body shaming here!!!!!!!!!!!!  Eat your good cooties (kefir, kimchi, yogurt, saukraut, etc) and live LARGE!!!!!!!!!!!!!! 

For what it's worth! - c

Thursday, August 15, 2019

Sew Chaotically! ~ Metamorphic dress, sun flowers, love and ~ HAPPY BIRTHDAY, Ruthie!


After the successful Metamorphic top, I embarked on the dress!  It's made up in two luscious fabrics:  Telio Viscose Denim in dark blue and Hudson Bay Hand Dyed Rayon Challis in Blue, both from Fabric.com  I cut the size corresponding to my bust measurement (size 10), utilized a one inch side seam on the bodice, and while I shortened the top by 3 inches, here I added 9 inches in length.  Because of the 'flimpiness' of both my fabrics, the dress is fabulously light weight and hangs nicely, though hemming was a bit of a nightmare in trying to keep things even and falling as they should.  In fact, after these pics were taken, I bit the bullet, whacked the muggled-up hem OFF, and completed a baby hem on both which made me much happier!!!  Not sure about the meaning of "FLIMPY"?  This post tells the tale:  Sew Chaotically! - Cute little summer dress ~ McCall's 7242


I love BOTH sides of this dress.  The waterfall color way is incredibly pretty, but I really like having the contrast effect on the "solid" side as well.  Plus, though not completely evident in these pics, the solid fabric has an especially lovely hand and a bit of a sheen to it.  I was super excited to get to wear it on a girls get-a-way with Roo down to Ruthie's!!!  And when Ruthie tells you she has a "special thing we are gonna do!  It's a surprise!" ~ She's for realz!!!!

How cute!!!  What????
Is this not SPECIAL??????
Keep'n it shady!  Yep, that's my Metamorphic dress (Sew Liberated) and check out Ruthie's Celestial dress (Pattern Fantastique) in a fab African Wax Print B picked for her!

Beautiful Roo, unfazed by the insane antics of her auntie and mum!




Thanks so much for a lovely visit, Ruthie!  Thanks for sharing it with me, Roo!  I don't know how I would manage without you two!!!  I am so lucky!!!  Much love to you both.  Happy, happy day Ruthie!!!!! ~ Cess

Wednesday, August 14, 2019

Neoadjuvant ipi/nivo as well as Neoadjuvant BRAF targeted therapy for unresectable melanoma lesions


Could neoadjuvant treatment (melanoma treatment administered BEFORE a lesion is surgically removed or radiated) be the way of future melanoma treatment???  Here's the data so far: Neoadjuvant reports related to melanoma

Now, there's this~

Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection.  Fujimura, Kambayashi, Sato, et al.  Front Med (Lausanne). 2019 Jun 26.

Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented. In addition, CD8+ T cells increased among the tumor-infiltrating lymphocytes that were surrounding melanoma cells and caspase 3+ cells. The present case suggests that pre-surgical administration of nivolumab with ipilimumab could be the optimal therapy for the treatment of unresectable advanced melanoma.

Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma.  Eroglu, Eatrides, Naqvi, et al. Pigment Cell Melanoma Res. 2019 Jul 22. 

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible.

A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging and clinical outcomes were evaluated.

Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST-response based on preoperative imaging and pathologic response. After a median of 43 months follow-up, only 1 patient (10%) with a pCR recurred; while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor.

Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS. 

Overall, still early days, but neoadjuvant treatment may be very good news for many melanoma patients, especially those for whom surgery is not an option.  Hang tough ratties!!  ~ c

Friday, August 9, 2019

Sew Chaotically! ~ #alteritaugust or #refashion - you choose!!!


I've been making and remaking garments for awhile. Some outcomes were more successful than others.  Here are a few highlights:

Roo's old running tees worked into a "quilt":  T-shirt quilt with Roo

Work tees also transformed into a quilt as well as exercise tops:  Refashion! (It covers a lot!)

Reworking a sweater, a project that provided lots of laughs with SAD results:  It's Sooooo bad!!!

Dresses to skirts are easy refashions!  One is a bit buried in this post:  Toaster sweater, refashion and plans!  There's this one:  Me mades - refashioned  And here, Roo's frumpy dress became a skirt AND a top, while my old knit skirt was transformed into a cute and comfy Niko top:  REFASHION!!! Skirt to Nikko and dress to useful separates

The Polly top, a fab FREE pattern from By Hand London, is a great way to use scraps or pieces from existing clothes that need an upgrade!  This post covers two!  Fabric from an old sweater comprised the center front piece on the pink one and an unused scarf found a beautiful new life as the back and contrast front piece in the version I made for Roo:  Another By Hand London, Polly Top

Sewing allows all of us to create new garments just as we wish them to be, transform old bits and bobs into something fresh, or adjust the fit of existing garments.  Sew!  Newly inspired by Mia, of Sew North's #alteritaugust sewing challenge, I FINALLY got around to adjusting a pair of rtw white jeans to fit my bootie.  Despite my slender build, I have chronically had problems with the waist band on many rtw pants standing up in the back rather than cinching in and laying flat as it should - often placing a couple darts in the band until I started making my own!!!  Not a very eloquent solution, but it was fast and did the job.  One reason I'd put off adjusting these particular pants was the fact that darts were not enough to solve the problem!!!
As you can see from this older pic, the front is terribly baggy too!!!
Forgive the plethora of bootie pics coming your way - butt... (Ha ha ha!!  I crack myself up!!!)

Pretty good, no?  To create this fix, I took off the center back belt loop and the waist band from the back of the pant for about 4-6 inches to either side of the center back seam.  Took the center back seam apart all the way down to the crotch. Fitted and stitched the seam back together.  Serged and trimmed away the excess and top stitched the seam back down.  Took a chunk out of the waist band, restitched it together, such that that seam would be hidden beneath the belt loop when it was reattached, then re-fixed the loop and waist band to the pant!  Literally a pain in the pa-toot to do, but well worth it now that I have a more wearable pair of pants!!
Look!!  The waist band actually FITS my waist!!!
And the front is now the "flat front" it should have been all along!
Thanks, Mia!  Your challenge was just the kick in the pants I needed!!!  #alteritaugust and sew chaotically! ~ les

Thursday, August 8, 2019

Treating melanoma by COMBINING targeted therapy AND immunotherapy!!


As usual, I've written on this topic previously:

As long ago as 2015, there was this:  BRAFi better when combined with or after immunotherapy and surgery!!!

And this in 2016:  BRAF/MEK combined with immunotherapy!!!

This from 2017:  The whole she-bang - immunotherapy WITH BRAF/MEK for melanoma...

This from ASCO 2017:  ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

Now there are these reports (highlights = my own):


Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.  Ribas, Lawrence, Atkinson, Agarwal, ..., Hodi, ..., Hamid.  Nat Med. 2019 Jun;25.

Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumabNCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.  Sullivan, Hamid, Gonzalez, et al.  Nat Med. 2019 Jun;25.


Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8%. The estimated median duration of response was 17.4 months with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.  Hellmann, Kim, Lee, et al.  Ann Oncol. 2019 Mar 27.

Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a PD-L1 inhibitor, atezolizumab, in patients with solid tumors.

This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary endpoints included ORR, PFS and OS.

Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received greater than/= to 1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had mCRC (n = 84), melanoma (n = 22), NSCLC (n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%) and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.

Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.

So - small numbers.  Pretty significant toxicity.  Only effective in the roughly 1/2 of melanoma patients who are BRAF positive.  Looks like BRAF/MEK with anti-PD-1/PD-L1 is demonstrating a 70% objective response rate while anti-PD-L1 with a MEK inhibitor alone attained a 40% response rate (ie = no better than the ipi/nivo combo).  Again, no matter the result...small numbers treated (only 37 melanoma patients total were in the first and last studies reported here - and Hamid et al ain't sharing their #'s unless you buy the paper - FYI).  Still, throwing the "kitchen sink" at melanoma may be a worthwhile treatment for some.

Hang tough ratties!!! - c