Surgery After Systemic Treatment for Melanoma

 In this time of neo-adjuvant treatment for melanoma, two concepts are at odds with previous melanoma treatment plans.  

1.  The response to therapy may be better by actually leaving the tumor in place.  

2.  The premise that by waiting on surgery, the treatment may decrease the size of the lesion (and thereby diminish the size/damage from said surgery) or perhaps evaporate the lesion altogether so that surgery is not needed at all.  The impact of these new aspects of melanoma treatments makes decisions about surgery for melanoma even more complicated.  Here are zillions of reports about neoadjuvant treatment:  Neo-Adjuvant treatment for melanoma  That said - there are plenty of good reasons to have surgery to remove your melanoma lesions.  We know that, neo-adjuvant care aside, folks with the lowest tumor burden respond better.  We know that sometimes, one lesion remains persistently present even if all other lesions resolve.  Some patients will become NED after systemic treatment but later develop a lesion.  There are folks who haven't responded well to systemic therapy may need radiation and surgery to tackle their lesions.  The varied reasons for needing surgery are just as mixed as melanoma can be itself.  Still, there is a significant body of evidence indicating the benefit of the adage - "When in doubt, cut it out!" 

There is this from 2019 ~ Cut it out!!! Prolonged overall survival following metastasectomy in Stage IV melanoma

And this from 2020 ~ Surgical removal of melanoma lesions -

That said, there are these reports on varied circumstances that looked at surgery and melanoma patients:

Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies.  Ch’ng, Uyulmaz, Carlino,…Long, Menzies.  Eur J Cancer.  Aug  2021.

Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customized to individual patient and tumor factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.

Survival Outcomes of Salvage Metastasectomy After Failure of Modern-Era Systemic Therapy for Melanoma.  Li, Vakharia, Lo, et al.  Ann Surg Oncol.  Aug 2021.

Background: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy.

Methods: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC.

Results: The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively.

Conclusions: Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy

The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.  Versluis, Hendriks , Weppler, et al..  Eur J Cancer. 2021 Jul.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma.

Patients and methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation.

Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone, without OS differences.

Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.

For what it's worth!!  Hang tough.  Melanoma is never easy, but there is hope. - c

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

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

Here we go:

SURGERY

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

RADIATION

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

IMMUNOTHERAPY

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

Old school immunotherapy

Interferon

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

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

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

Current Immunotherapy (also referred to as Check Point Inhibitors)

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

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

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

      

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

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

  

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

Sometimes pictures tell the story better:

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

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

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

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

Response rate and side effects for advanced melanoma patients:

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

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

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

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

Dosing:

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

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

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

TARGETED THERAPY

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

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

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

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

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

DRUGS, administration, and side effects:

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

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

EFFECTIVENESS and tumor work-around:

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

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

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

IMMUNOTHERAPY COMBINED WITH TARGETED THERAPY -

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

INTRALSIONAL (also referred to as 'intratumoral') THERAPY

Intralesional drugs include (but are not limited to):

T-VEC - also called OncoVEX, Imlygic, or Talimogene Laherparepvec - uses the herpes virus with GM-CSF and is the only intralesional currently FDA approved (2015)  However, the following (and others) have been used in clinical trials:
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 - see note above, is also being used

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

From 2021 - Intralesionals for melanoma - some new reports

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

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

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

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

The BUSINESS of Cancer - BMS and Nektar ending immuno-oncology program?

 

I've written about NKTR-214 (bempegaldesleukin) since 2013. 

There was this ~ regarding the NKTR/Opdivo combo trial, PIVOT, from 2018:  ASCO 2018 - PIVOT, PIVOT, PIVOT!!!!! (Sorry, FRIENDS flashback to Ross moving a couch in a stairwell!!!) But, really - NKTR-214 plus nivo

This report ~ covering the incredible muckup regarding some batches of Bempeg being "substandard" because they were "out of specification" resulting in "lower results for patients" in an astonishing interview Nektar CEO Howard Robin gave to FiercePharma in 2019:  NKTR- 214 (bempegaldesleukin) with Opdivo - PERHAPS the results from the PIVOT trial for melanoma patients were LOWER than they should have been? Meaning if the company who makes it (Nektar) gets its act together patients may demonstrate an even better response????

And in 2020 there was this report ~ in which Bempeg was used in TIL (on mice):  TIL ACT for melanoma patients - past and present...

Now, there's this ~  Game over: Bristol Myers, Nektar end $3.6B immuno-oncology program after 2 more late-stage flops, a report by Nick Paul Taylor, April 15, 2022, from FIERCEBiotech, which reads:

Bristol Myers Squibb and Nektar have read the last rites to their huge, failed cancer collaboration. With two more late-stage trials failing, the partners have ended clinical development of a combination they once saw as the future of immuno-oncology.  The chances of Bristol Myers’ $1 billion upfront bet on bempegaldesleukin, a prodrug of PEGylated IL-2, paying off shrank last month. One month ago, Bristol Myers revealed a combination of Nektar’s bempeg and its Opdivo failed to improve on the progression-free survival and objective response rate achieved by the PD-1 checkpoint inhibitor as a single agent in previously untreated melanoma patients. The failure triggered the end of another study and raised serious doubts about the future of the combination. 

Bristol Myers and Nektar confirmed those doubts late Thursday, revealing the combination has failed in two other clinical trials. In one study, the partners compared their drug cocktail to the investigator’s choice of two tyrosine kinase inhibitors (TKIs), namely Exelixis’ Cabometyx and Pfizer’s Sutent, in metastatic renal cell carcinoma (RCC) patients. The trial looked at intermediate/poor risk and all-risk populations.  

A preplanned interim analysis found the investigational combination failed to improve on the overall survival achieved by the TKIs in either population. Faced with the failure, Bristol Myers and Nektar have decided to unblind the trial and perform no more overall survival analyses.

Bristol Myers and Nektar also reported the failure of the combination in patients with cisplatin-ineligible, locally advanced or metastatic urothelial cancer. The single-arm phase 2 clinical trial failed to achieve the objective response rate needed to support the continuation of the program.

After going 0 for 3, Bristol Myers and Nektar have decided to discontinue all other studies of the drug combination. The list of studies now winding down include a pivotal program in muscle-invasive bladder cancer and a pair of phase 1/2 trials in RCC and pediatric tumors. Shares in Nektar fell 17% to around $5 after hours, wiping out the small gains they made after news of the melanoma failure dropped.  

The discontinuation of the clinical development program confirms the failure of one of the big bets of Thomas Lynch's time as Bristol Myers’ chief scientific officer. Bristol Myers paid $1 billion upfront, made a $850 million stock purchase at $102.60 a share—a price it only briefly hit in the immediate afterglow of the deal—and committed up to $1.8 billion in milestones, all for a 35% split of global profits. 

Bristol Myers put together the mammoth financial package in the belief IL-2 was one of three validated mechanisms in immuno-oncology, the others being PD-1 and CTLA-4. The IL-2 cytokine is the first cancer immunotherapy, with the FDA approving a recombinant form in the early 1990s, but problems such as its poor drug-like properties and toxicity limited uptake. Bempeg was designed to eliminate those problems. 

Now - This report is from a source that looks only at the money making aspect of medicine.  The existence of this publication ~ FIERCEBiotech ~ and their often first-to-publish accuracy (Over the years I've often found info regarding trials and drug development on their site long before I found it in medical journals!) speaks to the business of medicine.  The sad truth is that if the product isn't going to make money for the company in sufficient margins, then it isn't going to be produced on the 'free market'.  At times drugs have been protected when the government has stepped in - but that's a whole other story.  I am NOT certain (given the obvious crazy in the melanoma PIVOT trial) that the Opdivo/Bempeg combo, nor the use of Bempeg in melanoma affected mice given TIL, offered any real benefit to melanoma patients. Still, given the small share of the cancer market melanoma patients provide and the pronouncement in this article that Nektar and BMS are closing the doors on this immunotherapy combo, it seems unlikely that the PIVOT trial nor any others using Bempeg for melanoma patients will be completed, much less end up as a treatment option.

Hmmm.....  $$$$$!!!!  We'll see what happens. - 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

Relatlimab plus Nivolumab in advanced melanoma patients - better than Nivo (Opdivo) alone!

After the life changing immuno and targeted therapy developments for melanoma patients back in 2011 and a bit beyond, not much new has made our lives substantially better since.  I've been reporting on anti-LAG-3 since 2014.  Anti-LAG-3 reports!  Currently the anti-LAG-3 product Relatlimab is in trials and continues to look promising.  Here are a couple of reports from last year:  Something "new" in melanoma treatment???? Anti-LAG-3! Again...

Now, there's this:

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.  Tawbi, Schadendorf, Lipson, Ascierto…Hodi, Long.  N Eng J Med.  Jan 2022.

Background: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.

Methods: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.

Results: 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. 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.

Conclusions: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals.

Relatlimab plus nivolumab improves progression-free survival in metastatic melanoma.  MD Anderson News Release, Jan 5, 2022.

In patients with untreated, advanced melanoma, the combination of immune checkpoint inhibitors relatlimab and nivolumab doubled the progression-free survival benefit compared to nivolumab alone, with a manageable safety profile, according to the results of the Phase II/III  RELATIVITY-047 clinical trial reported by The University of Texas MD Anderson Cancer Center today in the New England Journal of Medicine.

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, with a 25% lower risk of disease progression or death in the combination arm. The benefit of the combination therapy was observed across pre-specified subgroups. The Food and Drug Administration granted priority review to the combination in September 2021 based on the results of this study.

“The results from this global effort advance the field of immunotherapy by establishing a third class of immune checkpoint inhibitors through the LAG-3 pathway and have the potential to be practice-changing,” said lead author Hussein Tawbi, M.D., Ph.D., professor of Melanoma Medical Oncology. “We’ve seen historic developments in melanoma treatment over the last decade with the combination of PD-1 and CTLA-4 inhibitors, which work well but also carry substantial toxicity. This study represents a significant and long-awaited next step toward providing patients with effective and safer treatment options.”

Relatlimab is a novel antibody that blocks lymphocyte-activation gene 3 (LAG-3), an immune checkpoint found on the surface of T cells. LAG-3 is often upregulated in melanoma, as is programmed death-1 (PD-1), the immune checkpoint inhibited by nivolumab. These data represent the first Phase II/III clinical trial results of a third-generation checkpoint inhibitor and the first clinical trial designed to compare combination checkpoint inhibitor therapy versus nivolumab monotherapy in melanoma.  

Currently, PD-1 and CTLA-4 inhibitor monotherapy and combination therapy are approved frontline treatment options for metastatic melanoma. The combination therapies benefit more patients than monotherapy, but also greatly affect quality of life, with toxicity rates of more than 50%.

In this study, grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the combination arm and 9.7% in the monotherapy arm. The most common grade 3 or 4 events included increased levels of pancreatic and liver enzymes, and fatigue. Investigators determined three deaths in the combination arm and two deaths in the monotherapy arm were treatment-related. Immune-mediated adverse events included hypothyroidism/thyroiditis, rash and colitis. No new safety signals were identified, and patients rated their health-related quality of life similarly across both treatment arms.

The trial enrolled 714 patients with untreated, unresectable stage III or IV melanoma across 111 international sites between May 2018 and December 2020. Patients were randomized to receive relatlimab and nivolumab or nivolumab alone once every four weeks. Sixty patients (8.4%) received prior targeted therapy or immunotherapy as adjuvant therapy at least six months before recurrence, or received interferon six weeks before randomization. The median age of participants was 63; 41.7% were female and 96% were white.

At the time of data cutoff (March 9, 2021), median follow-up was 13.2 months, with 470 patients (65.8%) having discontinued treatment. The top reason for discontinuation was disease progression (36.3% in the combination arm and 46% in the monotherapy arm).

The study met its primary endpoint of blinded independent central review-assessed progression-free survival, with progression defined as tumor growth or death due to any cause. The benefit was sustained across pre-defined subgroups, including BRAF status, tumor stage, lactate dehydrogenase (LDH) levels and LAG-3 and PD-1 expression.

“We now have evidence of a clear benefit for combination therapy compared to single-agent PD-1 inhibitors, and we’re looking forward to seeing response and overall survival data,” Tawbi said. “We’re also thinking about the populations that were excluded from this trial, including those with untreated brain metastases and uveal melanoma, so that all patients can have a chance to take advantage of the progress we’re making against melanoma.”

Hang tough, ratties!  ~ c

Then there's melanoma, GCC and me - Study shows increased secondary cancer risk after immunotherapy!!!!! Adjuvant treatment of Stage II GCC = no improvement in OS!!! Well! Isn't that nice???

As most of you reading these pages know, I was diagnosed with Stage IIIb melanoma in 2003, advanced to Stage IV in 2010 with brain and lung mets, subsequently enrolled in a Phase 1 Nivolumab (Opdivo) trial, taking nivo for 2 1/2 years.  On what was to be my last follow-up scan in 2018, something was found in my appendix.  Removal and biopsy indicated Stage II Ex-goblet cell adenocarcinoma of the appendix.  Appendiceal cancer is very rare - found in only 1-2 people per million in the US.  Of those, my type of appendiceal cancer is rarer still!  I completed (almost) a three month, 4 dose regimen of adjuvant CAPOX (Capecitabine and Oxaliplatin).

Currently, that means I am ~

219 months (18 YEARS!!!!) post my original melanoma diagnosis in 2003 at the age of 39
139 months Stage IV (11 and 1/2 years!!!)
133 months NED (well....for melanoma at least)
131 months after starting nivo (Opdivo)
101 months (more than 8 years) AFTER my last nivo infusion in June 2013.

I am also:  
39 months post my diagnosis of adenocarcinoma ex-goblet cell carcinoid (GCC) and the removal of my appendix with its 10.5 cm tumor, my ascending colon including ileocecal valve, gall bladder and ovaries
36 months (3 years!) post completion of 3 months adjuvant CAPOX chemo for same

Then there's this:

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016.  Deng, Wang, Liu, et al.  JAMA Dec 2020.

Importance: To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs).

Objective: To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs.

Design, setting, and participants: Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020.

Exposures: Receipt of immunotherapy or other anticancer agents.

Main outcomes and measures: The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs.

Results: Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 for small intestine cancer, 1.93 for lung and bronchus cancer, 2.77 for kidney cancer, and 7.29 for myeloma. From 2011 to 2016, SIRs were 9.23 for small intestine cancer, 1.54 for lung and bronchus cancer, 2.66 for kidney cancer, and 5.90 for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher in the pre-ICIs period and 98% higher in the post-ICIs period than the overall cancer incidence rate in the general population.

Conclusions and relevance: In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.

Well damn!  I think of you so often, my sweet Julie!!!!  And that last sentence - "Close monitoring and screening for Second Primary Cancers may be warranted in patients with metastatic melanoma."  Tell that to oncs and more importantly to insurance companies!!!!!!!!!!!!!!!!!!!!!  Though - before anyone panics I will add these thoughts:

1.  This study is not the end all be all.

2.  When you are dealing with melanoma - especially Stage IV as I was - you are facing death or treatment.  So, what choice is there, really?  Besides, despite Stage IV melanoma, despite immunotherapy side effects, despite a second cancer and the side effects from that treatment - I'm Still Here!!!!!!!!

3.  There are variables besides immunotherapy that have to be considered here as well - 

    a) The propensity of these patients to develop cancer - for whatever reason.

    b) The 9 gazillion scans used as follow-up/treatment management in these patients.

    c) The use of radiation in these patients as part of their treatment.

There may well be more, but those come to me at the moment.  In cancer world, we know that treatment, though necessary, is not benign.

Next up -

Gotta say, I thought I was a beast when I got through my 2 1/2 year nivo trial.  Working roughly 10-12 hours Mon, Tue, Wed as a pediatric NP in a busy office.  Driving the two hours to Atlanta on Thursday morning to catch the flight down to Tampa that afternoon.  Spending the night in the good ol La Quinta.  Treatment at the butt crack of dawn on Friday.  A mad dash back to the airport for the flight back to Atlanta.  Two hour drive home.  Usually arriving back in Chattown around midnight.  Rinse and repeat every 2 weeks for 6 months, then every 3 months for 2 years, missing only 3 days of work during that time.  Perhaps I was just insane.  Check out this post-it note sent home to B from a dear coworker during that time:  Friends in need are friends indeed! Here's to the caregivers!!!  Still, for all the fatigue, wheezing, arthralgias, rashes and oral lesions - immunotherapy was a walk in the park compared to CAPOX.  That shit kicked my ass - literally and figuratively!  Now, there's this.... 

Is adjuvant chemotherapy beneficial for stage II-III goblet cell carcinoid/goblet cell adenocarcinoma of the appendix?  Zakka, Williamson, Jiang, et al.  Surg Oncol.  2020 Dec.

Background: Goblet cell carcinoma (GCC), formerly known as goblet cell carcinoid, of the appendix constitutes less than 14% of all primary appendiceal neoplasms. Surgical resection is the main treatment and the role of adjuvant chemotherapy (AC) is not established. This study aims to evaluate the impact of AC in stage II-III appendiceal GCC.

Methods: Patients with pathological stage II and III GCC who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3 (goblet cell carcinoid) and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test.

Results: A total of 619 patients [over 9 years!!!] were identified. 54.4% males and 89.0% Caucasian; median age 56 (range, 23-90) years. Distribution across pathological stages II-III was 82.7% (N = 512) and 17.3% (N = 107) respectively. AC was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III patients. For stage II patients, AC was not associated with better OS. By contrast, in stage III patients, AC was associated with better OS. In the entire cohort 5-year OS for patients that received AC was 85.5% (74.0%, 92.1%) versus 82.7% (77.5%, 86.8%) with no AC. For stage II patients, 5-year OS was 96.9% with AC vs. 89.1% with no AC. For stage III patients, 5-year OS was 77.1% with AC vs. 42.8% with no AC.

Conclusion: AC was associated with improved OS in patients with pathological stage III GCC of the appendix, but not with pathological stage II.

Well, ain't that a bitch??!!!  Now this - 

Outcomes in Peritoneal Carcinomatosis from Appendiceal Goblet Cell Carcinoma Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC).  Zambrano-Vera, Sardi, Munoz-Zuluaga, et al.  Ann Surg Oncol.  2020 Jan 27.

Background: Appendiceal goblet cell adenocarcinoma (GCA) is often misclassified and mistreated due to mixed histologic features. In general, cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is standard of care for peritoneal carcinomatosis (PC) from mucinous appendiceal tumors; however, in PC from GCA, data are limited and the role of CRS/HIPEC is controversial. We report outcomes in PC from appendiceal GCA treated with CRS/HIPEC.

Patients and methods: A prospective institutional database of 391 CRS/HIPEC patients with appendiceal carcinomatosis from 1998 to 2018 was reviewed. Twenty-seven patients with GCA were identified. Perioperative variables were described. Survival was estimated using the Kaplan-Meier method.

Results: GCA occurred in 7% (27/391) of appendiceal CRS/HIPEC patients. Seven (26%) cases were aborted. Two patients underwent a second CRS/HIPEC for peritoneal recurrence. Median age at diagnosis was 53 years (range 39-72 years), and 12 (60%) were female. All underwent previous surgery. Seven (35%) had prior chemotherapy and received a median of 5 cycles (range 3-8). Median PCI was 6 (range 1-39). Complete cytoreduction was achieved in 95% (19/20). Grade III complications occurred in three (15%) patients, and no perioperative deaths occurred. Median follow-up was 97 months. Overall survival at 1, 3 and 5 years was 100%, 74% and 67%, respectively. Progression-free survival at 1, 3, and 5 years was 94%, 67% and 59%, respectively.

Conclusion: CRS/HIPEC should be considered as the main treatment option for patients with PC from appendiceal GCA. When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved.

Poor peeps!  I hope I never have to undergo that shit!!!!  Man!  Don't you love how researchers state things like "When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved." - as though 33% of patients dying within 5 years is a good thing?  Sigh.....

Y'all know I've been yelling for YEARS, as recently as earlier this month, about ctDNA use in melanoma - rather - how it SHOULD be used in melanoma!!! - A Zillion Posts  Now, there's this -

Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.  Reinert, Henriksen, Christensen, et al.  JAMA Oncol.  2019, May.

Importance:  Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC).

Objective:  To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance.

Design, Setting, and Participants:  In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction–based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years.

Results:  A total of 130 patients with stages I to III CRC (mean age, 67.9 years; 74 male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients. After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients. Similarly, shortly after ACT ctDNA-positive patients were 17 times  more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients. In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples.

Conclusions and Relevance:  Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

How could this not be a good thing, right???? So, I put my money where my mouth is.  Several months ago, I had the Signatera - Circulating tumor DNA blood test done.  The company analyzed a sample from my appendiceal tumor to create an assay generated by the mutations in my specific tumor to know what to look for in a simple blood draw.  It was negative.  Meaning - no bits or bobs of the tumor DNA they searched for was in my blood sample.  This is in no way an advert for that particular company. (Though medical folks from the company answered ALL B's questions in several phone calls, so that is something!!!)  This is simply a report of what I did, the research behind it, and how it went.  I told B I ought to do a two-fer and have them look for melanoma as well as GCC!!  Surprisingly, he was not amused!  Such a party pooper!  Poor boy.  

So, to finish up 2021 with a bang, a couple of weeks ago, routine follow-up scans were clear - the strange ascites that keep jogging around with me was diminished, so that's good, I guess.  Yesterday, I had a visit with my onc and labs (to follow relative proteins, iron, folate and such) drawn.  An uneventful event, though I had to be stuck twice.  Such is the life of a cancer patient.  And to think - having had bilateral complete lymphadenectomies of both arms in 2003 and 2007 - I was told never to have so much as a blood pressure check in either.  Well!!!  That went out the window YEARS ago!  I am moving to annual scans and doc visits with labs every 6 months.  Clearly, I am to be seen sooner if I have any problems. Though how to ID said 'problems' is a little unclear.  Leaving the visit, I told B I was tired of being a cancer patient.  But, as quickly as I said it I realized that when you ARE a cancer patient, getting to be one for so many years is pretty lucky, no?  Neuropathies to hands and feet continue.  B religiously applies Voltaren to my feet each night.  Again, not an advert.  I'm not really sure it does anything, but he is convinced.  We've tried a variety of things - icy hot type preparations, Blue emu something or other, a hemp oil ta-dah.  These well and truly did nothing at all!!!  I've learned to manage my bowel situation, though some days are better than others.  I still run and sew and work and play.  At the end of the day - especially at the end of THREE /18 crazy years - what more can one ask for?

Wishing each of you peaceful moments, much love, and a zillion small joys in the coming year.   ~ les

And, yes.  The observant among you will note that it took me a year to post the data included here.  Sometimes it takes a minute to face your reality. And, yes.  I am smiling. - c

Circulating tumor DNA (ctDNA) the little bits of tumor floating in our blood and how they can impact melanoma patients

In this post, replete with many links within - Circulating tumor DNA to monitor and predict response in melanoma patients - yes - AGAIN!!!!  - from earlier this year, I wrote:  "I first posted articles related to blood analysis to evaluate circulating tumor DNA in 2014.  It is a fairly non-invasive and relatively painless way to diagnose melanoma, measure tumor burden, and evaluate progression or response in melanoma patients.  It may even indicate those who are more likely to respond to a particular therapy.  Unfortunately, it is not commonly utilized."  Now there are these reports: 

Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.  Syeda, Wiggins, Corless, et al.  Lancet Oncol.  Feb 2021.

Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes.

Methods: In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAFV600-mutant ctDNA in pretreatment and on-treatment plasma samples from patients aged 18 years or older enrolled in two clinical trials. COMBI-d (NCT01584648) was a double-blind, randomised phase 3 study of dabrafenib plus trametinib versus dabrafenib plus placebo in previously untreated patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. COMBI-MB (NCT02039947) was an open-label, non-randomised, phase 2 study evaluating dabrafenib plus trametinib in patients with BRAFV600 mutation-positive metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG performance status of 0 or 1. Biomarker analysis was a prespecified exploratory endpoint in both trials and performed in the intention-to-treat populations in COMBI-d and COMBI-MB. We investigated the association between mutant copy number (baseline or week 4 or zero conversion status) and efficacy endpoints (progression-free survival, overall survival, and best overall response). We used Cox models, Kaplan-Meier plots, and log-rank tests to explore the association of pretreatment ctDNA concentrations with progression-free survival and overall survival. The effect of additional prognostic variables such as lactate dehydrogenase was also investigated in addition to the mutant copy number.

Findings: In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAFV600 mutation-positive ctDNA concentration was associated with worse overall survival outcome, independent of treatment group and baseline lactate dehydrogenase concentration, in COMBI-d. A ctDNA cutoff point of 64 copies per mL of plasma stratified patients enrolled in COMBI-d as high risk or low risk with respect to survival outcomes and was validated in the COMBI-MB cohort. In COMBI-d, undetectable ctDNA at week 4 was significantly associated with extended progression-free and overall survival, particularly in patients with elevated lactate dehydrogenase concentrations.

Interpretation: Pretreatment and on-treatment BRAFV600-mutant ctDNA measurements could serve as independent, predictive biomarkers of clinical outcome with targeted therapy.

Circulating tumour DNA and melanoma survival: A systematic literature review and meta-analysis.  Gandini, Zanna, De Angelis, et al.  Crit Rev Oncol Hematol.  Jan 2021.

We reviewed and meta-analysed the available evidence (until December 2019) about circulating tumour DNA (ctDNA) levels and melanoma patients survival. We included twenty-six studies (more than 2000 patients overall), which included mostly stage III-IV cutaneous melanoma patients and differed widely in terms of systemic therapy received and somatic mutations that were searched. Patients with detectable ctDNA before treatment had worse progression-free survival (PFS) and overall survival (OS), with no difference by tumour stage. ctDNA detectability during follow-up was associated with poorer PFS and OS; in the latter case, the association was stronger for stage IV vs. III melanomas. Between-estimates heterogeneity was low for all pooled estimates. ctDNA is a strong prognostic biomarker for advanced-stage melanoma patients, robust across tumour (e.g. genomic profile) and patients (e.g. systemic therapy) characteristics.

The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies-Beyond BRAF Mutant Detection.  Marsavela, Johansson, Pereira, et al.  Cancers (Basel).  Dec 2020.

In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analyzed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.

Yep!  THAT LAST SENTENCE!!!

Prognostic Value of ctDNA Mutation in Melanoma: A Meta-Analysis.  Zheng, Sun, Cong, et al.  J Oncol.. May 2021.

Purpose: Melanoma is the most aggressive form of skin cancer. Circulating tumor DNA (ctDNA) is a diagnostic and prognostic marker of melanoma. However, whether ctDNA mutations can independently predict survival remains controversial. This meta-analysis assessed the prognostic value of the presence or change in ctDNA mutations in melanoma patients.

Methods: We identified studies from the PubMed, EMBASE, Web of Science, and Cochrane databases. We estimated the combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) using either fixed-effect or random-effect models based on heterogeneity.

Results: Sixteen studies including 1,781 patients were included. Both baseline and posttreatment detectable ctDNA were associated with poor OS. For PFS, baseline detectable ctDNA may be associated with adverse PFS and baseline high ctDNA and increased ctDNA were significantly associated with adverse PFS. The baseline BRAFV600 ctDNA mutation-positive group was significantly associated with adverse OS compared with the baseline ctDNA-negative group. There were no significant differences in PFS between the baseline BRAFV600 ctDNA mutation-detectable group and the undetectable group.

Conclusion: The presence or elevation of ctDNA mutation or BRAFV600 ctDNA mutation was significantly associated with worse prognosis in melanoma patients.

Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma. Di Guardo, Randon, Corti, et al.  Oncologist. August 2021.

Background: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity after sustained response are unknown.

Patients and methods: This retrospective case series analysis conducted at a single Cancer Center in Italy included patients with BRAF mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020 and interrupting treatment after achieving complete response (CR) or long-lasting partial response (PR - i.e. greater than 12 months) due to cumulative toxicity.

Results: We included 24 patients with a median treatment duration of 59.4 months. CR and PR were achieved in 71% and 29% of patients, respectively. At a median follow-up after treatment discontinuation of 37.8 months, 12-months progression free survival after discontinuation (dPFS) rate was 70.8% and 24-months dPFS rate was 58.3%. Baseline patients and tumor characteristics as well as treatment duration and best response did not significantly impact on dPFS. Patients with CR and negative circulating tumor DNA (ctDNA) at time of discontinuation had a significantly improved dPFS compared to patients with either radiological residual disease or ctDNA positivity. No patient in CR with undetectable ctDNA experienced progression.

Conclusion: The risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy in clinical trials investigating optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted.

Implications for practice: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity are unknown. We analyzed patients with sustained responses (median treatment duration 59.4 months). Twelve and 24-months progression free survival following discontinuation were 70.8% and 58.3% respectively. Complete response and negative ctDNA at time of discontinuation are promising prognostic biomarkers in this setting.

Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression.  Marsavela, McEvoy, Pereira, et al.  Br J Cancer.  August 2021.

Background: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation.

Methods: Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy.

Results: ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response. However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15).

Conclusions: These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.

I think the vast preponderance of the evidence shows that knowing the presence of and/or quantity of bits of melanoma floating in your blood stream gives the patient and their physician important information that can impact treatment choice.  That same data can help make decisions about whether or not to stop or change treatments.  Many studies have demonstrated that this simple blood draw can tell you your status weeks to months sooner than tumors can be seen on radiographic studies.  The last study above stands in contrast to that but I try to be complete.  I will say that it is important to note that the study above was a retrospective review of 108 blood samples collected at the time of disease progression vs 66 patients monitored after response to systemic therapy.  I don't think that is the best way to collect and compare data - maybe that's just me.  I leave you with this ~

The prognostic value of circulating tumor DNA in patients with melanoma: A systematic review and meta-analysis.  Feng, Cen, Tan, et al.  Transl Oncol.  June 2021.

Background: Circulating tumor DNA (ctDNA) has been investigated as a potential prognostic biomarker to evaluate the therapeutic efficacy and disease progression in melanoma patients, yet results remain inconclusive. The purpose of this study was to illustrate the prognostic value of ctDNA in melanoma.

Objectives: To describe the clinical prognostic value of ctDNA for melanoma patients.

Methods: Searched for eligible articles from Pubmed, Web of Science and Embase. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the association between ctDNA at baseline or during treatment and overall survival (OS) and progression-free survival (PFS).

Results: A total of 9 articles were obtained, involving 617 melanoma patients. The pooled HRs revealed that compared with baseline undetectable ctDNA patients, detectable ctDNA was highly correlated with poor OS and PFS. A meta-analysis of these adjusted HRs was performed and confirmed that ctDNA collected at baseline was associated with poorer OS/PFS. During treatment, a significant association was shown between ctDNA and poorer OS/PFS.

Conclusion: Investigation and application of ctDNA will improve "liquid biopsy" and play a role in early prediction, monitoring disease progression and precise adjusting treatment strategies in melanoma patients.

For me, I think ctDNA can provide valuable information that we can use when having to make the incredibly difficult decisions faced by cancer patients.  Coming soon - putting my money and my blood - where my mouth is. Hang tough. - c