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

Brain Mets - A mixture of recent reports

I've covered the data related to brain mets in melanoma for a long time - A few zillion relative reports  

Unfortunately, some older posts are at the top of that list, so scroll through for newer posts if you are interested.  Also unfortunately, not a lot has changed since many of those postings, but here are some reports published over the past year (my comments in red as ever) ~

Tumor Control Probability of Radiosurgery and Fractionated Stereotactic Radiosurgery for Brain Metastases.  Redmond, Gui, Benedict, et al.  Int J Radiat Oncol Biol Phys.  Dec 2020.

Purpose: As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, tumor control probability (TCP) after stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for brain metastases was modeled based on pooled dosimetric and clinical data from published English-language literature.

Methods and materials: PubMed-indexed studies published between January 1995 and September 2017 were used to evaluate dosimetric and clinical predictors of TCP after SRS or fSRS for brain metastases. Eligible studies had greater than/= to10 patients and included detailed dose-fractionation data with corresponding greater than/= to 1-year local control (LC) data, typically evaluated as a greater than 20% increase in diameter of the targeted lesion using the pre-SRS diameter as a reference.

Results: Of 2951 potentially eligible manuscripts, 56 included sufficient dose-volume data for analyses. Accepting that necrosis and pseudoprogression can complicate the assessment of LC, for tumors less than/= to 20 mm, single-fraction doses of 18 and 24 Gy corresponded with greater than 85% and 95% 1-year LC rates, respectively. For tumors 21 to 30 mm, an 18 Gy single-fraction dose was associated with 75% LC. For tumors 31 to 40 mm, a 15 Gy single-fraction dose yielded ∼69% LC. For 3- to 5-fraction fSRS using doses in the range of 27 to 35 Gy, 80% 1-year LC has been achieved for tumors of 21 to 40 mm in diameter.

Conclusions: TCP for SRS and fSRS are presented. For small lesions less than/= to 20 mm, single doses of ≈18 Gy appear generally associated with excellent rates of LC; for melanoma, higher doses seem warranted. For larger lesions greater than 20 mm, local control rates appear to be ≈ 70% to 75% with usual doses of 15 to 18 Gy, and in this setting, fSRS regimens should be considered. Greater consistency in reporting of dosimetric and LC data is needed to facilitate future pooled analyses. As systemic and biologic therapies evolve, updated analyses will be needed to further assess the necessity, efficacy, and toxicity of SRS and fSRS.

Not stuff that we as melanoma patients have a lot of control of or say in - but there you go.

Long-term disease outcome and volume-based decision strategy in a large cohort of multiple brain metastases treated with a mono-isocentric linac-based Stereotactic Radiosurgery technique.  Alongi, Nicosia, Figlia, et al.  Clin Transl Oncol.  August 2021.

Purpose: Radiosurgery (SRS) is an effective treatment option for brain metastases (BMs). Long-term results of the first worldwide experience with a mono-isocentric, non-coplanar, linac-based stereotactic technique in the treatment of multiple BMs are reported.

Methods: Patients with multiple BMs, life expectancy greater than 3 months, and good performance status (less than/= to 2) were treated with simultaneous SRS with volumetric modulated arc technique. Data were retrospectively evaluated.

Results: 172 patients accounting for 1079 BMs were treated at our institution from 2017 to 2020. The median number of treated metastases was 4 (range 2-22). Primary tumor histology was: lung (44.8%), breast (32%), and melanoma (9.4%). The 2-year LPFS was 71.6%, respectively. A biological effective dose (BED) greater than/= to 51.3 Gy10 correlated with higher local control. Uncontrolled systemic disease and melanoma histology were independent prognostic factors correlated with decreased iPFS. Patients with greater than 10 BMs had a trend towards shorter iPFS. 31 patients received multiple SRS courses (2-7) in case of intracranial progression. The median iOS was 22.4 months. Brainstem metastases and total PTV greater than 7.1 cc correlated with shorter iOS. The 1- and 2-year WBRT-free survival was 83.2% and 61.1%, respectively.

Conclusion: Long-term results in a large patient population treated with a mono-isocentric, dedicated technique demonstrated its effectiveness and safety also in the case of multiple courses. The shortened treatment time and the possibility to safely spare healthy brain tissue allows the safe treatment of patients with a large number of metastases and to deliver multiple courses of SRS. In selected cases, the administration of WBRT can be delayed.

Not all melanoma patients here.  But good to know that multiple rounds of SRS were effective and well tolerated in some of these patients.

Time from stereotactic radiosurgery to immunotherapy in patients with melanoma brain metastases and impact on outcome.  Wegner, Abel, D’Amico, et al.  J Neurooncol.  Mar 2021.

Background: The role of immunotherapy for metastatic melanoma has expanded over the past decade triggering questions regarding the combination and timing of immunotherapy and radiation for brain metastases. We used the National Cancer Database (NCDB) to see if the time from radiation to immunotherapy in patients with melanoma brain metastases had an impact on survival.

Methods: We queried the NCDB from 2010 to 2015 for patients with melanoma brain metastases treated with immunotherapy and stereotactic radiosurgery (SRS). Receiver operator characteristic (ROC) curve analysis was done to determine a timepoint associated with outcome. Cox regression was used to identify predictors of survival. Propensity matching was done to account for indication bias.

Results: We identified 247 patients meeting the above criteria. The median patient age was 62 years (27-90) and the vast majority were Caucasian (99%). The median SRS dose was 22 Gy (18-24 Gy).The median time to SRS was 39 days (0-344) and the median time to immunotherapy was 56 days (6-454). The ROC analysis revealed 8 days from SRS to immunotherapy as associated with outcome. Fifty-six patients had immunotherapy prior to SRS, 30 patients had immunotherapy within 0-7 days of SRS, and the remaining 161 had immunotherapy greater than 7 days from SRS. Three year survival rates were 21%, 55%, and 35% for those timeframes, respectively. Propensity matching of the 0-7 day and greater than 7 day groups yielded 28 pairs and Kaplan Meier analysis showed 3 year overall survival of 55% and 35%, in favor of immunotherapy within 7 days of SRS. Multivariable Cox regression identified lack of extracranial disease, more recent year of treatment, and time from SRS to immunotherapy of 0-7 days as predictors of improved survival.

Conclusions: Immunotherapy within 7 days of SRS shows a possible association with improve outcomes in patients with brain metastases from melanoma.

Many other studies have already demonstrated this fact - outcomes are better when you DO NOT delay immunotherapy!!!!!!!!!!!!!!!!!!!!!!!!!!!!  Again = a zillion reports:  Radiation AND immunotherapy

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.  Hong, Waldstein, Shivalingam, et al.  Eur J Cancer.  Jan 2021.

Introduction: The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available.

Methods: A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarized and the evidence was assessed, leading to the development of recommendations.

Main recommendations: Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.

All conclusions seem true based on current data.  There is even this confirming report from 2019 regarding immunotherapy as first line treatment (without radiation) for folks with melanoma brain mets - IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma  However, as I noted in that post - with the vast preponderance of evidence showing that responses are better when immunotherapy is COMBINED with radiation, you would have a hard time convincing me to roll with immunotherapy alone.  But, maybe that's just me!

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.  Dimitriou, Zaremba, Allayous, et al. Eur J Cancer.  Jul 2021.

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.

Deciding when to stop therapy - esp when there has been no complete response, remains hard.

First line immunotherapy extends brain metastasis free survival, improves overall survival, and reduces the incidence of brain metastasis in patients with advanced melanoma.  Wang, Haaland, Hu-Lieskovan, et al.  Cancer Rep.  June 2021.

Background: Recent advances in targeted therapy and immunotherapy have improved the prognosis of melanoma patients but brain metastasis remains a major challenge. Currently, it is unclear how existing therapies can be best used to prevent or treat brain metastasis in melanoma patients.

Aims: We aimed to assess brain metastasis free survival (BMFS), overall survival (OS), incidence of brain metastases, and sequencing strategies of immunotherapy and targeted therapy in patients with BRAF-mutated advanced melanoma.

Methods and results: We retrospectively analyzed 683 patients with BRAF-mutated advanced melanoma treated with first line (1L) immunotherapy (N = 266) or targeted therapy (N = 417). The primary outcome was BMFS. Secondary outcomes included OS of all patients and incidence of brain metastases in patients without documented brain metastases prior to 1L therapy. The median BMFS was 13.7 months among all patients. The median BMFS for patients receiving 1L immunotherapy was 41.9 months and targeted therapy was 11.0 months. Median OS results were qualitatively similar to BMFS results. The cumulative incidence of brain metastases for patients receiving 1L targeted therapy was higher than for patients receiving 1L immunotherapy. Patients receiving 1L anti-CTLA4 plus anti-PD1 combination immunotherapy only or followed by second line (2L) targeted therapy had better BMFS, improved OS, and reduced incidence of brain metastases, than patients receiving 1L combination BRAF and MEK targeted therapy followed by 2L immunotherapy.

Conclusion: Patients with advanced BRAF mutant melanoma treated with 1L immunotherapy have significantly longer BMFS and OS, and reduced incidence of brain metastases, compared with those treated with 1L targeted therapy. Further studies evaluating the ability of immunotherapy and targeted therapy to improve OS and prevent brain metastases are warranted.

Interesting.

Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies.  Bander, Yuan, Carnevale, et al.  Cancer.  June 2021.

Background: Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed.

Methods: In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and time-dependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS.

Results: Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months. Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months vs 7.0 months). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination, increasing numbers of brain metastases at diagnosis, earlier MBM diagnosis year, higher serum levels of lactate dehydrogenase, receipt of immunotherapy before MBM diagnosis, and the presence of extracranial disease. The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy.

Conclusions: The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM.

Lay summary: Historically, melanoma brain metastases (MBM) have carried a poor survival prognosis of 4 to 6 months; however, the introduction of immunotherapy and targeted precision medicines has altered the survival curve for advanced melanoma. In this large, single-institution, contemporary cohort, the authors demonstrate a significant increase in survival of patients with MBM to 13 months within the last 5 years of the study. A worse prognosis for patients with MBM was significantly associated with the number of metastases at diagnosis, previous exposure to immunotherapy, spread of disease to the leptomeningeal compartment, serum lactate dehydrogenase elevation, and the presence of extracranial disease. The current age of systemic treatments has also been accompanied by shifts in the use of central nervous system-directed therapies.

Yep.  Things are better.  But, not yet good enough.  Still, we know - if you have melanoma brain mets - hit 'em hard with everything you've got!  No waiting.  No pussy footing around!!!

Immune checkpoint inhibitor therapy may increase the incidence of treatment-related necrosis after stereotactic radiosurgery for brain metastases: a systematic review and meta-analysis.  Kim, Suh, Kim, et al.  Eur Radiol.  June 2021.

Objectives: To compare the incidence of treatment-related necrosis between combination SRS+ICI therapy and SRS therapy alone in patients with brain metastases from melanoma and non-small cell lung cancer (NSCLC).

Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed up to August 10, 2020. The difference in the pooled incidence of treatment-related necrosis after SRS+ICI or SRS alone was evaluated. The cumulative incidence of treatment-related necrosis at the specific time point after the treatment was calculated and plotted. Subgroup and meta-regression analyses were additionally performed.

Results: Sixteen studies (14 on melanoma, 2 on NSCLC) were included. In NSCLC brain metastasis, the reported incidences of treatment-related necrosis in SRS+ICI and SRS alone ranged 2.9-3.4% and 0-2.9%, respectively. Meta-analysis was conducted including 14 studies on melanoma brain metastasis. The incidence of treatment-related necrosis was higher in SRS+ICI than SRS alone (16.0% vs. 6.5%). The incidence showed rapid increase until 12 months after the SRS when combined with ICI therapy (14%) and its pace of increase slowed thereafter. Histopathologic diagnosis as the reference standard for treatment-related necrosis and inclusion of only symptomatic cases were the source of heterogeneity in SRS+ICI.

Conclusions: Treatment-related necrosis tended to occur 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis showing high cumulative incidence within the first year. Treatment-related necrosis should be considered when SRS+ICI combination therapy is used for melanoma brain metastasis, especially in the first year.

Key points: • Treatment-related necrosis occurred 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis. • Treatment-related necrosis more frequently occurred in brain metastases from melanoma than NSCLC. • Reference standard for treatment-related necrosis and inclusion of only symptomatic treatment-related necrosis were a significant source of heterogeneity, indicating varying definitions of treatment-related necrosis in the literature need to be unified.

First of all, melanoma sucks.  Melanoma brain mets suck even more.  Yes, treatment necrosis is a real thing.  Yes, it seems to happen in melanoma brain mets more than in brain mets caused by other cancers.  BUT!  What 'cha gonna do?  Not treat and risk more mets and less survival?  Plus, this is a meta-analysis - NOT a real report with full intel on every rattie studied.  There are studies with real ratties that show this:  Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis.  Jessurun, Hulsbergen, Wit, et al.  Neuro Oncol.  August 2021.

Background: Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.

Methods: A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.

Results: After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS and systemic progression-free survival in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS.

Conclusions: Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

This article is proof that I share all the data that I find - even if it doesn't jive with most of the previous data.  To whit - steroids do NOT diminish response in melanoma patients - and are often in fact,  REQUIRED in order for melanoma patients to continue their life saving treatment!!!  While there may be some truth in the conclusion that folks who have to undergo steroids while on immunotherapy have a decreased response compared to those who do not - I think the REASON for that may not be the one first concluded - ie steroids themselves diminished the response.  RATHER, patients who must use steroids to tolerate immunotherapy often are unable to complete a sufficient quantity of immunotherapy to treat their disease effectively because they could not tolerate it.  The lack of knowledge about the specific patients in this review of 14 other studies demonstrates the severe limitations that this kind of compiled data in meta-analysis contains.  My opinions about the abstract of this study are much like those I discussed in a similar report from September of this year:  What to do about immunotherapy if you - take steroids or infliximab for side effects? Have a pre-existing autoimmune disease?????  If you are interested in the effects of steroids on immunotherapy, it is worth your time.  With repeated thanks to the Edster for help in analysis and provision of the complete article.

The studies in this post were all retrospective meta-analysis studies.  While reports like these can give a useful overview of the state of the science they are decidedly lacking in REASONS for outcomes.  For instance, there are absolutely NO elephants in Chattanooga, TN at this moment.  Further, I just clapped my hands three times.  Are those two things related?  Probably not!!!  Concurrent events and causative events are not the same.  Counting up a tally from some carefully chosen studies can be informative.  But, the results must be considered in the light of how they were attained and with recognition of the limited specifics known about the individual ratties in each of the studies, multiplied by how many studies and ratties there were.

See, Bentie?  All those crazy doctoral level statistic courses at UAB were worth the price of admission and tears of confusion, right????  BAHAHAHA!!!

Hang tough, ratties.  Melanoma isn't easy.  But there is hope. - c

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

I've been posting data and case studies of  Side Effects of Immunotherapy - Part 9! forever!!!

Here are two articles that address side effects with the ipi/nivo combo specifically:

Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. Callahan, Kluger, Postow, et al.  J Clin Oncol. 2017 Oct 17.

The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). 

Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. 

Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. 

This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

OK.  Here 94 peeps took the ipi/nivo combo in several different ways.  For all of them, the 3 year overall survival rate was 63% with the median rate not yet reached after f/u for 30-55 months.  This is significant evidence pointing toward the durability of a response to this combo.  Objective response rates were 42%, with a median duration of response at 22.3 months.  More than half of the patients experienced Grade 3 and 4 side effects.  Understand that these are things that are much greater than fatigue, rash, and mild to moderate joint pain.  Of the Grade 3/4 side effects the most common one was elevated liver and pancreatic enzymes.  One patient died from multi-system failure 70 days AFTER their last dose.

Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. Sznol, Ferrucci, Hogg, et al.  J Clin Oncol. 2017 Sep 15. 

The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. 

This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. 

Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four on-study deaths were attributed to therapy. 

Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

This study looked back on 448 patients who had been treated with the ipi/nivo combo in a traditional manner.  Again, more than 50% of the patients had Grade 3/4 side effects with more than 30% of those having to stop treatment.  Most common side effects generally, were related to skin and GI issues.  When looking at Grade 3/4 side effects, the most common ones affected the liver and GI tract (much like the prior study).  Onset of Grade 3/4 side effects took only 3 weeks for skin and 16 weeks for renal problems.  With endocrine side effects excluded, the average time it took for side effects to resolve was about 2 weeks for renal and 4+ weeks for pulmonary issues.  Resolution rates were between 79 and 100% with immune-modulating agents {read:  steroids or medicines like remicaid/infliximab and others}.  I suspect that side effects in the endocrine system, given the nature of that beast and the fact that they were "excluded" here, were NOT "resolved" with such immune-modulation, but rather required therapy for the duration of the patient's life, as treatment for diabetes and hypothyroidism is expected to be.

Three new cases of bullous pemphigoid during anti-PD-1 antibody therapy. Le Naour, Peuvrel, Saint-Jean, et al.  J Eur Acad Dermatol Venereol. 2017 Sep 2. 

Anti-programmed death 1 (PD-1) antibodies are revolutionizing the treatment of many cancers, including melanoma . Cutaneous adverse events (AE) of anti-PD-1 antibodies are common (20%) and mainly non-specific. Bullous pemphigoids (BP) are very rare immune-related AEs induced by anti-PD-1 antibodies, with only 12 cases previously published. We report here three new cases of BP during anti PD-1 therapy with nivolumab. 

So....one more lovely thing that can develop with immunotherapy, which I've reported on before in these posts:  immunotherapy and bullous skin eruptions

We already know that vitiligo, as a response to immunotherapy, is a good prognostic sign.  But, what do other toxic reactions mean in regard to response rates?  Below ~ an article that begins to address that issue:

Correlation between toxicity and outcome in melanoma patients treated with ipilimumab plus nivoumab (ipi/nivo).  Cohen, Jilaveanu...Sznol, et al.  Society for Melanoma Research 2016 Congress.  Published 29 January 2017.

Immune checkpoint inhibitors have become the standard of care for treatment of metastatic melanoma. However immune-related adverse events (irAEs) remain a serious concern. We report our experience investigating the potential correlation between degree of toxicity and progression-free survival (PFS). 74 pts were treated with the combination of ipi/nivo as part of the phase I trial, [NCT01024231], an expanded access protocol [NCT02186249] or with commercially available drugs from Dec. 2009 to Oct. 2015. irAEs were graded according to the CTCAE v4.0 and steroid use was studied as a surrogate for overall toxicity. 69 (93%) pts experienced an irAE of any grade. 39 pts (53%) had a grade 3 irAE and 4 (5%) had a grade 4 irAE. Pts often experienced greater than1 irAE. Females tended to get more toxicities than males. The median PFS in the patient population was 9 months (range 0–65). The median OS was 16 months (range 3–65). The objective response rate was 55%. 70 pts survived greater than 6 months. There was a statistically significant difference in the PFS in pts who experienced no irAEs when compared with those who had any irAEs. Similar findings were seen in the analysis of OS. PFS and OS were also stratified by length of time on steroids. Any steroid requirement at all was associated with a reduced risk of disease progression but the number of days on steroids above the median (23 days) corresponded with an increased risk of progression. Pts treated with the combination of ipi/nivo who received steroids to treat autoimmune toxicity had improved outcomes when compared with those pts who received no steroids, suggesting that pts who have some irAEs from immunotherapy may have improved outcomes. However, a fine balance between autoimmunity and anti-tumor response may be necessary for optimal long-term outcomes.

Here, of 74 patients treated with ipi/nivo, 93% had some level of side effects and 39 (once again, more than 50%) experienced Grade 3/4 side effects.  PFS was 9 months.  OS was 16 months.  Objective response rate was 55%.  70 of the 74 lived more than 6 months.  OKAY...but to the point of the current question:  "There was a statistically significant difference between the PFS in patients"  with NO side effects when compared to those who had ANY.  This was true of overall survival as well.  Furthermore, "Any steroid requirement at all was associated with a reduced risk of disease progression." However, the authors go on to employ a caveat, noting that if steroid use was prolonged (beyond the average 23 days) there was a corresponding "increased risk of progression."  Now...what is unclear about that statement to me is this:  Did prolonged steroid use actually account for the increased risk of progression?  OR...  Were these patients so badly affected by their adverse reactions to the treatment that they were unable to continue therapy and in the absence of treatment progressed?  Especially if side effects occurred early and the amount of immunotherapy they had received was minimal????  There is some data already addressing that point as is evidenced in these posts: 

Feb 2016: Time to Response...Ipi vs Nivo and ipi

ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!

Aug 2017: 40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!

All of these posts include data which demonstrated that patients who stopped treatment due to side effects, had about the same outcomes as those who completed treatment.  (There are many implications in that fact.... Are we simply treating folks too long?  Should we decrease the dosage of ipi, as it is the bad boy of side effects, when we combine it with nivo - as some current/on-going studies are doing?)

While it is far from absolute or simple...among these patients, it is looking as though side effects to immunotherapy are demonstrable proof of the immune reaction we are seeking to get rid of our melanoma and, within limits, those ratties have better outcomes than those with lesser or no side effects.  If nothing else, this data is certainly a testament to the truth in my 9 million rants that side effects to immunotherapy CAN and SHOULD be treated, even with immunosuppressive drugs, as patients will: A) survive their adverse event, and B) still attain a response to the treatment! 

My yelling from as far back as 2015:
Immune related side effects from immunotherapy can and SHOULD be treated!!!!

Side effects and how to manage them in targeted and immunotherapy for melanoma

To more recently:  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!

As ever, ain't noth'n simple in melanoma!  Hang in there ratties!!! - c

ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Survival, biomarker, and toxicity analysis of Nivolumab (NIVO) in patients that progressed on ipi.  ASCO J Clin Oncol 33, 2015. Weber, Gibney, Yu, et al.

PD-1 antibody, nivolumab was administered to 126 patients with unresectable melanoma that failed at least one regimen and were ipi naive (34) or progressed on ipi (92).  Patients refractory to ipi were given Nivo at 3 mg/kg. 2 cohorts were HLA 0201 positive: N = 10 had grade 2 or less ipi related AE's.  N = 21 had dose limiting grade 3/4 ipi related AE's.  A third cohort (N = 61) was not HLA restricted and had experienced grade 2 or less ipi related AE's.  RESULTS:  Median f/u for ipi refractory pts was 18.7 months. Response rate was 29%.  44% had clinical benefit with confirmed partial and complete response or stable disease at 24 weeks.  Median duration of response was 14.3 months.  Median progression free survival was 5.4 months and median overall survival was 20.1 months with 1 and 2 year OS of 69.2% and 39.1%.  Of 14 patients that have completed all therapy or stopped due to toxicity while stable or in response, all remain in remission. Of 21 patients with prior ipi induced grade 3/4 AE's, only 2 had subsequent dose limiting (and different) AE's with nivo, with 8 PR and 5 SD seen.  All 8 PR and 3 SD are without progression.  Biomarker studies showed that circulating MDSC (myeloid derived suppressor cells) were associated with progression and worse OS.  CONCLUSION:  Prior ipi related AE's were not replicated by NIVO.

Safety of pembrolizumab in patients who stopped ipilimumab due to immune-related adverse events.  ASCO J Clin Oncol 33, 2015.  Shoushtari, Postow, Horvat, Chapman, et al.

Pembro which blocks programmed death-1 was recently FDA approved (as was Nivo) for the treatment of patients with advanced melanoma after progression on ipi.  Ipi is associated with immune mediated adverse events which can lead to treatment cessation.  Researchers collected date on patients with melanoma who received pembro at Sloan Kettering and had received less that 4 doses of ipi due to AE's grade 2 or higher requiring steroids.  RESULTS:  N= 10.  12 AE's contributed to ipi cessation:  colitis, neuropathy, ALT elevation (increased liver enzymes), rash.  All were given steroids and 3 required infliximab.  Median pembro doses given = 5.  7/10 patients are still getting treatment.  2/10 had treatment with pembro interrupted due to AE's that required steroids.  Neither were the AE seen when on ipi.  CONCLUSION:  Patients who stop ipi due to AE's may have different AE's on pembro.  Severe AE's on ipi does not preclude a patient from taking pembro.


Efficacy and toxicity of treatment with the anti-CTLA4 antibody Ipilimumab in patients with metastatic melanoma who have progressed on anti-PD1 therapy.  ASCO J Clin Oncol 33, 2015.  Prithviraj, McArthur, Atkinson, et al.

Immunotherapy with anti-CTLA4 (ipi) and anti-PD1 antibodies has demonstrated overall survival benefits in patients with metastatic melanoma compared to standard therapy.  Early clinical trails suggests that combination therapy with ipi and anti-PD1 increases the response rate sompared to single agent treatment however is associated with increased toxicity.  Anti-PD1 therapy demonstrated equal efficacy and toxicity in patients that progressed on or were naive to treatment with the anti-CTLA-4 antibody Ipilimumab.  So far, only very limited evidence exists regarding efficacy and toxicity of ipi in pateints that have progressed on treatment with an anti-PD1 agent.  Study:  N= 10 patients who had received Nivo/Pembro in a clinical trial and were subsequently treated with ipi.  Ipi was given at 3mg/kg every 3 wks for 4 cycles and response was assesses by CT scan 4-6 wks after last dose.  Results:  Median time between last dose of anti-PD1 and ipi was 7 months.  4/10 patients had increased LDH on commencement of ipi therapy.  1/10 patients achieved a partial remission as their best response to anti-PD1 therapy with an additional 5/10 having stable disease. 4/10 were given all 4 doses of ipi.  F/U after last dose of ipi has been more than 3 months.  1/10 patients achieved a response to ipi with another 1/10 having prolonged stable disease.  3/10 experienced grade 3/4 immune related AE.  Conclusion: Ipi can induce responses in patients who have failed anti-PD1.  The response rate appears similar compared to patients who have not received prior anti-PD1 therapy.  AE's were observed.  Significance of these observation remains to be seen.

The first two reports are not really news.  Patients who had to stop taking ipi due to side effects can take anti-PD1 (Nivo OR Pembro) without being cursed with their prior side effects from ipi and gain a response.  Additionally, and this is newer as fewer patients have reached this position, you can get a response from ipi after having taken anti-PD1. And ~ myeloid derived suppressor cells need to get out of our way!!! Hang in there ratties.  Sometimes it's a long ride! - c

Primer for Current Melanoma Treatments - New and Improved Version 2022!!!!

Originally posted in 2017, sadly, this primer has needed little in the way of updates since.  Still, there have been a few FDA approvals, meds I didn't include in the first rendition, and some news in the research so it is getting a reboot. Initially created to save re-writes for those in need, I still answer melanoma questions on boards or via email at least every other week, but want to emphasize that this is not an all inclusive listing.  Rather, this is a basic guide to use in starting your research or discussions with your provider regarding melanoma care.  As recently, as 2010, NONE of the current, most effective treatments for melanoma were FDA approved.  Since then, doctors have become more knowledgeable about consistently offering and better skilled in managing these treatments.  Still, it is essential that you be seen by an oncologist who specializes in, or at the very least, has treated many patients with melanoma.  Sometimes a picture is worth a thousand words ~ 

Here we go:

SURGERY

Surgery remains a good choice for many melanoma patients.  Clearly this is the case for a new cutaneous lesion.  Surgery results in an immediate decrease in your tumor burden - almost always a good thing.  However, with data showing good results in NEO-adjuvant treatment, the possibility of using intralesional therapy, or if you are looking for a clinical trial, there are times when measurable disease is needed, so a discussion of these things before surgery is important.  However, for patients with advanced disease decreasing tumor burden through surgery remains an important option for increased survival.  This 2019 report addresses some of the conundrum:  Cut it out!!! Prolonged overall survival following metastasectomy in Stage IV melanoma 

RADIATION

Radiation, when combined with immunotherapy or targeted therapy, can be a very good treatment option for melanoma.  Together, radiation and systemic therapy can illicit responses that are greater than either treatment used as a single agent.  However, targeted radiation (SRS - stereotactic radiation or Gamma Knife) is the most effective whether you are talking about brain tumors or lesions in the body.  We have learned that whole brain radiation (WBR) is not the most effective way to treat melanoma and can lead to debilitation.  While there are those who must avail themselves of this treatment due to extreme circumstances, it should not be the first recommendation right out of the box for those with brain tumors.  Even multiple brain mets can be treated simultaneously with SRS.   Here are zillions of reports regarding the effectiveness of using radiation WITH immunotherapy: Radiation WITH immunotherapy  Here is a report from 2019 regarding the use of radiation prior to targeted therapy:  Better melanoma results with radiation BEFORE BRAFi (at least in this report)

IMMUNOTHERAPY

These are treatments that push our immune systems into action.  Side effects (as you might imagine) are usually related to an 'over activation' of the immune system.  Common side effects include - fatigue, rashes, joint pain.  More complicated side effects are inflammation of the lungs (pneumonitis) and colon (colitis) with difficulty breathing and wheeze or diarrhea and abdominal discomfort, respectively.  Patients can experience problems with thyroid function and other glands of the endocrine system.  Responses take time.  Experts are known to advise other docs to be 'patient with the patient!'  Immunotherapy works best with the lowest tumor burden.

Old school immunotherapy

Interferon

Discovered in 1957, interferons are a type of signaling proteins released by cells in response to viruses, bacteria, parasites, and tumors that help rally the immune response of the body against these invaders. In the early 1980's researchers and pharma were finally able to produce interferon for use as a medical therapy. There are many forms, used in treating various conditions (some more effectively than others) from multiple sclerosis to leukemia to melanoma. Often given as subcutaneous injections (though there are eye drops and inhalation forms), interferon causes significant side effects with fatigue, flu-like symptoms, hair loss, pain, depression and increased risk of infection due to neutropenia (decreased white cells) being common. Unfortunately, we have learned that in melanoma, interferon has a clinically insignificant effect on progression free survival as well as overall survival.

IL-2 (Interleukin 2) also known as aldesleukin, proleukin, and/or sylatron

Similarly, IL-2 is a signaling molecule that directs the actions of white blood cells in getting rid of invaders. Isolated in 1979, by the early 80's pharma (Ceta, Amgen, Roche) were in a mad dash to get a drug to market. It was FDA approved in 1992. It has been used in the treatment of HIV, renal cell carcinoma, and melanoma. Though it can be injected subcutaneously on an outpatient basis, in melanoma it is most often given in an IV infusion, with side effects (extreme swelling, rash/peeling skin, hallucinations, among other horrors) such that patients must be in the hospital, in an intensive care setting, for infusions that are given every 8 hours for up to 15 doses or as the patient can tolerate. It is also used in a low dose regimen with old school TIL therapy as a way to jump start the immune system after chemo has been given to eradicate existing regulatory T cells and new T cells grown from the patient's tumor have been infused.  See this 2021 report:  TIL - A report out of ASCO 2021 and incredible words from one of Melanoma's Most Fearless and Inspiring Leaders  It is also being studied as an intralesional (see below). Ultimately, we now know that the use of high dose IL-2 in melanoma can produce a complete response in about 5-6% of the patients, with some of those responses being durable (lasting).  

Current Immunotherapy (also referred to as Check Point Inhibitors)

Ipilimumab (Brand name = Yervoy, slang = 'ipi') – anti-CTLA-4 monoclonal anti-body

Ipilimumab is a monoclonal anti-body that is used to restart the immune system by targeting CTLA-4, a protein receptor that actually turns the immune response OFF!!! The concept of using anti-CTLA-4 antibodies to treat cancer was developed by Dr. James Allison, for which he was awarded a Nobel Prize in 2014.  It was approved for melanoma (Stage IV or unresectable Stage III) in 2011. It was approved as an adjuvant treatment for melanoma in 2015. However, we have since learned that melanoma patients with advanced disease respond much better to the ipi/nivo combo rather than ipi as a single agent and folks in need of adjuvant therapy do much better with one of the anti-PD-1 products.  Ipi as a single agent was administered via an IV infusion every 3 weeks, for a total of 4 doses, at 3mg/kg for Stage IV patients and 10mg/kg for adjuvant therapy. Some adjuvant treatment plans continued ipi at that same dosage but every 12 weeks for up to 3 years. Melanoma patients given ipi can attain a response rate of about 15%. Responses can be durable.   Patients experience more side effects with ipi than they do with anti-PD-1 products and ipi is the bad boy of side effects in the ipi/nivo combo.  Ipi at 10mg/kg produces more side effects than ipi at 3mg/kg.  The ipi/nivolumab combo was FDA approved in (2015).  In that treatment, patients are given an infusion of ipi at 3 mg/kg after nivo at 1mg/kg is given on the same day, every 3 weeks, for 4 doses, followed by one year of nivo as a single agent. 

Anti-PD-1 (Brand names = Opdivo and Keytruda, Nivolumab and Pembrolizumab respectively.)

      

Background:  PD-1, also called programmed cell death protein 1, is a membrane protein and a T cell regulator, first discovered to be an immune checkpoint in 2000.  PD-1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or digestion of debris or pathogens). Compared to CTLA-4, PD-1 is keyed to specific tissues with the PD-L1 ligand, while CTLA-4 is less specific.

PD-L-1 is a ligand present on the surface of melanoma tumors (as well as some others) that can bind to infiltrating t-cells and turn them off!!

  

ANTI-PD-1 (the drugs) are monoclonal antibodies that block the switch on T cells so that PD-L1, on the surface of melanoma tumor cells, does NOT bind with them and turn them off....thereby allowing these cells to carry on and destroy melanoma tumors.

Sometimes pictures tell the story better:

    Nivolumab: (Brand name = Opdivo, slang = 'nivo') - anti-PD-1 monoclonal antibody

I wrote a little story about the development of nivo here, but basically, in 2014 Nivo was approved for the use in advanced melanoma patients only AFTER they had failed ipi and, if BRAF positive, BRAF inhibitors as well.  In November 2015 it was approved as a first line drug for unresectable or advanced melanoma BUT you had to be BRAF positive.  (A cosmically ridiculous judgement since we already had studies proving that BRAF status made little to no difference in response!!)  Finally, in 2016, based on the results of the  Checkpoint-067 study, nivo was approved for use alone or in combination with ipi, in advanced melanoma patients, no matter BRAF status.  And in 2017, it gained approval as an adjuvant treatment option.  This was seriously good news!!!  It meant even if you are Stage IV with all tumors removed (or zapped) - you can still take nivo.  Or, if you are Stage III with melanoma that went to your lymph nodes - you can take nivo!   Since then, nivo has also been approved for use in NSC lung cancer, urothelial and renal cell cancers, gastric and esophageal cancers, hepatocellular carcinoma as well as head and neck cancers.

      Pembrolizumab: (Brand name = Keytruda, slang = 'pembro') - anti-PD-1 monoclonal antibody

Pembro was similarly approved for advanced melanoma in 2014.  Since then it has been approved in various algorithms for NSCLC, head and neck squamous cell cancers, Hodgkins lymphoma, and endometrial cancers.  In 2019, it was approved for adjuvant treatment of Stage III melanoma and for Stage II adjuvant melanoma in December of 2021.

Response rate and side effects for advanced melanoma patients:

Both anti-PD-1 drugs as single agents effect about a 40% response rate in melanoma. They can work in the brain and the body.  Median time to response is about 3 months.  But, there are outliers, with documented responses, that do not occur until 6 - 9 months.  Here's a cool graph...

Here's a post with more info: Time to Response...Ipi vs Nivo and ipi 

Responses to immunotherapy have proven to be durable!!!   This post includes neat charts regarding response and durability to Pembro: Dr. Daud review from ASCO 2016   There is this from 2020:  Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice  And this from 2021:  ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

Side effects are similar for both drugs and are those typical for immunotherapy, but less severe than those encountered with ipi.  As expected, the ipi/nivo combo has greater side effects than when nivo or pembro are used alone.  On the topic of side effects...they SHOULD be treated!!!  As quickly as possible.  At times, a break from medication and immunosuppressive drugs are required.  While oncologists not familiar with immunotherapy may fear decreased therapeutic response if steroids are used...the preponderance of the data indicates that THIS IS NOT THE CASE!!!!  Clearly, one should not take immunosuppresive drugs unless absolutely needed.  Many patients require varying doses of steroids in order to tolerate necessary, life saving melanoma treatments  and go on to do well!  Further, folks with pre-existing autoimmune disease can be managed on immunotherapy and gain a response as well.  Here are a zillion reports on all of that jazz:  What to do about immunotherapy if you need steroids or have a pre-existing autoimmune disease?

Dosing:

When Pembro is used as a single agent = is dosed at 2mg/kg with max of 200 mg IV every 3 weeks - for one year as adjuvant, end point undefined for advanced melanoma patient.  Nivo as single agent = is dosed at 240 mg IV every two weeks or 480mg IV every 4 weeks - for one year as adjuvant, endpoints vary for advanced melanoma patients. When ipi is combined with nivo, response rates in melanoma rise to 50+%, though side effects increase as well - mostly due to ipi.  For the combo, dosage is:  nivo at 1 mg/kg followed by ipi at 3 mg/kg on the same day, every 3 weeks for 4 doses, then nivo alone at 240 mg q 2 wks or 480 mg q 4 wks. endpoint varies. Many patients cannot tolerate all 4 doses of the ipi/nivo combo due to side effects.  However, outcomes can be good even if you have to stop early. Here's a report from ASCO 2016:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  Further, the ASCO 2021 data (link above) notes "Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N."  Finally, most folks who cannot tolerate the combo can go on to tolerate nivo alone, once their side effects are brought under control with a medication break and/or steroids.  

   Anti-PD-1 (Opdivo) plus Anti-LAG-3 (Relatlimab):

In March of 2022, Relatlimab (an anti-LAG-3 drug) was approved in combination with Nivolumab for advanced melanoma patients in the form of a new drug combo - Opdualag.  Here is a report that covers lots of pertinent data- FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

TARGETED THERAPY

At this point in melanoma, the only approved targeted therapy is for patients whose tumor is positive for the BRAF V600 mutation.  About 50% of melanomas are.  However, researchers are looking at drugs that could target other points in the molecular pathway of melanoma.  This diagram shows what I mean by "pathway"...

A Melanoma Molecular Disease Model (See the link below for credit and more info)

Here's just one example from March of this year:  What tangled 'paths' we weave: Nilotinib for KIT mutated melanoma and Buparlisib for the PI3K pathway in melanoma brain mets

But....for current purposes....I am focusing on the BRAF mutation.  Here's a post I made a bit ago that really breaks down what BRAF is, what it means in melanoma, and how the drugs work:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

Usually when we combine drugs, we end up with increased side effects. However, in the case of BRAF targeted therapy we now know that BRAF inhibitors should ALWAYS be given with a MEK inhibitor.  Strangely enough, when the combo is given, patients experience better response rates, DECREASED side effects, and DECREASED rates of tumor work-around.  The only exception is when MEK inhibitors are used as a single agent in specially mutated patients.

DRUGS, administration, and side effects:

BRAF inhibitor (BRAFi) drugs include:  Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Sorafenib (Nexavar), and Encorafenib (Braftovi)
MEK inhibitors (MEKi) include:  Trametinib (Mekinist), Cobimetinib (Cotellic) and Binimetinib (Mektovi)

These drugs are administered orally.  So that's super cool.  Dosing depends on the particular drug.
Side effects include joint pain, rashes, extreme sun sensitivity, development of benign skin cancers, fevers and sometimes liver toxicity.

EFFECTIVENESS and tumor work-around:

For patients who are BRAF positive, BRAF inhibitors combined with a MEK inhibitor have impressive response rates, clearing tumors rapidly, and often completely, in about 70-80% of patients and are effective in the brain and body. However, those responses are not very durable, with most tumors learning to work around the inhibition in about 7-9 months. BUT!!!!  By using an "alternate dosing schedule" (one that is varied, rather than absolute with an 'every so many hours daily' dosing pattern), combining BRAFi with MEKi, as well as the development of the newer drugs that time can be stretched out a bit.  Furthermore, despite the statistics, there are some melanoma peeps whose melanoma has been successfully managed for years on BRAF/MEK combo's!!  Finally, some melanoma specialists use BRAF/MEK combo's in BRAF positive patients, to rapidly decrease the tumor burden, then switch the patient to slower acting, but more durable immunotherapy.  Picking which targeted therapy to use can be difficult.  Here are two posts that attempt to pull response rates and PFS out of the data ~

From 2018:   Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

From 2019:  BRAF/MEK combo's for melanoma analyzed ~

IMMUNOTHERAPY COMBINED WITH TARGETED THERAPY -

In 2020, the PD-L1 blocking antibody Atezolizumab (Tecentriq) combined with Cobimetinib (Cotellic) and Vemurafinib (Zelboraf) was FDA approved.  Here is a report from 2019 that links to other reports on combining targeted and immunotherapies and includes data from the early atezo/BRAFi/MEKi trials - Treating melanoma by COMBINING targeted therapy AND immunotherapy!

INTRALSIONAL (also referred to as 'intratumoral') THERAPY

Intralesional drugs include (but are not limited to):

T-VEC - also called OncoVEX, Imlygic, or Talimogene Laherparepvec - uses the herpes virus with GM-CSF and is the only intralesional currently FDA approved (2015)  However, the following (and others) have been used in clinical trials:
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 - see note above, is also being used

These drugs are injected directly into a relatively superficial melanoma tumor.  They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy.  I summarized response rates, side effects, and pretty much everything else current about these drugs in these posts which include many links within them: 

From 2021 - Intralesionals for melanoma - some new reports

Out of ASCO that year - Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

                                     -------------------------------------------
I hope this primer will continue to be a helpful jumping off point for those in need.  What has served me best in attaining effective treatment for my melanoma has been seeking out a melanoma specialist (or at least an oncologist who cares for many melanoma patients) and never being afraid to ask questions. Asking this question of my doctor may have been the most beneficial:  "What treatment would you recommend if it were YOU or your brother, sister, wife, father, mother.... in need?"

I wish you all my very best. Hang in there.  And as ever, with enduring thanks to the ratties! - love, c

P.S. If all the acronyms are driving you crazy, here's a post that defines at least some of them:  Melanoma abbreviations ~ and random thoughts on posting melanoma crap-ola....
P.S.S.  A sense of humor really does help!!  AND FINALLY - while not all inclusive, this post from 2019 includes a list of world class melanoma specialists:   Internationally renowned melanoma specialists:  - c