Sew Chaotically! ~ She's done! B's Valentine Quilt...

Such a lot of learning and fun went into this quilt.  It developed over years as I collected bits of cloth left over from garment making.  Seeing Julie Lou's Carolina Chain Quilt was a real inspiration.  The realization that I'd need to practice before I embarked on my Sashiko Quilting Project especially since B made me an incredible Quilting Frame nudged this particular quilt to life!  I read many books and blogs, but as ever, the real learning began with simply beginning.  B helped me figure out loading the frame.  I think we did well. I did learn - in the end - that attaching the pieces to be quilted to the free edge of the leaders is best.  I quickly realized I did not possess the skill to create the teeny tiny stitches and delicate designs that some lovely quilters employ.  While I find their work beautiful, I know that even had I their talents, their style would not really fit my life nor this rustic quilt top.  From there I decided on a simple stitch, made as evenly as I could, using DMC cotton perle, #8 to frame the linear 'diamonds' in both directions.  To do this on my frame, I stitched up and away from me as far as the frame allowed for the rows perpendicular to the frame, leaving the threads hanging forward.  Then, I stitched to my left on both sides of the rows horizontal to my frame.  Once that section was complete, I rolled the quilt toward me to complete another section, picking up the threads where I had left off.  A simple linear, diamond pattern was used in the solid areas on the quilt edges.  These were marked prior to loading the quilt with a hera marker and stayed perfectly visible through the quilting process, the indentions washing out nicely after it was done.  The quilting along the rows was completed by stitching roughly 1 cm from the seams.  As I learned in making the top, utilizing a variety of fabrics made the quilting a bit more difficult than it would have been had they been consistent, as did quilting along all the seams, but it was worth it.  Both in making these random scraps useful and creating the design I wanted to achieve.  So...here she is ~   

Initially, I thought I was making this quilt as a house warming gift for a dear one, whose color preferences align very much with my own.  However, as I stitched, B's love and encouragement colored all the stitches.  He would mention his memories of the fabric purchases or the garments the scraps were from as he checked on my progress.  His lovely frame and endless encouragement made it all possible.  So as I stitched, as though with a mind of its own, this quilt became his!!!  As it should be!  In time, quilts for others will be purposely made.  But the love in these stitches and this project, belong to him.  Thanks, B! 

It looks right at home in his chair, doesn't it?

I am so pleased with what this room has become.  Most of the furniture purchased more than 30 years ago.  Books we love.  B's art.  My handmade afghans, poof, and pillows.  This - is us.  Happy Valentine's day, B!!!  ~ love, les  

The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants!

We have known that the bacteria, good and bad, within our intestines impact our health in ways, good and bad, for far longer than the current run of research and discussion of the microbiome sometimes remembers.  I posted this in 2015 - and it was old news then:  Cooties in our gut keep us skinny, smart and cure cancer!?????   For more on all things microbiome there are these:  The intestinal microbiome

Now, there are these additional reports:  

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients.  Peters, Wilson, Moran, et al.  Genome Med. 2019 Oct 9.

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression

Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up. Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis.

This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

NOTE:  While what follows is positive news, many reports have shown that taking probiotics from a bottle do not provide the help our intestinal microbiome really needs, while a diet high in fiber and live cultures like those within yogurt, kefir, sauerkraut, and kimchi does.  Now, this:

Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth.  Li, Elmen, Segota, et al.  Cell Rep.  2020 Feb 11.

Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process.

When you need your cooties to work for you, it makes sense that killing them off with antibiotics would not serve you well.  Clearly, the development of antibiotics has prolonged and saved untold lives.  However, when they end up in the food chain, are used to treat viruses (for which they do NO GOOD) or are otherwise used inappropriately, real harm can result.  Not the least of which is a poor response in melanoma patients to immunotherapy.  There have been many concerning reports - Antibiotic use may diminish the positive effects of immunotherapy  

Now - there's this:

Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: An up-to-date systematic review and meta-analysis.  Yang, Wang, Yaun, et al.  Int Immunopharmacol.  2020 Aug.

Objective: Immune checkpoint inhibitors (ICIs) have recently achieved inspiring performance in improving the prognosis of various solid tumors. Gut microbiome plays a crucial modulatory role in the efficacy of ICIs, which can be influenced by antibiotic (ATB) administration. In this meta-analysis, we aimed to clarify the correlations of ATB administration with the prognosis of solid cancer patients receiving ICI treatment.

Method: The eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before 29 February 2020. The correlations of ATB administration with overall survival (OS) and progression-free survival (PFS) were determined using Hazard ratios coupled with 95% confidence intervals.

Results: A total of 33 studies enrolling 5565 solid cancer patients receiving ICI treatment were included in this meta-analysis. As a whole, ATB administration was significantly correlated worse OS  and PFS. This significant association was then observed in the subgroup analysis based on region (except for OS in Europe), sample size, age, therapeutic strategy and ICI type. The similar results were also found in subgroup analysis for lung, renal cell (except for OS) and other cancers (such as melanoma) but not for mixed cancers. In addition, the ICI efficacy was more likely to be diminished by ATB administration within a time frame from 60 days before to 60 days after ICI initiation.

Conclusion: ATBs should be used cautiously in solid cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

And this:

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI).  Creen, Bertrand, Deley, et al.  Oncoimmunology.  2020 Nov.

Background: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota's composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. 

Methods: Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient's first ever course of ipilimumab. The primary outcome was overall survival. 

Results: We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection. In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival. 

Conclusions: In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient's first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.

In 2017 I reported on the positive effects of fecal transplants in poor little cancer affected mice - Back to the cooties in our guts....again!!!  Now, there seems to be a real benefit of same, for melanoma ratties!

Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients.  Davar, Dzutsev, McCulloch, et al.  Science. Feb 2021.

The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy. Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

 

Certainly something melanoma peeps who are not responding to anti-PD-1 might wish to discuss with their docs! 

And that brings us up-to-date with the most recent bits and bobs regarding the cooties in our guts!   Kefir smoothie, anyone? - c

Neo-adjuvant care for melanoma patients with BRAFi or immunotherapy continues to show good results!

As I mentioned in regard to adjuvant therapy in melanoma a couple of posts ago - initially, CLND (complete lymph node dissection - the removal of all lymph nodes in the area of a positive node) was recommended for melanoma patients.  Gradually, we learned that such a procedure merely increased the rate of complications like lymphedema, but did NOT extend overall survival in patients.  (Review the posts and articles that pop up when you enter 'CLND' in the search bubble at the top right if you want to check out tons of research that went into that decision over time.)  As the data was revealed, changes in the standard of care followed.  Today, SLND (sentinel lymph node dissection - the removal of only the node - occasionally 2 or 3 - that 'light up' nearest the initial lesion when the area is injected with radiographic material) is the recommended procedure.  Standard of care also recommends that these patients are then treated with adjuvant therapy (treatment provided once all gross evidence of tumor has been removed) utilizing either targeted or immunotherapy.  This standard of care, led to the approval of immunotherapy for adjuvant use in 2017 and for targeted therapy in 2018.  

That said - there is a "new" methodology in town!  NEO-adjuvant therapy ~ Therapy for melanoma patients with either targeted or immunotherapy when affected nodes are left IN PLACE!  I began reporting the data on this method in 2015. Find reports addressing it here:  Neoadjuvant treatment in melanoma 

Now, there's this:

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).  Menzies, Amaria, Rozeman, et al.  Nature Medicine.  Feb 2021.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%,) and OS (pCR 2-year OS 95% versus no pCR 83%). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.

The positive nature of this data is even making it to the lay press for medical advances.  This link takes you to - Melanoma breakthrough: New treatment saving lives - Published in Medical X-press today.

It seems data collected for over 6-plus years indicates that if you find yourself in the position of a Stage III melanoma patient, consideration of leaving any positive node(s) in place and availing yourself of treatment with either BRAFi or immunotherapy BEFORE that node is removed is one worth discussing with your oncologist. 

For what it's worth.  Perhaps a new way of looking at melanoma treatment, especially for Stage III patients, may be in the offing. - c

Results for Stage III melanoma peeps who recurred after adjuvant targeted therapy

The positive benefits noted in yesterday's update on adjuvant therapy for Stage III melanoma - utilizing immuotherapy as well as targeted therapy in the form of BRAF/MEK inhibitor combos - have been practically miraculous in preventing many melanoma patients from advancing to Stage IV and even death.  Despite the benefits, there are still those whose melanoma does recurr.  This report addresses outcomes of melanoma peeps who advanced after taking BRAF/MEKi as adjuvant targeted therapy.

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.  Bhave, Pallan, Long, et al.  Br J Cancer. Feb 2021.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy.

Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

So - in folks who were given targeted therapy as adjuvant treatment for their Stage III melanoma - 22% recurred.  Recognizing the small numbers in this break down - responses to treatment that they were given at that relapse point follows:

anti-PD-1 garnered a 63% response rate

ipi/nivo  = 62% RR

targeted therapy rechallenge = 25% RR

ipi as a single agent = 10% RR

33% of the relapsed patient died of melanoma.  

The two year overall survival for those treated with anti-PD-1 = 84%, ipi/nivo = 92%, targeted therapy = 49%, ipi alone = 45%.

Pretty clear to me.  If you relapse, go for the ipi/nivo combo.  Not that we didn't already know that! - c

Melanoma - All things adjuvant

I have kicked and screamed about the need for adjuvant treatment for so many years (especially the more effective anti-PD-1 products vs ipi) that it was almost unbelievable when they were finally FDA approved for adjuvant use in 2017 (Opdivo) and 2019 (Keytruda).  Sadly, recent trial results for the ipi/nivo combo as adjuvant did not prove more effective - providing instead only a greater side effect profile.  Here's a history of adjuvant care in melanoma - ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....   At this point, targeted therapy in the form of BRAF/MEKi combo's, for BRAF positive patients, and NEO-adjuvant treatments are also available for melanoma patients in need of such care.  Here are zillions of adjuvant related reports - Adjuvant care in melanoma

Now, there are these (my comments in red as ever):

Adjuvant Therapy is Effective for Melanoma Patients with a Positive Sentinel Lymph Node Biopsy Who Forego Completion Lymphadenectomy.  Farrow, Raman, Williams, et al.  Ann Surg Oncol, 2020 Dec 27.

Background: Multiple adjuvant therapies for melanoma have been approved since 2015 based on randomized trials demonstrating improvements in recurrence-free survival (RFS) with adjuvant therapy after surgical resection of high-risk disease. Inclusion criteria for these trials required performance of a completion lymph node dissection (CLND) for positive sentinel lymph node (pSLN) disease.

Objective: We aimed to describe current practice for adjuvant therapies in patients with pSLN without CLND (active surveillance [AS]), and to evaluate recurrence in these patients.

Methods: Melanoma patients with pSLN between 2016 and 2019 were identified at two institutions. Demographic information, disease and treatment characteristics, and recurrence details were reviewed retrospectively. Patients were stratified by recurrence and patient-, treatment- and tumor-related characteristics were compared using Fisher's exact test and t test for categorical and continuous variables, respectively.

Results: Overall, 245 SLN biopsies were performed, of which 36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom 22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1) inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred, including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did not. Tumor ulceration was significantly associated with recurrence. While not significant, acral lentiginous subtype appeared more common among those with recurrence.

Conclusion: The majority (68.8%) of patients with pSLN managed without CLND were treated with adjuvant therapy. The 1-year RFS for patients managed with adjuvant therapy without CLND was 82%, which is similar to modern adjuvant therapy trials requiring CLND.

Back in the day, including when I was first diagnosed in 2003 and when I recurred in 2007, patients were routinely treated with a complete lymphadenectomy (CLND) of the area around a positive lymph node.  I went through it twice, to both axilla.  Times have changed and the process of CLND is no longer recommended.  In fact, NEO -adjuvant treatment is being studied to see if starting treatment with the positive node in place provides better results and the data is looking positive.  In this report, researchers were looking for differences between melanoma peeps who had a complete lymphadenectomy and those who simply had the positive node removed and started adjuvant treatment.  Of 245 sentinel node biopsies they examined - 36 were positive.  Of those, 4 patients had CLND and 32 had only the positive node removed.  22 were given adjuvant treatment - 16 were treated with nivo, 3 with ipi, and 3 with BRAF/MEK.  At 13.3 months of follow-up - 7 of the 32 patients had recurred - 4 of whom had been treated with adjuvant therapy (abstract does not note which) and 3 had not.  Tumor ulceration was significantly associated with recurrence (which is not news).  Overall, the patients who had adjuvant treatment after a positive node, but NO CLND had a recurrence free survival rate of 82% which is similar to patients who were given a CLND and adjuvant therapy.  Again, this is no longer news, rather confirmation of what we have understood for some years now.

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  2020 Nov.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients and methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual, stage IIIA (at least one lymph node metastasis greater than 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups

At three years follow up, Stage III patients of all stripes did better after treatment with Pembro than those treated with placebo - demonstrating a recurrence free survival rate of 63.7% for those treated with pembro vs 44.1% for those given placebo.  YEP.

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.  Rauwerdink, Molina, Tompers, et al.  Ann Surg Oncol.  2020 Dec.

Background: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era.

Methods: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs.

Results: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%).

Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.

This study looked at 102 resected Stage III and Stage IV patients. (Stage III patients whose positive node was removed as well as Stage IV like me when I entered my Phase 1 Nivo trial in 2010, whose metastatic disease had been removed.)  46 were given adjuvant anti-PD-1.  3 were given BRAF/MEKi.  26 had surgery alone.  At 17 months 20% of those treated with anti-PD-1, 13% treated with targeted therapy, and 42% of the surgery-only patients had recurred.  Recurrence free survival lasted an average of15 months for anti-PD-1 patients, 18 months for the BRAF/Meki group, and only 12 months for those given surgery alone.   {While this type of data analysis of outcomes of adjuvant therapy is much needed - TAKE THESE NUMBERS WITH A HUGE GRAIN OF SALT!!!!!  THE 46 patients treated with anti-PD-1 and 26 given surgery only -is barely sufficient to make valid statistical analysis possible; the THREE treated with BRAF/MEKi does NOT!!!!!!!!!!!!!!!!!!!!}

The data presented in the reports included in this October 2020 post New follow-up data confirms effectiveness for targeted and immunotherapy as adjuvant in melanoma patients!!! is much better! To whit ~ 

From Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.  Drummer, Hauschild, Saninami, et al.  New England Journal of Medicine.  September 17, 2020.  

870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos.  At 5 years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.

From Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  September 18, 2020.

1,019 patients with complete lymph node dissection ofcutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity.   3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively.

From Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.  Ascierto, Del Vecchio, Mandala, et al.  Lancet Oncol.  September 18, 2020.

906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months with nivolumab and 50·9 months with ipilimumab; 4-year recurrence-free survival was 51·7% in the nivolumab group and 41·2% in the ipilimumab group. With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths, 4-year overall survival was 77·9% with nivolumab and 76·6% with ipilimumab.

NOW - even with all this - it is hard to compare THESE numbers! (Though they are clearly more statistically valid than those noted in the article I started with and also demonstrate the falseness of the claim those authors purport in the last sentence of their abstract!!!!!)  To that end,  I noted when I published them - 

So, there you go.  ALL of these adjuvant therapies provided Stage III/IV melanoma patients whose obvious disease was removed via surgery or radiation better results - no matter if they were treated with ipi, nivo, pembro or the dabrafinib/trametinib combo - than when they were left untreated.  Per these reports, here's how things panned out ~

Dabrafinib/trametinib - at 5 years, stage III melanoma patients alive without relapse was 52% with treatment vs 36% with placebo.

Pembrolizumab (Keytruda) - at 3 years, Stage III melanoma patients with recurrence free survival was 63.7% when treated with pembro, vs 44.1% for placebo.

Ipilimumab (Yervoy) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 41.2%.  4 year overall survival was 76.6%.

Nivolumab (Opdivo) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 51.7%.  4 year overall survival was 77.9%.

My thoughts:

The fact that Stage IV patients were included in the study looking at adjuvant ipi and nivo (CheckMate 238 trial) is HUGE!!!!!!  It makes comparison to the studies using pembro and the dabrafinib/trametinib combo as adjuvant in Stage III peeps ONLY, difficult to say the least.   I would really like to see an adjuvant study in Stage III melanoma patients where Keytruda and Opdivo are compared head to head, using the exact same result parameters and time frames.  I doubt there would be any significant difference in results as that has already been found to be the case when those agents are used in treatment of Stage IV melanoma patients - but still.  And finally, while the numbers for adjuvant ipi weren't that bad, and certainly much better than placebo, the side effects were greater - so I don't find ipi as a single agent a good choice for adjuvant therapy given the other options.

FYI - Time frames of follow-up matter.  As time goes on, more peeps have a chance to progress.  So data at three years is often better than outcomes reported at five years.

For instance in this article:  2017 - Nivo better than ipi as adjuvant  The data (drawn from Stage III AND Stage IV melanoma patients who took the drugs as adjuvant) demonstrates this:

Recurrence free survival at 12 months:

70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:

66.4% for nivo                    52.7% for ipi

That is why it is important to compare apples to apples in all aspects.  c

KEYNOTE-695 Interim Data - Pembrolizumab (Keytruda) combined with TAVO (intratumoral plasmid IL-12 ~ tavokinogene telseplasmid)

In July of 2020 I posted on the combo of TAVO and Pembro here -  Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro  That is:  "intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab".

Now there is this from November 2020 ~

OncoSec Announces Positive Interim Data from KEYNOTE-695 Trial in Anti-PD-1 Checkpoint Refractory Metastatic Melanoma at SITC 2020

The report notes:

-- 30% overall response rate (ORR) and 6% complete response (CR) rate achieved 
-- 35% ORR achieved in patients with Stage IV M1c or M1d disease 
-- TAVO + pembrolizumab demonstrated durable responses for up to two years

TAVO + KEYTRUDA led to a 30% ORR in the first 54 out of 100 planned patients. This interim investigator assessed ORR is much higher than the primary efficacy endpoint for the study, which is a 20% ORR determined by blinded independent review.  The data were selected for a Poster Walk discussion and will be additionally presented in the virtual Poster Hall on Wednesday, November 11 and Friday November 13 and as part of a Company Symposium on November 11th at the Society for Immunotherapy of Cancer (SITC)'s 35th Anniversary Annual Meeting.

"Achieving an overall response rate of 30% with several complete responses and no serious adverse events is extremely encouraging for checkpoint resistant metastatic melanoma patients who currently rely on systemic administration of immune-stimulating drugs  associated with severe toxicity. The data reported, in addition to its ease of use, demonstrate the potential of TAVO in combination with pembrolizumab as a next-generation intratumoral IL-12 therapy that can induce regression of both locally treated and untreated distant and visceral lesions," said Paolo A. Ascierto, M.D., Director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, Italy.

Key highlights of KEYNOTE-695 include:

• Of the first 54 out of 100 planned patients ~

• ORR was 30% (95%CI [18.0%, 43.6%]) (16/54)

• Complete response rate was 6% (3/54)

• All responses were confirmed by scans taken no earlier than after 6 months on study

• 9% (5/54) patients had 100% reduction of target lesions

• ORR was 35% (n=6/17) in patients with Stage IV M1c/M1d disease

• ORR was 40% (n=6/15) in patients with prior exposure to ipilimumab

• Median duration of response (mDOR) is currently 12.2 months

• Median study follow-up was 13.5 months

• Excellent safety profile resulting from intramural treatment approach

• Only 5.4% Grade 3 treatment-related AEs

• No grade 4/5 treatment-related AEs

• This study enrolled rapidly progressing patients with a short interval of 1.2 months (median) between the last dose of anti-PD-1 and study treatment

Adil Daud, M.D., a  Professor of Medicine at The University of California, San Francisco, Director of the Melanoma Clinical Research, and lead author of the study added, "the TAVO-electroporation (TAVO-EP) delivery system works by optimizing cellular uptake of DNA-based IL-12 in the tumor microenvironment, leading to local, sustained production of IL-12 in the tumor, where it matters, with negligible systemic exposure.  This recruits and primes immune cancer-fighting cells in the tumor leading to systemic immune responses without systemic toxicity. The totality of the safety and efficacy data establishes TAVO-EP as a best-in-class intratumoral therapy."

Daniel O'Connor, Chief Executive Officer of OncoSec, added "Patients with recurrent metastatic melanoma are in great need of effective treatment options. We believe this data demonstrates not only strong levels of efficacy, but also very low treatment related adverse events with the TAVO + pembrolizumab combo. This, combined with its ease of administration to accessible lesions within minutes in an outpatient setting, plus TAVO's low-cost/simple manufacturing process and its off-the-shelf availability, build a strong case that the TAVO + pembrolizumab combination, in a real-world setting, could equip clinicians with more options for their patients."

Results are still not as good as those achieved with the ipi/nivo combo.  But, for those who can't tolerate that treatment or remain in need of additional treatment, this combo may be a viable option.  For what it's worth! - c

Advanced Melanoma - A smattering of 2020 literature for Stage IV peeps

Unfortunately, though some promising trials are underway, no major breakthroughs have occurred in melanoma research of late.  Still, there are studies and data that are meaningful.  Here is a collection of reports that may be valuable to Stage IV melanoma peeps.  (My comments in red.) -

Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.  Farrow, Turner, Salama, Beasley.  Oncol Ther. 2020 Dec.

Introduction: Since 2011, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.

Methods: Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient, tumor, and facility characteristics.

Results: Of 268,668 patients, 136,828 were classified as historic and 131,840 as contemporary. Among all stages, immunotherapy utilization was significantly higher among contemporary patients. Adjusted OS was improved in the contemporary cohort. There was no difference in OS among stage I/II patients between groups, while OS was significantly improved for contemporary stage III/IV patients. Among stage III/IV patients who received immunotherapy, OS was improved for the contemporary cohort.

Conclusions: Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease, particularly those that received immunotherapy and BRAF/MEK targeted therapies.

Confirmation of what we already know - targeted therapy (BRAF/MEK combo's) for BRAF positive melanoma patients and immunotherapy - have made a world of difference for melanoma peeps.  

Systemic Therapy for Melanoma: ASCO Guideline.  Seth, …Kirkwood, Kudchadkar…Weber, Agarwala, Ascierto, …, Faries… Robert,…Sondak, et al.  J Clin Oncol, 2020 Nov 20.

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.

Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. 

YEP!

Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma.  Robert, Long, Brady, et al.  J Clin oncol.  2020 Nov.

Purpose: The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein.

Patients and methods: In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Results: Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.

Conclusion: Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.

So over comparing any melanoma treatment with dacarbazine.  At the onset of this study, I suppose it was okay - but hopefully we are well past that now!!!  At any rate - important points are just relative to nivo only treatment and survival.  Overall response rate was 42%.  Of patients alive at five years ORR was 81%.  Of the patients on nivo with a complete response, 88% were alive at 5 years.  Of nivo treated patients alive at 5 years - 83% had needed no additional treatment, 23% were still on treatment, and 60% were treatment free.

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).  Hodi, Chapman, Sznol, et al.  Melanoma Res.  2020 Nov.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged greater than/equal to18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82%  and 70%, respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Again - ipi/nivo with better survival than nivo alone, though with a more significant side effect profile.

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.  Marcaillous, Linder, Chaltiel, et al.  Melanoma Res. 2020 Dec.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017. Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group and 27.26% in the other group. The cumulative incidence was 9.49% in the anti-PD-1 group vs 30.11% in the other group . In multivariable analysis, anti-PD-1 reduced the risk of brain metastases by almost 70%. The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

Yep.  Been yelling it for over 10 years!!!  Immunotherapy works in the brain.  Folks treated with anti-PD-1 had an incidence of brain met development of 9.49% vs 30.11% in patients not treated with anti-PD-1.  Analysis found that anti-PD-1 reduced the risk of brain mets by almost 70%.

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Ribas, Algazi, Ascierto, et al.  Nat Commun.  2020 Dec.

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

In this trial of either Durvalumab (anti-PD-L1) combined with dabrafenib/trametinib or just with trametinib or given sequentially - patients given the combination of the three drugs had a 69.2% response rate, of the 2 a response rate of 20% and in the sequential group (not clear, but I suspect that they got the three drugs) a response rate of 31.8%.  For comparison here is a report on atezo and pembro when combined with a BRAF/MEK therapy from 2019 that includes links to other reports of results when immunotherapy was combined with targeted therapy - Treating melanoma by COMBINING targeted therapy AND immunotherapy!!  When atezo and pembro were combined with a BRAF/MEK combo - responses rates were 70+%.  Of course, this treatment option is only available to about half of us as patients need to be BRAF positive.

Chemotherapy combined with antiangiogenic drugs as salvage therapy in advanced melanoma patients progressing on PD-1 immunotherapy.  Wang, Weiran, Zhihong, et al.  Transl Oncol. 2020 Nov.

Background: This study aimed to evaluate the effect of salvage therapy with nab-paclitaxel (nab-p) or temozolomide (TMZ) combined with antiangiogenic drugs in programmed death 1 (PD-1) inhibitor-resistant patients with unresectable metastatic melanoma.

Methods: We conducted a retrospective review of 69 metastatic melanoma patients who received nab-p or TMZ combined with antiangiogenic drugs after developing PD-1 inhibitor resistance and were treated at the Beijing Cancer Hospital between 2016 and 2019. The disease control rate (c-DCR) and progression-free survival (c-PFS) of salvage CA (chemotherapy combined with antiangiogenic drugs) regimens were investigated. Univariate and multivariate analyses were performed to evaluate the clinical pathological factors affecting the outcomes. Then, a nomogram was formulated to predict the probability of 3-month and 6-month c-PFS based on the multivariate analysis results.

Results: The c-DCR was 63.8%, and the median c-PFS was 3.0 months. In the univariate analysis, factors associated with the c-DCR were included the melanoma subtype, baseline platelet-to-lymphocyte ratio (PLR) and best response status to PD-1 inhibitors. Factors influencing c-PFS included age, baseline lactic dehydrogenase, PLR, neutrophil-to-lymphocyte ratio (NLR), PFS duration of anti-PD-1 therapy (p-PFS), and the best response and progression pattern of PD-1 inhibitors. In the multivariate analysis, age <65 years, heterogeneous progression pattern and baseline PLR<200 were significantly associated with improved c-PFS. The concordance index (C-index) of the nomogram was equal to 0.65.

Conclusions: CA regimens demonstrated promising effects in PD-1 inhibitor-resistant patients. The nomogram could be a valuable predictive module for salvage therapy choice in PD-1 inhibitor-resistant patients.

So these peeps created a fancy scale to determine whether a chemo cocktail would provide 3 vs 6 months of progression free survival in unresectable Stage IV melanoma folks who had become unresponsive to anti-PD-1.  Sad thing to face.  But, if this formula works, perhaps it can provide patients with knowledge that may inform their decision to accept or decline such therapy.

So there you have it.  Final 2020 reports in review for advanced melanoma patients - my take, anyway.  Over the coming days, I will plow through some other 2020 research on other topics pertinent to melanoma.  Stay safe.  Wear a mask.  Get a COVID vaccine when you can.  - c