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, BRAF^V600mutation-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), BRAF^V600-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.gov, NCT01972347, 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

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

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

31 years with my best friend....

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

I love you, Bentie!

You ARE my dragonfly.

...les

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

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

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