Weber presentation on ipi combo's and combo's coming soon!

Here is a link to Weber's presentation in Paris July 2014:
Combination therapy presentation by Weber

My synopsis:

Nivolumab (anti-PD1) and ipilmumab (anti-CTLA-4) given concurrently-
Nivo at 1mg/kg and ipi at 3mg/kg for 4 doses then followed by nivo alone for 96 weeks.
Best results so far, but with significant toxicities.
Trial requires that when dose limiting toxicity develops, patient must stop trial.
Weber feels you can treat the patient with steroids and then safely resume with nivo alone.
Positive or negative BRAF status did NOT matter in regard to response.
PDL1 tends to "fall out" as a factor...folks positive or negative for it could still respond to concurrent therapy.
In concurrent cohorts = 43% overall response, 17% complete response, 79% 2 year survival
Though that still leaves 50% of patients who did not respond.

Nivo and ipi given sequentially-
Group with nivo first, followed by ipi - another with ipi first, followed by nivo
He is working on the study currently with Hodi.
The hope is that a higher dose of ipi can be administered in this manner without invoking dose limiting toxicity and yet increase response rates.

Ipi and Tvec-
The idea here is that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic ipi.
Overall response rate of 56%, with 6 of 18 patients acquiring complete responses.
Weber likes the idea of priming tumors locally and following with systemic therapy, either ipi or anti-PD1.

Ipi and INCBO24360 (an IDO inhibitor)-
The problem with immunotherapy is that there are suppressive influences in the immune system - the absence of effector cells, the presence of t-reg suppressor cells (activated by LAG-3), myeloid suppressor cells, IDO (which is generated by antigen presenting cells as well as T-cells)....all working to prevent an immune response against melanoma! In this study, an IDO inhibitor was given (at either 25 or 50mg) orally, twice daily, everyday.  Ipi was given at 3mg/kg every 3 weeks.
Was well tolerated.  33% response rate.
Immunotherapy naive patients did better.
This study speaks to the ability to overcome micro-environmental immune suppression as well as increase the influx of effector cells by decreasing IDO.

Nivo and peptide vaccine-
Idea was that if you gave multi-peptide vaccine you could amplify the immune response against the peptide, and get a better response from nivo.  No evidence that this worked at all, though nivo itself did well.
100 patients, initial ones got peptide vaccines with escalating nivo dose, depending on cohort, every 2 weeks for 6 months, then nivo alone every 3 months for 2 years.
Cohort was added (later) that allowed patients who had dose limiting effects on ipi-
20 evaluable patients as one dropped out.
Got nivo alone (no vaccine).
8 confirmed partial responses and 3 stable patients at 24 weeks.  All patients who responded still remain in remission, with one being out 1 1/2 years.
Only 2 patients had dose limiting toxicity on nivo...rash and pneumonitis.
However, these were not the same DLT that they had experienced on ipi.
40% response rate.
Most anti-PD1 trials haven't allowed patients with prior bad responses to ipi.  Weber feels as these patients go to doctors seeking anti-PD1 as it comes on the market, they should be treated with it!
Back to general results-
The presence of peptides or not, ipi refractory or naive - made no difference in results.
26% response rate in these very ill patients, s/p multiple treatments.
NOTE by Weber:  The pembro studies demonstrate a significant difference in response rate between ipi naive and ipi refractory patients [with refractory doing less well].  "It makes you wonder- Are these drugs really the same?"
Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.
There was worse overall survival in female patients.
Given responses in this group with 2 1/2 year end-point of anti-PD1 infusion...Weber questions whether patients really need to continue anti-PD1 infusions until progression as the Pembro trials/indications have been written.

Ipi and Peg interferon-
Ipi at 3mg/kg every week for four doses with 3mg/kg peg interferon sub-q weekly for up to 3 years.
30 patients. 1 compete response. 13 partial responses. 3 with stable disease.  46% response rate.

Planned combo's-
Pembro and T-vec
Pembro and IDO inhibitor
Pembro plus BRAF plus MEK
MEDI 4736 and anti-PDL1
Nivo and anti CD137 (to start in the next month or so!!!)
Nivo and anti-LAG-3
Adjuvant ipi and Nivo (now being expanded with 1,500 patients!!!!)
     So far, in patients in the first cohort - there has been a 45% response rate, with only 20 patients and only at 8 month f/u...no relapses, and includes patients with Stage IV/IIIC melanoma.

So there you have it folks.  Hope this helps! - 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 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

Ipilimumab in combination with other medications for melanoma....per ASCO

Ipilimumab (ipi, yervoy) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that down regulates the immune system in melanoma patients. Alone, it has a response rate of 10-15%.  But, has 4 year survival rates of 37-49%, and 3-10 year survival rates in 17-25% in melanoma patients.  Given its potential, investigators have been examining drugs that can be safely combined with ipi, in ways that will improve response rate.

A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma
Abstract 9098, Kudchadkar, Gibney, Corman, Merek, Weber, et al.

Ipi, at 3mg/kg every 3 weeks for 4 doses was given with concurrent peginterferon at 3mcg/kg weekly for up to 156 weeks.  31 patients.  2 complete responses, 9 partial responses, 3 with stable disease, and 12 with progressive disease in 26 patients evaluable for response so far.  5 patients have not yet completed the first cycle.  Toxicities for peginterferon were dose-limiting with 7 patients requiring dose reduction (nausea, vomiting, leukopenia, dehydration, and hyponatremia). Conclusion:  The combo had a 42.3% response rate.  

Outcome with stereotactic radiosurgery and ipilimumab for malignant melanoma brain metastases.
Abstract 9076, Shoukat, Marcus, Rizzo, et al.

Patients with melanoma brain mets who underwent SRS between 1998-2012 (n=176) were compared to those who additionally received ipi (n-38).  Median overall survival for the cohort was 9 vs 7 months in the non-ipi group.  Patients in the ipi group had a median survival of 28 vs 7 months in the non-ipi group.  No increased toxicity or need for repeated SRS in the ipi group.  Conclusion:  SRS with ipi appears safe and associated with an increase in overall survival in patients in melanoma brain mets.

Preliminary results from a phase 1/2 study of INCB024360 combined with ipi in patients with melanoma
Abstract 3010, Gibney, Hamid, Gangadhar, et al

Indoleamine2,3-dioxygenase 1 is a tryptophan-catabolizing enzyme that is over expressed in cancers and induces immune tolerance by suppressing T-cell responses. It has been well tolerated as monotherapy.  This was an ongoing dose-escalation study of INCB024360 with ipi.  7 patients were enrolled at 300mg twice daily.  5 patients developed ALT elevations after 30-76 days on treatments and enrollment was stopped.  ALT increases reversed with steroids and discontinuation of the drug.  6 of 7 patients had scans before discontinuation and all showed immune response stable disease.   Enrollment was restarted at 25mg twice daily with 8 patients.  1 patient progressed with extensive liver mets.  6 of the 8 patients had tumor reduction by the first evaluation.  Confirmed disease control rate was 75%.  3 patients had confirmed immune response partial response.  A 50mg twice daily cohort is enrolling.   Clinical trial info = NCT01604889.  This study started enrolling in 2012, but as of postings in Feb and March 2014, it seems recruiting is ongoing.  Locations appear to be available in CA, FL, PA, NC, and IL.  It is ipi and drug vs ipi with placebo. Hopefully the lower doses of INCB024360 will not cause problems with elevated liver enzymes.

Phase 1 study of the BRAF inhibitor dabrafenib with or without the MEK inhibitor trametinib in combination with ipi for V600E/K mutation-positive unresectable or metastatic melanoma
Abstract 2511, Puzanov, Callahan, Linette, et al

Patients with Stage IIIC/IV BRAF V600E/K, melanoma with one prior treatment or less are eligible.  10 patients enrolled thus far.  4 had ipi and dabrafenib.  2 had dabrafenib only [thus far]. 4 had ipi/dabrafenib/trametinib.  In the ipi + D group - no dose limiting toxicities were observed.  Most common adverse events = chills, fatigue, hand-foot syndrome, fever, and rash.  Of the 4 patients - 2 are ongoing and 2 had disease progression.  Patients are currently being enrolled at this level.  At the ipi/D/T level - 1 dose limiting toxicity (colitis associated with ipi occurred), most frequent adverse effect = fever, chills, arthralgia, insomnia, and rash.  One patient had renal insufficiency that reversed rapidly.  Of these 4 patients, 1 stopped due to the dose limiting colitis and 3 are ongoing.  Clinical trial info - NCT01767454.  Recruitment began in 2012, but was verified to be continuing as of April 2014.  Participants must have the V600 mutation, measurable tumor, treated/stable brain mets, and NO prior ipi, anti-PD1, Brafi, or MEK. Patients will be given dabrafenib and ipi or dabrafenib + trametinib and ipi.  Locations:  San Fran, LA, Boston, St Louis, NY, Nashville, Houston.

Sending my love to the 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

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

It goes without saying that over the years I have posted a zillion reports about all things immunotherapy:  anti-PD-1 ~ Pembrolizumab (also referred to as Pembro and Keytruda) as well as Nivolumab (also called nivo and Opdivo) both of which have very similar side effect profiles and a roughly 40% response rate when used alone; anti-CTLA-4 ~ ipilimumab (also called ipi and Yervoy) which has similar side effects but with greater frequency and intensity than the anti-PD-1 products {though many tolerate it well} with about a 15% response rate when used alone; as well as the ipi/nivo combo which has a response rate of 50+%. (Here's a link:  ASCO 2016: Checkmate 069 - ipi/nivo combo in Stage IV melanoma demonstrated a 68% ORR)  Consistently, treatment naive patients have responded best to all of the above, responses are the most durable we have ever had in any melanoma treatments, many folks continue to respond even if they have to stop treatment due to side effects.  We have also learned that side effects need to be treated as soon as possible, often with steroids, so as to save lives and prevent greater damage than has already occurred, AND the use of steroids, if needed, DOES NOT IMPEDE RESPONSE!!!!  Feel free to use the blog's search bubble to find more info and data on all of this.  Now researchers are looking at:

Pembro plus ipi:

Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.

ASCO 2017. J Clin Oncl, 35, 2017. Carlino, Atkinson, Cebon, et al.

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAF^V600mutant, and 13% received greater than/= to 1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61%; the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

Here 153 Stage IV melanoma patients (no brain mets) but some with increased LDH were given Pembro 2mg/kg and ipi at only 1mg/kg, together every three weeks for 4 doses and then pembro alone q 2 wks.  There were no treatment related deaths, though ALL patients had side effects, but were grade 3/4 in only 45%.  The way the data was examined ~ with one near endpoint and another 7 months later...proved...AGAIN...that responses can occur late....and as per Weber and Agarwala, when it comes to immunotherapy, "Give the patient time!" ~ for an ultimate ORR of 61% and CR of 15%.  So....these responses are no better than those demonstrated in the ipi/nivo combo.  But...what is interesting is that ipi was dosed at only 1mg/kg whereas in the ipi/nivo combo it is used at 3mg/kg. (AGAIN!!!  Why can't researchers [and Big Pharma!!!!] construct trials so that you can REALLY compare results!!!) At any rate, this tidbit of data may prove important in decreased side effects and it would be important/interesting to see if nivo with ipi at only 1m/kg would continue to do as well as the combo does currently.  I'm betting it would....but that's just me.

While the next couple of articles did not come out of ASCO this year...they pertain to the topic at hand...so I've included them here.

Here, researchers looked at the response to ipi after patients have progressed on pembro:

Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma  KEYNOTE-006 Poster Spotlight: G. Long (Australia).  European Cancer Conference, Jan 2017.

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti–PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab.

Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported.

Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAF^V600-mutant tumors at baseline. Best response to pembrolizumab was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks, and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks. Median duration of ipilimumab was 8 weeks. The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received greater/= to 1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months.

Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.

So in 97 patients, most of whom had taken pembro for about 18 weeks with a PR in 16% and SD in 12%, PD in 62% (clearly, these were folks who were not responding to pembro as well as the usual data) were, in about 5 weeks placed on ipi at 3mg/kg, with most folks taking it for 8 weeks.  At that point, the ORR to ipi was 14% (which is what responses to ipi usually run at).  Additional data showed:  CR in 3%, PR in 11%, SD in 33%, PD in 33%.  While not great, this certainly shows that if you are not a responder to pembro....switching ASAP to ipi can gain a response of about 15%.  A similar response was attained in the last abstract noted in this post from ASCO 2015:  ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Here researchers looked at how tumors, and subsequently the patients!!!, responded to pembro:

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Nishino, Giobbie-Hurder, Manos, et al. Clin Cancer Res. 2017 June 7.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.
Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained less than 20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with less than 20% tumor burden increase from baseline had longer OS than patients with greater than/= to 20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with less than 20% tumor burden increase during therapy had significantly reduced hazards of death.  Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of less than 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention.

Here 96 patients with measureable disease were given pembro.  ORR was the expected 44%.  Folks whose tumor burden increased less than 20% from their baseline, once therapy was started, did best, and this was 55% of the peeps in the study.  They ended up with a longer OS than those whose known tumor burden increased more than 20% from baseline while on pembro.  Of course!  If your tumors mostly just shrink while on treatment...you do better!!!   BUT!  The pseudoprogression thing is real for some...albeit in small numbers...3 patients had target lesions increase in size but went on to gain a response and 1 patient that didn't have measureable disease when they started treatment developed a new lesion that then regressed.

Well, there you have it.  Things remain about as clear as mud if you are a melanoma patient who is progressing on immunotherapy as to trying to decide what to do next!!!  But....it is clear...that there is hope.  Love and luck to all the ratties - c

Background and latest info on anti-PD1 for melanoma

With the publicity of Merck's expanded access program (Hopefully they will actually TREAT a patient SOON!) for their anti-PD1 product, and the buzz around anti-PD1 generally...there have been many questions posed on the various forums about anti-PD1 lately.  Having had anti-PD1 (in the form of Nivolumab, BMS' product) as an ever present part of my world since December of 2010, I forget some folks don't know what it does and how.  I even looked back on my blog, and realized I hadn't posted many of the latest official results and info...so...here you go:

What is anti-PD1?  In the simplest possible terms:  Anti-PD1 drugs are antibodies that block the switch on white cells so that they can now attack melanoma cells.  Specifically, programmed death ligand-1 [PD-L1] is produced by the surface of melanoma tumors.  That ligand binds to the infiltrating T-cells, down-regulating them.  Basically, turning those cells "OFF" to melanoma.  ANTI-PD1 blocks that potential interaction, so that the T-cells can now attack melanoma cells.

How is it given?  In your vein through an IV or port.

At what dose?  They are still checking the results of various Nivolumab doses: 1, 3, or 10mg/kg.  I was given 1mg/kg.  If I had to guess, the FDA approved dose will probably be 3.  Positive effects against melanoma have been seen at all dosage levels.

What are the side effects?  
Rashes and Fatigue - very common.
Arthralgias - joint pain is frequently reported.  Inflammation triggered by the immune response does not make joints happy.
Mucositis - irritation of the mucus membranes, from redness and tenderness to pain and lesions.  (The gut is just one long tube that starts in the mouth after all....see Colitis below.)
Hypothyroidism - not as common, but certainly has happened.  Often treatable with thyroid hormone in pill form, synthroid.
Colitis - irritation and inflammation in the bowel that can cause diarrhea and bleeding.  Sometimes, causing dehydration and the need for hospitalization, fluids, discontinuation of the drug for a time or permanently, and at times prednisone to stop the progression.  This is a fairly common cause of patients being taken off ipi and anti-PD1.
Pneumonitis - significant inflammation in the lungs that may be treated as noted above and has even been a cause of death for patients on ipi and anti-PD1, and obviously removal from a trial or treatment.
Pituitary failure and vision problems related to the optic nerve, as well as retinitis, have occurred but are not reported as common events.
Vitiligo - the depigmentation of the skin (and/or hair), leaving white patches.  Thought to occur because of the shared antigens located on melanoma cells and normal pigment cells.  It is considered a good prognostic sign that the drug is working against melanoma and occurs in 5-9% of patients on ipi or anti-PD1.


Survival, Durable Tumor Remission, and Long-Term Safety in Patients with Advanced Melanoma Receiving Nivolumab  Topalian, Sznol, Sosman, Hodi, et al.  Journal Of Clinical Oncology.  March 3, 2014

107 patients with "advanced melanoma [out of 306 patients with various cancer types], enrolled between 2008 and 2012, received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation."
In the 107 melanoma patients:  Median survival was 16.8 months.  1 year survival = 62%.  2 year survival = 43%.  In 33 patients with objective tumor regression, estimated median response duration was 2 years.  Toxicities in all 306 patients were similar to those previously reported. 
Conclusion:  Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations.  Responses were durable and persisted after drug discontinuation.  Long-term safety was acceptable. 


NOTE:  The above trial is the one that Dr. Weber was comparing the Moffitt trial results to on my last visit.  Link to the results we discussed:  discussion of my anti-PD1 trial results

The report below is from the sister arm, of NON-resected patients, from my anti-PD1 trial, though I am in the NED arm.  Also keep in mind, that when I started, folks who had been given ipi were not allowed in, but later arms were created that allowed patients who had failed ipi to participate.  Additionally, those of us originally enrolled in all arms were given vaccines, but since they were found to have no positive effect, later arms did not take them.  This report addresses all those arms EXCEPT mine, the NED cohort.

Safety, Efficacy, and Biomarkers of Nivolumab with Vaccine in Ipilimumab-Refractory or -Naive Melanoma.   Weber, et al.  Journal of Clinical Oncology.  December 1, 2013.

"We report the results of treatment of patients with unresectable metastatic melanoma who were ipilimumab naive (34 patients) or refractory (56 patients) and received nivolumab at 1, 3, or 10mg/kg.  Some patients also received an HLA-A 0201-restricted multipeptide vaccine."

"90 patients were enrolled at Moffitt Cancer Center between August 2010 and December 2012. 87 were evaluated for response, and three were too early for response evaluation. 74 patients had primary cutaneous melanoma. 8 had ocular mel. 8 had an unknown primary. 3 patients experienced progression on BRAF-i before enrollment.  10 had radiated brain mets. 5 patients in cohort 6 had untreated brain mets."

"Most common adverse event = fatigue. One patient experienced grade 3 bilateral optic neuritis, one had fevers, 2 others had pneumonitis...all resolved with steroids over 4 weeks to 4 months and discontinuation of treatment. Colitis was not seen in this trial.  Rashes were common, 1 required prednisone.  No treatment related deaths were observed."

"Median follow-up times were 20.3 months for patients in cohorts 1-3, 6.8 months for cohorts 4-6, and 8.1 months for all patients.  In ipi naive patients (n=34):  2 patients had a complete response, 6 had partial response, 7 had stable disease at 24 weeks, and 19 had progressive disease. Disease control rate = 45%.   In responders, median follow-up of 21.2 months, median duration of response was not reached.  In ipi refractory patients (n=53): 14 patients had partial response, 11 had stable disease at 24 weeks,  28 experienced progression.  Disease control rate = 47%.  In responders, median follow-up of 8.4 months, median duration of response was not reached.  For all 87 evaluable patients (ipi refractory and naive) the response rate was 25%, with a disease control rate of 46%.  Median duration of response was not reached at a median of 8.1 months.  PD-L1 tumor staining was associated with responses to Nivolumab, but negative staining did not rule out a response."

NOTE:  "12 of the 18 non-responders in cohorts 1-3 subsequently received ipi at 3mg/kg for a planned 4 doses. 2 patients had partial response.  2 had mixed response. 8 had progressive disease. 2 required steroids and infliximab for dose limiting colitis with ipi.  But, it demonstrates that patients who progress on Nivo can respond to ipi."

Hope that helps.  Wishing each of you 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

Combination therapies for melanoma

New Combinations and Immunotherapies for Melanoma, Latest Evidence and Clinical Utility
Menzies and Long, Ther Adv Med Oncol. 2013;5(5):278-285.

Despite being a little over a year old, and most of the studies referenced - I've already posted, this article still presents a very good overview of the combination therapies with some clear explanations.  Here are the highlights:

Combination BRAF and MEK Inhibitors

Several trials have combined BRAFi and MEKi for patients with V600 BRAF-mutant melanoma.
1.  Dabrafenib with trametinib (CombiDT)
2.  Vemurafenib with cobimetinib
3.  LGX818 with MEK 162

The reason for the combinations is twofold:  to prolong the progression-free survival by delaying or preventing the development of MAPK-dependent resistance and to reduce BRAFi related toxicities as a result of the paradoxical activation of the MAPK pathway in non-melanoma BRAF wild-type cells.

In normal cells, growth factors bind to the cell surface receptor tyrosinekinases (RTKs).  There they trigger signals down various pathways:  RAS-RAF-MEK-ERK(MAPK) and P13K-AKT-mammalian target of rapamycin (mTOR).  This [normal] signaling creates regulated cell proliferation, growth and survival.  Melanoma causes abnormal activation of the MAPK pathway, and include activation of mutations in BRAF (40-50%), NRAS (20%), and KIT (less than 5%).

1.  Dabrafenib with trametinib (CombiDT)
Initial data showed that response rates were higher with CombiDT than with dabrafenib alone, BUT, only 19% of patients who had failed prior BRAFi therapy got a response.  The randomized section of the trial showed a higher response rate (76% vs 54%), longer median progression free survival (9.4 vs 5.8 months), and fewer toxicities in MAPK inhibitor naive patients compared with dabrafenib monotherapy.  All BRAFi toxicities:  hyperkeratosis, alopecia, arthralgia and rash were less frequent.  Cutaneous squamous cell carcinoma with CombiDT was 1/3 of that with dabrafenib alone (7% vs 19%).  Fever was the most common AE and occurred in 70% of patients on CombiDT, but was found in only 26% of dabrafenib only patients.  Mechanism is not understood.  Fevers occur early, are often repetitive, can be managed with brief dose interruption, or if recurrent...with corticosteroid prophylaxis.

2.  Vemurafenib with cobimetinib
In the phase 1 trial, 70 patients with Cobas-positive metastatic melanoma, of which 38 (54%) had failed to respond to prior vemurafenib.  {The Cobas 4800 BRAF V600 mutation test by Roche, is a polymerase chain reaction based test that is very sensitive and specific for V600E BRAF mutation, but only detects 40-70% of V600K and no other V600 mutations.}  All 25 BRAFi naive patients had a reduction in tumor size.  In 32 patients previously treated with BRAFi, the response was only 19%.  Squamous cell carcinoma, rashes, arthralgia, and fatigue were decreased with the combo compared to vemurafenib alone.  MEK inhibitor AE's:  creatine kinase elevation, diarrhea and chorioretinopathy were reported in 4-6% of patients.

3.  LGX818 with MEK 162
The phase 1 trial of the BRAFi, LGX818 and the phase 1/11 trial of the combo, LGX818 and the MEKi, MEK162 allowed any V600 BRAF mutation, including rare variants like V600R.  The phase 1 trial of the BRAFi LGX818 monotherapy enrolled 26 BRAFi naive and 28 BRAFi pretreated patients.  Results showed a confirmed response rate of 58% in BRAFi naive and 11% in BRAFi pretreated patients.  Unlike vemurafenib and dabrafenib - photosensitivity, liver enzyme elevations, and fever were rare.  In the combo trial - 9 BRAFi naive and 14 BRAFi pretreated patients were studied.  There was a confirmed response rate of 88% in naive patients and an 18% response in pretreated patients.  No fever, photo-sensitivity, nor squamous cell carcinoma reported thus far.

Anti-PD1 and Anti-PD-L1 Antibodies [immunotherapy]  (Note:  what follows is pretty old news but a good summation of data, especially from the early trials.)


Unlike CTLA-4 antibodies, the PD-1 and PD-L1 antibodies aim to potentiate the antitumor T-cell response at a tumor-specific level, by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells.  T cells interact with tumor cells in peripheral tissues.  Tumor cells can present antigen to the T-cell receptor, resulting in a stimulatory signal to the T cell.  Tumor cells may also express PD-L1, which interacts with PD-1 on activated T cells, and results in inhibition of the antitumor T-cell response.  (See below)

Nivolumab (BMS-936558, MDX-1106, ONO-4538, Opdivo)  Anti-PD1
A fully human immunoglobulin monoclonal PD-1 antibody and was first of its class to be tested in a phase 1 trial with 107 patients with metastatic melanoma with no exclusions. Approximately 25% of patients had received 3 or more lines of systemic therapy, responses were seen throught the range of doses given every 2 weeks, with an overall response rate of 31% (41% in the 3mg/kg group).  Median duration of response was over 2 years.  Well tolerated generally.  Toxicities were immune related and were less frequent and less severe than with ipi.  Common toxicities were: fatigue, rash, diarrhea, and itching.  Grade 3/4 AE's occurred in 21% of patients = lymphopenia, fatigue, diarrhea, nausea and anemia.  Pneumonitis was a rare but significant side effect, resulting in the death of three patients.  There was no association between drug dose and efficacy or toxicity.

Lambrolizumab (MK-3475, Pembrolizumab)  Anti-PD1
A humanized monoclonal PD-1 antibody, studied in phase 1 trial that included 132 patients with metastatic melanoma.  67% of patients had BRAF wild type, 9% had brain mets.  Overall response rate was 51% in the 85 patients dosed at 10mg/kg.  Ipi naive patients had a response rate of 55%. Patients who had progressed on ipi had a 41% response rate.  15.9% of entire cohort had immune related AE, only 5.3% of those were grade 3/4.  All grade 3/4 toxicities were at the 10mg/kg dose and included: nephritis, pleuritic pain, pancytopenia, pneumonia, v/d, thyroiditis.  Pneumonitis occurred in 3% of patients, all grade 1/2 and was managed with dose interruption, and in once case, steroids.

BMS-936559 - PD-L1
A fully human PD-L1 antibody, was tested in 55 patients with metastatic melanoma.  56% of the patients had received prior immunotherapy and 9% had had BRAFi.  Overall response rate was 17%.  Highest response rate was in the 3 mg/kg dosage. Of the 9 who responded, 5 had an ongoing response for over a year, and overall, 27% of patients had stable disease for over 6 months.  Toxicity was mild.  9% of patients had grade 3 AE's, 39% had immune adverse event of any grade - rash, hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, DM, and myasthenia gravis.

Future Implications

• MAPK inhibitors in combination result in response in almost every patient and are more durable than single agent responses, but acquired resistance is still an obstacle, and most patients relapse within a year.  However, there is a subgroup of patients that may benefit for a prolonged period.
• PD-1 and PD-L1 immunotherapies provide faster and more frequent responses than ipi, but durability remains unknown {though we are gaining more info daily!!}.
• Combining MAPK inhibitors and immunotherapy seems to have a real possibility of greater success.  However, the first combo trial tried (vemurafenib and ipi) had to be terminated due to liver toxicity, a known side effect of both drugs.  Trials with dabrafenib and ipi with/without trametinib are underway.
• IPI and nivo combined, and ipi combined with radiation, are producing good results.
• Though not compared head-to-head, anti-PD1 and anti-PDL1 are probably more active and have fewer toxicities than ipi.  Also, the possibility that tumor PD-L1 expression may be a biomarker to predict response is appealing. In one nivo trial, no responses were seen in 17 patients with tumors that did not express PD-L1, while 9 of 25 patients with PD-L1 expression had a response.  Pretreatment biopsies have been collected for all patients on the lambrolizumab trial and results are awaited.
• The greatest role for systemic treatments may be in the adjuvant setting.  The risk of distant relapse and death in patients with high-risk early stage melanoma (11C/111) is approximately 50%.  The only approved adjuvant, interferon, is toxic and has little impact on survival.  Several drugs ipi, MAGE-A3, vermurafenib, and CombiDT are in ongoing trials as adjuvants vs placebo....so.....

We've come a long way, baby!!!  But, we still have a long way to go!!!! - c