Intralesionals for melanoma - some new reports

I was a fan of intralesional therapies for melanoma long before they were used with any frequency in real live melanoma peeps! I first posted about Rose Bengal (the name I much prefer to the current PV-10) in 2012!!  Rose Bengal sustains high response rate in Melanoma patients!!!  These days the medications used intralesionally for melanoma patients has grown.  Even this list isn't comprehensive:

CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 and IL-12 (tavo) -  are also being used

This link, including an update from June of this year, will give you - A zillion more posts on all things intralesional  Now, there are these ~

False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).  Mulder, Stahlie, Verver, et al.  J Surg Oncol.  Jul 2021.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T-VEC treatment, tumor response is often evaluated using [18F]2-fluoro-2-deoxy- d-glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one-third of patients developed new-onset FDG uptake in uninjected locoregional lymph nodes during T-VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as "suspected metastases" without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new-onset FDG uptake in locoregional lymph nodes during T-VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T-VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T-VEC.

Given the real (and wonderful) possibility of "by-stander response" - ie the positive response in lesions NOT injected when intralesional therapy is used - why oh why would you assume that uptake visible on scans is progression you silly silly radiology peeps???!!!!  Live and learn people!  Live and learn!

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Jul-Aug 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Treatment of in-transit melanoma metastases using intralesional PV-10.  Thompson, Saw, Dalton, et al.  Melanoma Res.  June 2021.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.  Stahlie, Franke, Zuur, et al.  Cancer Immunol Immunother.  August 2021.

Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.

Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time greater than 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.

Results: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting greater than 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.

Conclusions: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Much like every other treatment in the melanoma arsenal, intralesional therapy (no matter the type you choose) is not a 100% cure nirvana.  Still, to my mind, it is a valuable weapon available to melanoma patients with in-transit lesions and as a supplement to Stage III and IV patients being treated simultaneously with systemic therapy.  As ever, those with the lowest tumor burden do best.  And sadly, nobody does the Even Steven clinical trials I want to see, placing similar patients on the various intralesionals - with and without equivalent systemic therapies - and THEN comparing outcomes!!!!  Why not, oh brilliant researchers?  WHY?????

For what it's worth - c

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