For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

The minute B found this article he was yelling, "Oh, this might be important to Jubes!!!"  Well, I hope not!!!  Many (actually - probably most!!!) folks who take immunotherapy deal with some amount of arthralgias (joint pain).  However, my sweet Anne-Louise dealt with significant arthritis/spondylitis due to her immunotherapy treatment for melanoma!  However, after prednisone and other meds like infliximab she got her joint pain under control and threw melanoma to the curb!!  But....immune disease and side effects with immunotherapy remain a significant double decker problem. 

First....what if you already know you have an immune disease like rheumatoid arthritis?  Can you still take immunotherapy?  The short answer is YES!!!  You can!!  Here is a recent post on the subject with more links within:  Immunotherapy for melanoma with a pre-existing autoimmune disease??? YES!!! You can!
Here's another report:  Patients with preexisting immune disease, melanoma, and treatment with Anti-PD-1? Yes, this can be done. Yes, autoimmune flares should be treated with immunosuppressive therapy while on immunotherapy. And YES!!!! These patients can still attain a response!

Second...there are the folks who didn't have arthritis or other autoimmune diseases (that they knew of) at the start of treatment...but end up with all sorts of immune related side effects caused by their immunotherapy.  What should we do with them????  Treat them!  Sometimes with a break of their immunotherapy, but with prednisone and other drugs as needed.  Right then, right there!  And, YES!!!  They can still go on to have a response and rid themselves of melanoma in the process!  (Just like Jubes!!!)  Here are related posts:  One more time: Immunosuppressive therapy to manage side effects to immunotherapy does NOT affect response! New report.
And this:  Immune related side effects from immunotherapy can and SHOULD be treated!!!!
And this:  Side effects and how to manage them in targeted and immunotherapy for melanoma
And finally...this post with a treatment algorithm for neuro side effects and links to algorithms for other immune related side effects:  Neurologic side effects to immunotherapy with treatment algorithm

Okay!  You'd probably like me to get to a point!  What if there was a drug that helped folks with their rheumatic disease AND helped get rid of their melanoma????  Well now, there's this:

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth. Hanson, Robinson, Al-Yousuf, et al.  Oncotarget. 2017 Dec 17.  

Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAF^V600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.  

In this study, researchers say that leflunomide...a drug used to treat rheumatoid arthritis...seemed to have "therapeutic value" when it was combined with vemurafenib (a BRAF inhibitor) as well as when it was combined with selumetinib (a MEK inhibitor)...in both BRAF positive and BRAF wild type patients!  So far, it seems that this is in petri dishes and real live furry ratties.  However, if this works this could be super cool for getting rid of melanoma as well as a boon for folks already dealing with arthritis...or perhaps debilitated by arthralgias due to their melanoma treatment.  

It's got a ways to go before we can get too excited.  But, I like the direction!!!  As for my dear Anne-Louise....I hope that she NEVER needs another melanoma or arthritis treatment....EVER!!!!  And...I do hope to hear her play her fiddle someday!!! 

Hang in there, ratties!  (Those that are furry and those who are not so much!) - c

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

Do glucocorticoids or dexamethasone reduce the effectiveness of immunotherapy in melanoma???

For years and years the vast preponderance of the evidence has demonstrated that folks with significant side effects to immunotherapy not only NEEDED to be treated with steroids in order to deal with the problem presented, but also (thank goodness!!!) showed that steroid treatment, did NOT decrease their survival/response to immunotherapy itself in the end.  Here is one post with links to zillions of reports on studies that looked at this issue:  For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

Now, there's this:

High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.  Faje, Lawrence, Flaherty.Cancer. 2018 Jul 5.

It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.
In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy.
Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group. Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group. Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group.

Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.

So, in this study, in order to avoid muddying the waters in regard to survival due to possible differences in outcome caused by the particular side effect itself, the researchers looked at only one side effect - hypophysitis (inflammation of the pituitary gland, which is located at the base of the brain) after melanoma patients were treated with ipilimumab (Yervoy).  In those 98 patients, some folks were treated with high dose glucocorticoids and others were given a low dose.  In those patients, the low dose folks had an overall survival of 23 months vs only 14 months in the high dose group.  But, to me...here is the bigger news ~ "All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group."     I do have one question about this study.  Did the folks treated with a higher dose require it in order to deal with their hypophysitis?  Meaning, would a lower steroid dose have been insufficient for an effective response in them?   In the end, despite the fact that these peeps with hypophysitis were treated with steroids....they ALL did better than melanoma peeps with no hypophysitis and no steroids!!!  I think all this reports really tells us is that this pretty horrible side effect seems to come with better survival in melanoma and, of course, we should try to treat side effects using the lowest effective dose of steroids that we can.

Now there is also this (link to entire article and abstract below with thanks to my dear Eric...for sharing it):

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.  Giles, Hutchinson, Sonnemann, et al.  Journal for Immunotherapy of Cancer, June 11, 2018.

Background: Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.

Methods: Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. 

Results: Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 costimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. 

Conclusions: Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response. 

First and foremost, this study was done by looking at cells in a petri dish and poor little real live mice.  And, it seems as though the limiting effects created by dexamethasone (a steroid) on T cells was present when the cells were treated with anti-PD-1 but not when treated with ipi (Yervoy).

Well, damn!  When something seems simple in melanoma....we should realize, "NOPE!  Melanoma gonna be crazy!  You'll see!!!"  Still, these are only two studies among YEARS of other research that indicates treatment of side effects caused by immunotherapy, with steroids, did not diminish the good response in patients with melanoma.  And, like the first report above, we have some indication that side effects may even be an indicator of a good response AGAINST melanoma. Additionally, if you are dealing with a potentially deadly side effect...and you die from it because it went untreated....how good is your outcome going to be then????  However, I do think these results tell us that we should continue to look at this issue and be as conservative in management of side effects with steroids (ie doing so only when really needed and with the lowest effective dose) as possible!

Hang in there ratties!  With melanoma it is always a bumpy ride!!! - c