The Microbiome and melanoma - (Yes, again!) - Fecal transplants help folks who aren't responding to immunotherapy while antibiotics do NOT!

For those of you who have flipped through a few of my pages, you already know that I've been talking about the cooties in our guts for years with my first post in 2015 and this post - The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants! - earlier this year.  Now there are these...

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

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.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.  Baruch, Youngster, Ben-Betzalel, et al.  Science.  Feb 2021.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

As weird as all this sounds - fecal transplantation may be something to talk to your doc about if you are having trouble getting a response to immunotherapy!

Antibiotic use and the subsequent diminished response to immunotherapy has been noted here before - now this ~

Effects of Antibiotic Use on Outcomes in Cancer Patients Treated Using Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.  Yu, Zheng, Gao, et al.  J Immunother. Feb 2021.

Antibiotic (ATB) use seems to negatively affect the outcomes of immune checkpoint inhibitors (ICIs). The aim of this review is to clarify whether ATB use influences the efficacy of ICI treatment in cancer patients. Databases of MEDLINE, Embase, and Cochrane Library were searched for reports published in English between January 2007 and December 2019. We included studies that compared the outcomes of ATB use and no-ATB use in cancer patients using ICIs. Two reviewers independently selected eligible studies and extracted the data. Meta-analysis was performed with pooling of unadjusted hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and with pooling of odds ratios (ORs) for objective response rate (ORR). Thirty-eight studies involving 8409 patients were finally included for qualitative or quantitative analyses. Cancer types included renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, melanoma, gastrointestinal cancer, and others. Meta-analyses revealed that ATB use was associated with poor OS, PFS and ORR. Subgroup analysis found that these relationships were not influenced by cancer type or ICI regimens, but were dependent on the timing of ATB use. Narrative results of multivariable analyses further confirmed the negative effects of ATB use on OS and PFS. In cancer patients using ICIs, pre-ATB use close to the start of ICI treatment (within 60 d) was detrimental to outcomes in terms of OS, PFS, and ORR.

Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.  Tsikala-Vafea, Belani, Vieira, et al.  Int J Infect Dis. 2021 May.

Objectives: Observational and experimental studies suggest that the use of antibiotics close to administration of immune checkpoint inhibitors (ICI) can have a negative effect on tumour response and patient survival, due to microbiome dysbiosis and the resultant suppression of host immune response against neoplastic cells.

Methods: A systematic search of PUBMED and EMBASE was undertaken for studies published between 1 January 2017 and 1 June 2020, evaluating the association between the use of antibiotics and clinical outcomes in patients with cancer treated with ICIs. A meta-analysis of the association between the use of antibiotics and clinical outcomes was also performed.

Results: Forty-eight studies met the inclusion criteria (12,794 patients). Use of antibiotics was associated with shorter overall survival and progression-free survival, decreased response rate and more disease progression. The negative association between the use of antibiotics and progression-free survival was stronger in patients with renal cell carcinoma or melanoma compared with lung cancer. 

Conclusions: Recent use of antibiotics in patients with cancer treated with ICIs was associated with worse clinical outcomes. Such patients may benefit from dedicated antimicrobial stewardship programmes.

As I've said before, when really needed, antibiotics can be life saving.  However, I would have some tough meaningful talks with my doc about whether I absolutely needed antibiotics were I facing initiation of immunotherapy.

Finally, from all these years of looking at microbiome data as it relates to immunotherapy and melanoma in particular combined with nutrition course work, my best advice is:  Eat your veggies.  Up your fiber.  Boost your own gut cooties by including yogurt, kefir, kimchi, sauerkraut, and other culture rich foods in your diet.  Take antibiotics ONLY if absolutely required - especially before or at the start of immunotherapy treatment. Discuss your microbiome with your oncologist - and if they act like you're talking out your patoot - it might be a sign that you need a new one!!!

Take care, melanoma be crazy! - c

Sew Chaotically! ~ Maison Fauve - The Sparrow Shirt! (And a little Tate Top out of the scraps!)

Maison Fauve has so many pretty designs.  Though the patterns are in French, between common sense, B's translation and in the case of the Sparrow - a sewing video on the site - they go together easily!  This past winter, I made several Bob Fauve - the cutest hat, easily stitched and FREE!!!  

On to The Sparrow, another early spring make from shirting purchased at Mood in what seems a lifetime ago!!!  As seen in the link, Sparrow comes in a male and female version.  Both with a hidden front button placket and lots of ways to individualize.  Mine has bracelet sleeves and a fixed cuff.  I may have to make one for B!!! Much like Orageuse and Republique du Chiffon, size 40 was perfect for me.

Isn't that collar detail the cutest????  And because I think the FREE Tate Top by Workroom Social is just PERFECT for summer - 

I made another with the remaining bit of shirting.  I can't begin to tell you how much wear it had!!!  This fabric is perfect for dressing up or down.  Check out either of these excellent pattern makers.  I know you won't be disappointed!  Happy sewing! ~ les

September Reads ~

The Book of Two Ways - Jodi Picoult.  I really liked this book.  It made me think about how we get to where and who we are.  How way leads on to way.  I have loved being a nurse and nurse practitioner.  Spending my life taking care of children still seems what I was simply meant to do. But, had I not gotten the scholarship to my community college, had the recruiter from a hospital in Chattanooga not come down just as I was graduating, planning for a job in Pensacola - where would I be now?  Who would I have become?  If I hadn't been a nurse, I would love to have been an archeologist or journalist.  Since first reading about the digs and tells in Agatha Christie's Come, Tell Me How You Live ever so many years ago, seeing ancient sites in Athens, incredible pieces in the British Museum - goodness!  I still long to travel to Syria. Istanbul. Egypt.  Picoult's tale brings such thoughts to mind in the midst of a love story.  Enjoy.

The Paris Wife - Paula McLain.  The story of Hemingway's life in Paris in the 20's, told by his first wife, Hadley, herself.  While McLain's work is categorized as historical fiction, having recently watched the Ken Burn's series on Hemingway and the film, Hemingway and Gellhorn - it rang true.  

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44 Scotland St. - Alexander McCall Smith

Espresso Tales - Alexander McCall Smith

Love Over Scotland - Alexander McCall Smith

The World According to Bertie -Alexander McCall Smith

The Unbearable Lightness of Scones - Alexander McCall Smith

The Importance of Being Seven - Alexander McCall Smith

Bertie Plays the Blues - Alexander McCall Smith

Sunshine on Scotland Street - Alexander McCall Smith

Bertie's Guide to Life and Mothers - Alexander McCall Smith

The Revolving Door of Life - Alexander McCall Smith

The Bertie Project - Alexander McCall Smith

A Time of Love and Tartan - Alexander McCall Smith

The Peppermint Tea Chronicles - Alexander McCall Smith

A Promise of Ankles - Alexander McCall Smith

After some heavy reads, anything by Alexander McCall Smith is a lovely break. His stories are populated by very real characters, and you won't like all of them!  But somehow, the very realness of people getting on despite whatever comes their way at work, at home, in politics - is incredibly comforting.  While the Isabel Dalhousie series remains my favorite thus far, I do love Bertie!!  In both of these collections, you can count on Mr. Smith to include art, Scottish history, music, gardens, a real feeling for Scotland generally and Edinburgh in particular.  I really must visit Scotland someday!

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The Man with the Silver Saab - Alexander McCall Smith.  Then there is Ulf Varg a detective in Sweden.  The focus of his work does not however, involve horror and vicious murder.  Rather, as head of the Department of Sensitive Crimes, he and his team deal with what might be considered less important injustices and the vagaries of human nature.  In this latest and third publication of his series, he remains the perfectly wrought understated man, who chooses kindness in his detective work and personal life whenever he can.  Another lovely series by this incredible author.  

To me the sign of a really good read is when you continue to think of the characters once the final page has turned.  That is true of me and these stories.   Happy reading.  ~ les

Sew Chaotically! ~ A refashioned refashion with Visible Mending! Or - The 'Borrowed' Jacket!

It's not been all quilting all the time around here!  In early spring I completed several sewing projects.  One was refashioning this jean jacket with visible mending.  I 'borrowed' B's jacket over 25 years ago.  It was worn to zillions of soccer games, family hikes and everywhere else.  Over time it became softer and better.  Though, with all its wear it began to fray along the placket and became decidedly threadbare on the back yoke.  A few years ago I reinforced some seams, used a random piece of yellow rickrack to strengthen the placket and a remnant of matching floral fabric to repair the back yoke.  I wore it a good deal, but that sort of print and rickrack didn't really work for my general wardrobe.  So, I re-did it!

I reworked the button holes by hand, used sashiko style stitching to reinforce the placket and collar, applied tiny bits of a remnant to bind the edges of the cuffs and placket, and patch weak/holey spots.

I used a bit of the same remnant to replace the back yoke, sort of quilting it into place.

I do so enjoy hand stitching.  Now my jacket matches my style and is ready for many more years of wear!  Happy stitching! ~ les

August Reads ~

I Alone Can Fix It - Carol Leonnig and Philip Rucker   My third in a somewhat dispiriting series reporting what can happen when those who are undeserving of office attain it.  On the other hand, there are those who rise to the occasion when much needed and perhaps more than we can even comprehend at this moment may be at stake.

East of Eden - John Steinbeck  Speaking of rising - Thou Mayest.  My fourth reading over the years of my life.  Each one has revealed new perspectives.  This round reminded me of the import surrounding the lives of the lesser characters.  So very much to think about.  

The Code Breaker:  Jennifer Doudna, Gene Editing, and the Future of the Human Race -Walter Isaacson  For anyone who thinks that the current, effective mRNA vaccines against COVID appeared over night, this tale should clarify and reassure you.  Ms. Doudna is definitely in a league with Marie Curie, not only in her incredible contributions to human knowledge and understanding, but in the egalitarian leadership she demonstrated at the onset of our ongoing pandemic.  A well told, readable story that made complex scientific mysteries of DNA, RNA, and CRISPR technology comprehensible.

Not the lightest fare this month.  The last two being very different, but brilliant examples of the triumph of human intelligence and spirit over our lesser selves.   Much needed in this time.

Read well.  Seek peace. - les

What to do about immunotherapy if you - take steroids or infliximab for side effects? Have a pre-existing autoimmune disease?????

 Okay.  This post is A LOT!!!  

Clearly steroids are potent medications that NOBODY should take lightly.  Steroids should NOT be administered if you have a cold - a sore joint - or lots of things medical providers use them for far too frequently.  However, when they are truly needed and dosed appropriately, they can not only save lives, but make life much more livable.  Back in the day, docs thought that if you took steroids while on immunotherapy you would defeat that entire purpose and fail to gain a beneficial response from that therapy.  WRONG!!!!  Again, these drugs should be taken only when they are absolutely needed!  But, given the unfortunate side effects that can be caused by immunotherapy, steroids and other immunosuppressive drugs are often required in order to deal with life threatening side effects, enable the continuance of life saving therapy and we've learned - those patients CAN ATTAIN A GOOD RESPONSE!!!  Here are a zillion articles:  Steroids and immunotherapy

Now, there's this:

Early use of high-dose-glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy.  Bai, Hu, Warner, et al.  Clin Cancer Res.  August 2021.

Background: Programmed cell death receptor-1 (PD-1) inhibitors are front-line therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.

Methods: In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.

Results: Of the entire cohort of 947 patients, 509(54%) developed irAEs. In the MGH cohort (irAE(+)n=90), early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose-GCC use ({greater than or equal to}60mg prednisone equivalent qd) was independently associated with poorer post-irAE PFS/OS compared to irAE without early-high-dose-GCC use. These findings were validated in the combined validation cohort. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.

Conclusions: Early high-dose-GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.

Given the title of this article and the data included in the abstract this sounds pretty bad!  The authors indicate that the folks who had high dose steroids early in their treatment did not do as well as those who did not take steroids.  HOWEVER!!!!!!!!!!!!!!  Thanks to having super duper friends who can gain access to the whole enchilada (ie the entire report) like my Edster - here's some very important information that the title and abstract fail to share:

"We further tested the correlation between irAEs that led to the use of high-dose-GCC and post irAE OS.  Notably, in the 8-week landmark analysis, irAEs that led to high-dose-GCC were associated with poorer post-irAE OS in both cohorts.  For patients with and without high-dose-GCC associated within 8 weeks after anti-PD-1 monotherapy...."

"In the 26-week landmark analysis, marginal significant negative correlation between high-dose-GCC associated irAEs and post-irAEs OS was only observed in the MGH exploratory cohort but not in the combined validation cohort."

"The major limitation of this study is that it is a retrospective analysis, making it susceptible to potential selection, measurement, and reporting biases.  Although we used objective measurements for most cases, those biases cannot be entirely excluded.  Over half of the irAEs that led to early use of high-dose-GCC also led to the early discontinuation of anti-PD-1 monotherapy, which may contribute to the poorer survival."

YOU THINK???????  Oh! EMMMM!  Geeeee!!!!  Yet you research peeps felt just fine giving it the title you did.  Wowsers!!!  

Do I think it is good to take steroids in the midst of immunotherapy?  No.  Because that means you are having trouble tolerating the very thing you are taking - Not for fun.  Not to look cute.  Not because you don't have anything better to do with your time - BUT TO SAVE YOUR LIFE!!!!  And if we can't tolerate the thing we need to kill melanoma before it kills us - then we have a problem!!!  A big one!  If we had a way to enable those with serious side effects to tolerate therapy without steroid use - that would be great!!!  Many researchers are working on drugs that can be combined with immunotherapy that will help diminish side effects as we currently know them.  Hopefully, that research will find options soon.  Still, if I were queen of the world, I would make a great deal more use of flexible dosing schedules for folks with side effects.  For instance - in my Phase 1 trial back in 2010 - my cohort was given nivolumab (Opdivo) at only 1mg/kg and we did pretty well!!!!  Granted, the cohort after me was treated with 3mg/kg and the next was given 10mg/kg.  For those of you who aren't aware - phase 1 trials are actually simply dosing studies.  They are not created to see response rates and such.  Nope.  Just how much drug can you take without growing three heads!!!  And, indeed - we found that those treated with the most nivo did best, but they also had the most side effects.  That's how we ended up with what is the roughly 3mg/kg dose we use today.  BUT, that  pretty much proves my point, doesn't it?  If folks can't tolerate the full dose without impossible side effects, why not see if they can tolerate a lesser one?

Now - what happens to those for whom steroids do not do enough to control their side effects and require infliximab?

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab.  Alexander, Ibraheim, Sheth, et al.  J Immunother Cancer.  Jul 2021.

Introduction: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.

Methods: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria.

Results: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade greeater than 2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding and absence of colonic crypt abscesses. Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%).

Conclusion: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

This is not the first time that researchers have found that folks with side effects - particularly vitiligo, rashes and colitis - are associated with good melanoma outcomes:

From 2017 ~ Do melanoma peeps with side effects to immunotherapy have a better response? - Side effects of immunotherapy - Part 10!!!

From earlier this year ~ This stuff is still weird - Side effects to immunotherapy - Part 11! Heart problems, diabetes, arthritis - Oh MY!!! BUT!!! Colitis may be associated with a favorable response!!!!

Interesting, no?  Now, if you have had a bad reaction to immunotherapy can you resume that therapy?

Response to immune checkpoint inhibitor rechallenge after high-grade immune related adverse events in patients with advanced melanoma.  Shah, Punekar, Pavlick.  Melanoma Res. Jun 2021.

Twenty to sixty percent of patients receiving immune checkpoint inhibitors (ICIs) experience high-grade immune-related adverse events (irAEs) which may prevent the continuation of treatment. Limited clinical evidence is available to guide treatment for these patients. Patients with stage IV or unresectable stage III melanoma at NYU Langone Health were reviewed from 1 January 2014 to 1 July 2019. Patients with first-line ICI systemic therapy, a high-grade irAE and a rechallenge with ICI therapy were included. Postrechallenge irAE recurrence, response rate, overall survival (OS) and progression-free survival (PFS) were evaluated. Postrechallenge irAEs recurred in 71.9% (n = 23/32) of patients at a median of 5.1 weeks from rechallenge, with 46.9% (15/32) recurring as high-grade events. Clinical response was achieved in 46.9% (15/32) of patients, including 40.6% (13/32) with a complete response and 6.3% (2/32) with partial response. Median OS from first ICI initiation was 85.4 weeks (45.7-140.7) and median PFS was 42.9 weeks (29.2-114.2). Patients with a shorter time to initial irAE and shorter time to postrechallenge irAE were at greater risk for disease progression. Those with greater duration to rechallenge (greater than 10 weeks) were at lower risk for disease progression. ICI rechallenge can be considered in patients with advanced melanoma, as the risk-benefit profile appears favorable. Treatment toxicity should be appropriately managed, as longer durations to rechallenge may lower the risk of disease progression.

That last sentence circles back to my conclusion to the first article (as well as that of the authors within the report) in that the longer we can keep folks on therapy, the better they do.  So, if we can control side effects and allow patients to stay on therapy - even if steroids are required - they are less likely to experience progression of their melanoma!  Further, if folks have to stop immunotherapy due to side effects - can they return to that therapy?  There is this from 2017:  Melanoma patients continuing Nivo after having adverse reactions to the ipi/nivo combo??? Yes, you can!

I would suggest that this would be the time to seek the care of a melanoma specialist if you aren't managed by one already.  After all, these side effects don't play and resuming that which caused you harm should be done with great care!

Finally, what if you have an autoimmune disease at the start????

Safety and Clinical Outcomes of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Diseases.  Yeung, Kartolo, Holstead, et al.  J Immunother. Jun 2021.

Immunotherapy has revolutionized treatment outcomes in numerous cancers. However, clinical trials have largely excluded patients with autoimmune diseases (ADs) due to the risk of AD flares or predilection for developing organ-specific inflammation. The objective of this study was to evaluate the safety and efficacy of immunotherapy in patients with cancer and preexisting ADs. A retrospective, single-center study of patients with cancer initiated on immune checkpoint inhibitors between 2012 and 2019 was conducted. The primary outcome was the development of immune-related adverse events (irAEs) with respect to the presence of AD at baseline. Associations were assessed using Kaplan-Meier curves, bivariate and multivariable analyses. Of the 417 patients included in this study, 63 patients (15%) had preexisting ADs. A total of 218 patients (53%) developed at least 1 irAE. There was no association between the presence of baseline AD on the development, grade, or number of irAEs; time to irAE or irAE recovery; systemic corticosteroid or additional immunosuppressant treatment for irAEs; permanent treatment discontinuation; or overall response rate. Two smaller cohorts were studied, melanoma and non-small cell lung cancer, and there was no effect of baseline AD on overall survival on either cohort. However, a greater proportion of patients with baseline ADs had full recovery from their irAE. Furthermore, age below 65, baseline steroid use, and single-agent immunotherapy regimens were protective in terms of the development of irAEs. Our study suggests that immune checkpoint inhibitors have similar safety and efficacy profiles in patients with preexisting ADs.

"...immune checkpoint inhibitors have similar safety and efficacy profiles in patients with preexisting autoimmune diseases."  That is a heartening sum-up!  A dear one, Jubes on the MRF patient forum, had to take infliximab due to debilitating arthritis - which helped her a great deal and did not cause an adverse flare of her melanoma.  This report was written in her honor, but includes many links to articles that address the particulars of folks with pre-existing immune conditions as well as the other points I am covering today:  For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

Immunotherapy has been a great blessing in melanoma world.  However, it is not for sissies!  Hope this helps.  Wishing you all my best.  - c

Ipilimumab or ipi/nivo combo after recurrence in patients previously treated with immunotherapy ~

How to treat a melanoma recurrence when you have already been treated with ipi or anti-PD-1 (nivo/Opdivo or pembro/Keytruda) as single agents or the ipi/nivo combo has been a question for sometime now.  From 2017 there were these:

Response to ipi or ipi/nivo after failing anti-PD1 as single agent in Stage IV melanoma

ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

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

There was this in 2020:  How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

And also, this:  After progression on anti-PD1 / anti-PDL1 treatment of melanoma

Now, there are these:

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.  Da Silva, Ahmed, Reijers, et al.  Lancet Oncol.  June 2021.

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged greater/= to 18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162) or ipilimumab plus anti-PD-1 (n=193) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months, the objective response rate was higher with ipilimumab plus anti-PD-1 (60 of 193 patients) than with ipilimumab monotherapy (21 of 162 patients). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months) than with ipilimumab monotherapy (8·8 months). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months) than with ipilimumab (2·6 months). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. 

In this report, it is evident that the ipi/nivo combo did better as follow-up to progression on anti-PD-1 as a single agent, than the response that was provided by ipi alone.

Now, what to do if you took the combo from the start?

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.  Hepner, Atkinson, Larkin, et al.  Eur J Cancer.  Aug 2021.

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%). Time to AR was 11 months. After a median follow-up of 16 months, responders to reinduction had a median progression-free survival of 14 months, and in the whole cohort, the median overall survival from reinduction was 17 months. Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

This report notes that despite failing the ipi/nivo combo, a repeated course can provide response and disease control.

Here's something to consider if serious adverse reactions have been an impediment to repeating treatment using immunotherapy ~

Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.  Klee, Kurzhals, Hagelstein, et al.  Melanoma Res. July 2021.

Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.

After progressing on anti-PD-1, these patients were treated with a low dose ipi/usual dose nivo combo.  Side effects were decreased and responses were attained.

Hang tough, peeps.  Melanoma doesn't make it easy, but there is hope.  - c