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

FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

Finally, an additional FDA approved treatment for melanoma!!  With FDA approvals for the first immunotherapy and targeted therapy in melanoma in 2011, the addition of Nivo and Pembro in 2014, a few additional BRAF/MEK combo's in 2013 and 2018, T-VEC approved as an intralesional in 2015, immunotherapy approved as adjuvant in 2017, targeted as such in 2018 - that's been about it for new melanoma therapies.  I recently reported on study results for Relatlimab combined with Nivolumab (Opdivo) for treatment of advanced melanoma in February:  Relatlimab plus Nivolumab in advanced melanoma patients - better than Nivo (Opdivo) alone!  The main take-away from the data being:

1.  The combination of the anti-LAG-3 product relatlimab with anti-PD-1 agent Nivolumab provided better progression free survival than when melanoma patients with advanced disease were treated with nivo alone - "The median progression-free survival was 10.1 months (6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (3.4 to 5.6) with nivolumab. Progression-free survival at 12 months was 47.7% (41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab."

2.  Nivo and Pembro when used as single agents are both known (through data collection over many years) to have an approximate response rate of 40%.  The second article in the link above addressing relatlimab combined with nivo notes (though tallied as PFS):  "Median progression-free survival was 10.1 months in the combination arm and 4.6 months in the monotherapy arm. After 12 months’ follow-up, progression-free survival rates were 47.7% in the combination arm versus 36% in the monotherapy arm..."  The ipi/nivo combo is recognized to have a response rate of 50%+.  The fourth article in this 2021 post - ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!! - notes:  "In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively)."  But, we know that PFS and OS is higher earlier on after treatment, so in the first article from this 2017 report - Do melanoma peeps with side effects to immunotherapy have a better response? - it notes:  " 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."

3.  Though the combo had greater side effects than when nivo was taken alone - "Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group."  - we know that about 40% of patients on ipi/nivo have to stop the combo due to side effects, with about 55% experiencing grade 3/4 adverse events. 

4.  This post reviewed the Relativity trial of relatlimab and nivo in 2021 - Something "new" in melanoma treatment???? Anti-LAG-3! Again....  Despite the new data and having been reporting on anti-LAG-3 since 2014, I think my summation there still stands:

My take:  It seems that the combination of relatlimab and nivolumab (Opdivo) has a response rate that is slightly less than that of the ipi/nivo (Ipilimumab/Yervoy and Nivolumab/Opdivo) combo which has proven to be around 50+ percent, but one that is possibly better than the 40% response rate when anti-PD-1 (nivo or pembro) is used alone. Perhaps the two most important things these (still preliminary - after all these years) reports tell us is that ~

1.  Side effects, that can be so devastating and difficult in the ipi/nivo combo may be much decreased in the relatlimab/nivo combo.

2.  For reasons we don't fully understand, melanoma responds differently to the same treatment in different folks.  For me, thus far, nivolumab alone was 100% effective.  Obviously that is not the case for most melanoma patients.  So having another effective immunotherapy combination, that may well be far less than 100% effective in all of us, may still be completely effective in some.

And, finally, as ever - the drug company did not see fit to configure the trial such that the new combo went up against the old one directly.  Why not BMS?  Why not????  Why not three arms?  One with nivo alone.  One with the ipi/nivo combo? And the third with relatimab/nivo?  WHY???

5.  We still don't have durability of response data to this combo - but I would presume (given the durability we know about responses to nivo) they would be good.

SOooooooooooooooo - there you have it - a newly FDA approved combo for melanoma dubbed - OPDUALAG!!!!  (Seriously, these names!  My word!)

Now, this:

FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma

March 18, 2022  Krista Rosa OncLive

The FDA has approved the fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.1

The regulatory decision is based on data from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which showed that the doublet (n = 355) resulted in a median progression-free survival (PFS) of 10.1 months vs 4.6 months with single-agent nivolumab (n = 359; P = .0055).

“Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we’ve seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma,” F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute, stated in a press release. “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

To be eligible for enrollment to RELATIVITY-047, patients had to have previously untreated, unresectable, or metastatic melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were randomized 1:1 to receive the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg administered every 4 weeks vs single-agent nivolumab at the same dose and schedule.

Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 M stage.

The primary end point of the trial was PFS per blinded independent central review (BICR). Secondary end points included overall survival (OS) and ORR per BICR. End points were tested in hierarchy, with PFS evaluated first, followed by OS, and then objective response rate (ORR).

Baseline characteristics were well balanced between the arms. The median age of participants was 63 years, 41.7% were female, and 66.9% had an ECOG performance status of 0. The serum lactate dehydrogenase level was above the upper limit of normal in 36.1% of patients.

LAG-3 expression was 1% or higher in 75.2% of patients, and it was lower than 1% in 24.8% of patients. PD-L1 expression was at least 1% in 41.0% of patients, and lower than 1% in 59.0% of patients. Moreover, 38.5% of patients had BRAF-mutated disease, and 61.5% had BRAF wild-type disease. Lastly, 65.7% of patients had AJCC M stage of M0/M1any[0], and 34.3% had M1any[1].

Data presented during the March 2022 ASCO Plenary Series showed that at a median follow-up of 19.3 months, the median OS with the doublet had not yet been reached vs 34.10 months with nivolumab monotherapy.  Although this benefit was not found to be statistically significant, it was considered to be clinically meaningful.

Additional data showed that PFS rates continued to be higher in the doublet arm vs the monotherapy arm. At 12 months, these rates were 48.0%  and 36.9%, respectively; at 24 months, these rates were 38.5% and 29.0%, respectively.

Notably, PFS and OS benefit favored the doublet over the monotherapy across all stratification factors that were assessed.

In the investigative arm, the complete response rate achieved was 16.3%, the partial response rate was 26.8%, and 17.2% of patients experienced stable disease. Additionally, 29.6% of patients in this arm had disease progression.

The median duration of response had not yet been reached in both the relatlimab/nivolumab arm and the control arm. Moreover, the disease control rate achieved with the doublet was 62.8% vs 50.7% with the monotherapy.

Notably, fewer patients who received the doublet went on to receive subsequent therapy vs those who received single-agent nivolumab, at 40.8% and 42.6%, respectively. Specifically, fewer patients in the investigative arm received systemic therapy vs those in the control arm, at 32.7% vs 34.5%, respectively. Additionally, 11.8% of patients who received relatlimab/nivolumab went on to receive PD-L1 and/or CTLA-4 inhibitors vs 15.9% of those who received nivolumab monotherapy.

Specifically, 4.2% of patients on the relatlimab/nivolumab arm went on to recive nivolumab and ipilimumab (Yervoy), 4.2% received nivolumab monotherapy, 3.7% received ipilimumab, 1.7% received pembrolizumab (Keytruda) monotherapy, and no patients received single-agent avelumab (Bavencio); these rates were 6.7%, 5.6%, 5.3%, 2.8%, and 0.3%, respectively.

Additionally, 12.4% of patients on the investigative arm went on to receive BRAF and/or MEK inhibitors vs 14.8% of those on the control arm. Other subsequent treatment was received by 13.8% of those who received the doublet vs 12.3% of those who were given the monotherapy. Slightly more patients on the investigative arm received radiotherapy at 14.6% vs 12.3% on the control arm; however, more patients on the control arm underwent surgery, at 8.1% vs 7.0%, respectively.

The fixed-dose combination is associated with severe and fatal immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions. The doublet is also linked with complications of allogeneic hematopoietic stem cell transplantation and embryo-fetal toxicity.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” Samit Hirawat, chief medical officer of global drug development at Bristol Myers Squibb, added in the press release. “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”

An updated "Primer of Melanoma Treatments" to be posted soon.  Hang tough, peeps! - 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

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

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

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

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

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

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

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

Now, there are these:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

 As disheartening as it can be to experience treatment that does not do all that we need it to or have dear ones who do not respond to current melanoma treatments - therapies for melanoma have come a long way, baby!!!!  Not only are more folks than ever before responding to therapy - these responses are proving durable!  Here are some outcome studies ~

Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).  Georgina V. Long, Victoria Atkinson, Serigne Lo, et al.  ASCO 2021.

Background:  Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242).

Methods:  This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety.

Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only.

Conclusions:  Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129).Clinical trial information: NCT02374242.

My takeaway - Immunotherapy works for brain mets!  BUT - most folks need the combo!!!!

As was mentioned briefly in yesterday's post - the ipi/nivo combo can be a rough road in regard to side effects and a good 40% of patients cannot tolerate all of the approved doses.  However, as far back ASCO 2016 we knew that folks who had to stop therapy early due to side effects, responded about as well as those who completed all doses:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  This study wanted to see if those responses were durable ~

Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.  Ma, Sun, Sitto, et al.  ASCO 2021.

Background:  Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes.

Methods:  We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis.

Results:  199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS and OS compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS and OS. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 for PFS and HR 0.56 for OS.

Conclusions:  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. Longer follow up and prospective studies are warranted to validate our findings.

Per this report, it looks as though those who showed benefit to therapy early, did indeed have similar survival, even when they took fewer that the 4 recommended combo doses!

This study looked at the characteristics of peeps who lived 5 years past immunotherapy for melanoma ~

Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).  Loo, Goldman, Panageas, …Chapman…Wolchok…Postow, et al.  ASCO 2021.

Methods:  We retrospectively reviewed all patients treated at Memorial Sloan Kettering for unresectable stage III/IV melanoma who survived at least five years following their first dose of ICB (N = 151). Demographics, disease characteristics, and nature of progression were examined. Overall survival (OS) was calculated from 5 years post-ICB. Time to Treatment failure (TTF) was calculated conditionally from 5 years out until next therapy, progression, or death.

Results:  Of the 151 long-term survivors, median age at first ICB treatment was 62 years (range 22-83), with 101 (66.9%) male and 50 (33.1%) female patients. Stage at first ICB treatment was unresectable stage III (26, 17.2%), M1a (21,13.9%), M1b (39, 25.8%), M1c (52, 34.4%), M1d (13, 8.6%). Melanoma subtype was cutaneous (122, 80.8%), unknown primary (24, 15.9%), mucosal (3, 2%), and acral (2, 1.3%). First ICB was ipi (108, 71.5%), PD-1 (nivo or pembro) (5, 3.3%), and nivo+ipi (37, 24.5%). The best overall response to first ICB was CR (76, 50.3%), PR (27, 17.9%), SD (16, 10.6%) and PD (32, 21.2%). Of the patients who progressed after initial ICB, 38 received subsequent systemic treatment as follows: PD-(L)1 in 20 (53%), BRAF ± MEK in 9 (23.7%), ipi in 7 (18.4%), and chemotherapy in 2 (5.3%). Median duration of follow-up among survivors (N = 138) was 93 months (range 60-192). From 5 years post-ICB, 85% (95% CI: 73-92%) survived an additional 5 years. In those who made it to 5 years without treatment failure (N = 72), the probability of remaining failure-free was 92% (95% CI: 86-99%) at 7 years. Of the 151 patients, only 4 patients (2.6%) experienced disease progression after 5 years. Three patients had radiographic or pathologic disease progression in the lymph nodes and one in the subcutaneous tissue. No patients progressed in the lungs, visceral organs, or CNS after 5 years. At time of analysis, 13 (8.6%) patients died after 5 years post ICB, none died of progressive melanoma. 6 patients died of unknown causes, 2 died of other causes, and 5 died of other non-melanoma cancer-related causes.

Conclusions:  Patients who survive five years after their initial immunotherapy have excellent overall survival and treatment failure-free survival. Given the anxiety surrounding survivorship and late progression, long-term survivors should be reassured of their excellent prognosis. These data suggest that aggressive follow-up schedules and imaging of melanoma patients after 5 years of survival may not be required.

WHOOP!  WHOOP!!!  The C-word (NO!  Not cancer!  CURE!!) was not used, but this data on peeps 5 years out who may no longer need scans to follow up and can carry on with their lives is AWESOME!  On a personal note, Weber let me off the hook for continued follow-up for melanoma at 8 years post my Stage IV diagnosis. I am currently 11 years out.

This study looked at peeps treated with nivo alone vs the ipi/nivo combo.  Now we are blessed to look at 6.5 year outcomes. These reports would not exist without the lives and dedication of all the ratties; and sometimes a special mouse!!!  Thanks, Edster!!!!

CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Wolchok, Chiarion-Sileni, Gonzalez, et al.  ASCO 2021.

Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes.

Methods:  Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety.

Results:  With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached with NIVO + IPI, 25.2 mo with NIVO, and 8.0 mo with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred.

Conclusions:  This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505.

My takeaway - AGAIN - though nivo alone works for many (look at me!!) - BUT - data shows responses and durability were better with the ipi/nivo combo.  Way to rock it out, ratties!!  Thanks, dear Ed!

Finally, a non-ASCO report from earlier this year looking at folks who chose to stop anti-PD-1 monotherapy with nivo (Opdivo) or pembro (Keytruda) at 1 year of therapy ~

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma.  Pokorny, McPherson, Haaland, et al.  J Immunother Cancer.  Jan 2021.

Background: Randomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.

Methods: Data of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (greater than 6 months and less than 18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.

Results: Of 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3-49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7-30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.

Conclusion: In this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

In my 2010, nivo as a single agent, phase 1 study, we took nivo for 2 1/2 years on a rather different schedule than is utilized currently (every 2 weeks for 6 months, then every 3 months for 2 years) and at dosages of 1mg/kg (my cohort), 3 mg/kg, and 10 mg/kg.  The 3mg/kg dosage is basically what is used today.  Still, even with all that, Weber often said that he felt we were treated too long and explained that while a certain amount of drug would be helpful, beyond that, benefit was nil and the risk of side effects was increased.  Today - whether we are looking at anti-PD-1 as a single agent or the ipi/nivo combo - researchers are still trying to figure out exactly what that "certain amount" is.  It is likely that the answer may vary person to person.  As this study pointed out, the ratties who elected to stop therapy at one year had experienced treatment response or stable disease.  Clearly, that is an important factor.  Additionally, in this rather small study of 52 patients, recurrence was associated with those who were younger, had a history of brain mets and elevated LDH when therapy ceased.  Interesting, in that I was 39 at diagnosis and 46 with brain mets at the start of my trial.  However, I took nivo for 2 1/2 years, never had an elevated LDH and have yet to have a melanoma recurrence.  So many variables.  So many different peeps.  It is a hard road to walk, much less to predict.

Hang tough, guys.  There is hope! - c  

New treatments - kinda. Anti-LAG-3 plus anti-PD-1 to boost response. Ipi/nivo plus tocilizumab to decrease side effects.

Unfortunately, as mentioned in yesterday's post, current melanoma treatments do not meet the needs of all melanoma patients.  Also as mentioned, a great deal of current research is building on existing immunotherapies - attempting to fortify response rates by adding a wide variety of pharmaceuticals to existing products.

Here is another study looking at combining an anti-LAG-3 product with yet another anti-PD-1 product: (Note:  Yesterday's post includes a link to previous data and info about anti-LAG-3 generally.)

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.  Hamid, Wang, Kim, et al.  ASCO 2021.

Background:  Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021).

Methods:  Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1.

Results:  48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade greater than/= to treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade greater than/= to serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing.

Conclusions:  The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Fingers crossed!

With its 50%+ response rate and durable results, the ipi/nivo combo has thus far been the best thing going for melanoma patients.  However, side effects caused by the treatment force roughly 40% of patients to discontinue therapy. (With that in mind, you may find this report from 2017 of interest:  40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!)  Anyhow, in an effort to DECREASE those side effects, this trial is adding tocilizumab - a monoclonal antibody that blocks interleukin 6 and is often used to treat rheumatoid arthritis - to the combo.  Interesting too, to look back on the addition of leflunomide (another drug used for RA) to targeted therapy as noted in this post:  An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib?)  

Ipilimumab, nivolumab and tocilizumab as first-line therapy for advanced melanoma.  Mehmi, Hamid, Hodi, et al.  ASCO 2021.

Background:  Interleukin 6 (IL-6) functions in the maintenance of hepatocytes, haemotopoietic progenitor cells, a variety of other tissues, and regulates the innate and adaptive immune system. IL-6 may play a role as a chronic inflammatory mediator in altering levels of acute phase proteins synthesized by the liver and circulating myeloid cells which have been shown to be associated with short survival with checkpoint inhibition and which are immune suppressive. The immunomodulatory properties of interleukin-6 may in part also be responsible for immune related adverse events, given the reversal of those toxicities observed with IL-6 receptor blockade in clinical practice. To assess if blockade of IL-6 binding is associated with a decrease in irAEs and/or an increase in efficacy defined as overall response rate (ORR) at week 24 in patients receiving ICB, we added tocilizumab to ipilimumab and nivolumab therapy.

Methods:  The current phase II trial is a two-stage design to assess the safety, tolerability, and grades 3-5 immune related toxicities of tocilizumab administered every 6 weeks up to week 24 in combination with ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12 week induction period, then administered every 6 weeks with nivolumab at 240 mg flat dose every 2 weeks in maintenance for up to 24 weeks, and nivolumab alone will be given at 480 mg flat dose every 4 weeks thereafter for up to 2 years. Eligible patients include those age 18 or older with measurable and unresectable stages III/IV melanoma (cutaneous, acral, mucosal), without prior systemic treatment for metastatic disease. Adjuvant therapy (IFN-alpha, ipilimumab and/or nivolumab, or pembrolizumab) is allowed. Patients with metastatic melanoma of brain are allowed, if neurologically stable and off immunosuppressive steroids. A total of 18 patients will be treated in the first stage, and 49 additional patients in the second stage for a total of 67. The comparator data are from the N3I1 arm of Checkmate-511 trial, in which treatment-related grades 3-5 irAEs were 33.9% with a 45.6% response rate (1). Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in January 2021.  Clinical trial information: NCT03999749.

For what it's worth.  - c

P.S. With great thanks to the Edster - this link, that includes an explanatory video from the Wizard Weber, gives important background on the whys and wherefores related to IL-6 in this instance and indicates that adding an IL-6 blockade may not only decrease side effects from immunotherapy but ADD effectiveness - Elevated Levels of Serum CRP and IL-6 Are Biomarkers of Poor Prognosis in Patients Receiving Immune Checkpoint Inhibitors.  Gotta love a man in a bow tie who can elucidate the difference between predictive and prognostic!!!!  - c