Something "new" in melanoma treatment???? Anti-LAG-3! Again...

With ASCO around the corner, perhaps (HOPEFULLY!!!) I spoke too soon about there being nothing new in the world of melanoma!  However, I have been reporting on anti-LAG-3 for YEARS!!!!  Here is my first report from 2014!!!!  It gives a pretty good breakdown of how our immune system functions and how anti-LAG-3 may give it, especially if combined with anti-PD-1 (nivolumab/Opdivo or pembrolizumab/Keytruda), a boost - How to make anti-PD1 work better with a new player...LAG-3????

And this - ASCO 2017: Anti-LAG-3 plus nivo, for melanoma already treated with anti-PD-1/PD-L1

Now ~  This report (from Evaluate Vantage) regarding the study looking at relatlimab andNivolumab combo, noted:  "Relativity-047, a trial in first-line melanoma, has yielded a 12-month progression-free survival rate only slightly below that in Yervoy/Opdivo’s corresponding Checkmate-067 study. But there is a vital advantage: severe treatment-related adverse events were 19% with the relatlimab combo – less than a third of that seen with the notoriously toxic Yervoy."

Gotta love those names, right???  Similarly, there is this from Fierce Biotech regarding the combo for melanoma:  

ASCO Bristol Myers, leading the LAG-3 pack, posts phase 3 melanoma data for Opdivo-boosting relatlimab - 

"Bristol Myers Squibb is no stranger to mixing checkpoint inhibitors—see the many indications approved and in development for the combination of Opdivo and Yervoy.

Now, the drugmaker is one step closer to offering a new checkpoint inhibitor cocktail for the treatment of advanced melanoma, with the first phase 3 data for a LAG-3 antibody in tandem with the PD-1 blocker Opdivo. 

The combination did twice as well as Opdivo at staving off cancer progression: patients who received the combo went a median of 10.1 months before their cancer got worse, compared to 4.6 months for the patients who received Opdivo alone.

The phase 3 results, to be presented virtually at the annual meeting of the American Society for Clinical Oncology, come from more than 700 patients with metastatic melanoma who had not tried any other therapies and whose cancer could not be treated with surgery. About half of the patients received the fixed-dose combination of Opdivo and the LAG-3 antibody relatlimab, while the other half got Opdivo.

At the one-year mark, nearly half (48%) of the patients who received the combo still had not seen their cancer worsen, compared to 36% of those who received Opdivo alone. The trial hasn’t been going long enough to report how long the combination is helping patients live, but the company will present those numbers when they’re ready, said Samit Hirawat, M.D., chief medical officer at BMS. 

Patients taking the combination experienced severe or life-threatening side effects at about twice the rate of patients who got Opdivo alone (18.9% versus 9.7%). Side effects led 14.6% of the combo group and 6.7% of the Opdivo group to quit the study and there were three treatment-related deaths in the combo group and two in the Opdivo group, which come out to less than 1% of patients in each group. 

...  That said, it’s important to note that BMS compared the Opdivo-relatlimab combination to Opdivo alone, and not to Opdivo and Yervoy. 

“It’s impossible to say one is better than the other because we did not do that study,” Hirawat said. 

So, where does BMS see the new combination in the spectrum of melanoma treatment? 

“Currently, patients with melanoma in the firstline setting are divided into thirds: one-third gets I-O plus I-O... One-third gets single-agent I-O and one-third is without an I-O-based regimen,” Hirawat said. “So, one could say 66% of patients are undertreated to an extent because they’re not getting the best treatment available.”  Though PD-1 drugs like Opdivo, Merck’s Keytruda and Roche’s Tecentriq have transformed the treatment of melanoma and other cancers, they don’t work for everyone—that’s why so many clinical trials are testing combinations to see which drugs might boost their efficacy. The hope is that adding relatlimab to Opdivo could give doctors another option to get the PD-1 blocker to work in more people. 

The LAG-3 protein is an immune checkpoint receptor found on the surface of T cells. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer. 

“We look forward to discussing these registrational data with health authorities to potentially bring this treatment to patients,” said Jonathan Cheng, M.D., senior vice president and head of oncology development at BMS, in a statement.  If all goes well with its studies in other cancer types, such as non-small cell lung cancer and liver cancer, BMS aims to launch additional phase 3 studies of relatlimab and Opdivo in those indications toward the end of this year and early next year, Hirawat said. "

From BMS there is this - Bristol Myers Squibb Announces LAG-3-Blocking Antibody Relatlimab and Nivolumab Fixed-Dose Combination Significantly Improves Progression-Free Survival vs. Opdivo (nivolumab) in Patients with Previously Untreated Metastatic or Unresectable Melanoma

"BMS today announced results from the Phase 2/3 RELATIVITY-047 trial, which showed that the fixed-dose combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, administered as a single infusion, demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit compared to Opdivo (nivolumab) alone in patients with previously untreated metastatic or unresectable melanoma. This is the first regimen to demonstrate a statistical benefit over anti-PD-1 monotherapy in metastatic melanoma. Among patients treated with the combination, the median PFS (mPFS) was significantly longer at 10.12 months vs. 4.63 in those who received Opdivo. The PFS benefit of the fixed-dose combination was observed early, at the time of the first scan, and was consistent over time. In exploratory, descriptive analyses, the combination of relatlimab and nivolumab extended PFS regardless of pre-specified subgroups and stratification factors.

These findings (Abstract #9503), the first from a Phase 3 trial evaluating a LAG-3-blocking antibody, will be presented in an oral abstract session on Sunday, June 6, 2021, from 8:00 a.m. – 11:00 a.m. EDT during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting and have been selected for the official ASCO press program.

“LAG-3 represents a new immunotherapy target and the results of the RELATIVITY-047 study demonstrated the significant benefit of inhibiting both LAG-3 and PD-1 with the novel combination of relatlimab and nivolumab,” said Dr. F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute. “With the observed efficacy and safety profile, the combination with relatlimab may provide an important new treatment option for patients with metastatic melanoma.”

The safety profile of the fixed-dose combination of relatlimab and nivolumab was manageable and consistent with those previously reported for relatlimab and nivolumab. No new safety signals or new types of clinically important events were identified with the fixed-dose combination when compared to Opdivo monotherapy. Grade 3/4 drug-related adverse events were 18.9% in the combination arm compared to 9.7% in the Opdivo arm. Drug-related adverse events leading to discontinuation were 14.6% in the combination arm compared to 6.7% in the Opdivo arm.

Lymphocyte-activation gene 3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor infiltrating lymphocytes (TILs) and contribute to tumor-mediated T-cell exhaustion. Combination therapy with relatlimab, a novel LAG-3-blocking antibody, and nivolumab, a PD-1 inhibitor, enables T-cell activation, leading to the initiation of an improved immune response and promoting tumor cell death.

Relatlimab (in combination with nivolumab) is the first LAG-3-blocking antibody to demonstrate a benefit for patients in a Phase 3 study. It is the third distinct checkpoint inhibitor (along with anti-PD-1 and anti-CTLA-4) for Bristol Myers Squibb.

“Bristol Myers Squibb is a pioneer in the development of immunotherapy combinations in melanoma. As the global incidence of melanoma has continued to increase, we have leveraged our deep insight into the interplay between tumors and the immune system to develop a novel immunotherapy combination,” said Jonathan Cheng, senior vice president and head of oncology development, Bristol Myers Squibb. “The RELATIVITY-047 data provide evidence that a LAG-3-blocking antibody coupled with nivolumab may bring the benefits of dual immunotherapy to more patients and address a remaining need in this space. While there have been significant treatment advances and long-term survival benefits provided by checkpoint inhibitors over the years, there remain patients with metastatic melanoma who could benefit from another innovative approach. We look forward to discussing these registrational data with health authorities to potentially bring this treatment to patients.”

Globally, the incidence of melanoma has been increasing for the last 30 years. The World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths.

Bristol Myers Squibb thanks the patients and investigators involved in the RELATIVITY-047 clinical trial. The company has several ongoing trials evaluating combination use of relatlimab for the treatment of additional cancers.

About RELATIVITY-047 (CA224-047)

RELATIVITY-047 (CA224-047) is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of relatlimab and nivolumab in patients with previously untreated metastatic or unresectable melanoma versus Opdivo alone. The primary endpoint of the trial is progression-free survival (PFS) by Blinded Independent Central Review (BICR) and the secondary endpoints are overall survival (OS) and objective response rate (ORR). A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of relatlimab 160 mg and nivolumab 480 mg or Opdivo 480 mg by intravenous infusion every four weeks until disease recurrence, unacceptable toxicity or withdrawal of consent. Follow-up for the secondary endpoints of OS and ORR is ongoing and the Company remains blinded.

About LAG-3

Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. Preclinical studies indicate that inhibition of LAG-3 may restore effector function of exhausted T cells and potentially promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.

Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types."

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???

AND NOW - Colon cancer alert - Cause, you know?  Nothing like having a foot in the door of 2 deadly cancers to keep you on your toes! 

There is also this, regarding anti-LAG-3's use in colon cancer, this time combining Merck's version - favezelimab with Keytruda (pembrolizumab) ~  A report from Fierce Biotech states:  

"PD-1 inhibitors work well in about one-fifth of patients with colorectal cancer, but the other 80% are not so lucky. Their tumors are immunologically “cold,” meaning they don’t respond to immunotherapies like Merck’s Keytruda. 

Enter favezelimab, Merck’s LAG-3-targeting antibody, which helped Keytruda make a dent in metastatic colorectal cancer in very sick patients with microsatellite stable tumors. The phase 1 data will be presented virtually at the annual meeting of the American Society for Clinical Oncology next month. The combination is poised for a phase 3 study in the same type of colorectal cancer.

The combination, given to 80 patients whose cancer had worsened despite trying two other treatments, shrank tumors in five patients (6.3%), one of whom saw their tumors cleared completely. The treatment kept cancer progression at bay for a median of 2.1 months and helped patients live a median of 8.3 months—on par with the six- to nine-month range the investigators had cited in the study abstract.  

However, the combination did better in a group of 36 patients whose tumors expressed high levels of PD-L1, as measured by the Combined Positive Score, or CPS. It shrank tumors in 11.1% of patients and helped patients live a median of 12.7 months. After one year of treatment, 51% of these patients were still alive, compared with 40.8% in the overall combo group. 

That 11.1% may seem low, but it’s an improvement on the 0% Merck would expect had the patients taken Keytruda alone, said Eric Rubin, M.D., senior vice president of global clinical oncology at Merck Research Laboratories. Because immunotherapies don’t work in this patient group, they rely on chemotherapy and, later on, tyrosine kinase inhibitors. Cancers can develop resistance against the latter, underscoring the need for more treatment options. 

“The data are limited, but it does look like PD-L1 staining is predictive for efficacy in this combination. Like any biomarker, it’s not perfect, but I think it identifies a patient population that is more likely to benefit from this treatment,” Rubin said. It will come in handy down the line when Merck starts designing registrational studies for the combination, he added. 

Of the 20 patients who received favezelimab alone, none responded to treatment, which was “not terribly surprising” given what Merck has seen in its earlier research. 

Side effects struck patients in the monotherapy and combination groups at similar rates: 65.0% and 65.2%, respectively. Slightly more patients who received the combination suffered severe side effects (20%) compared with those who received favezelimab alone (15%).

The most common side effect for the combination was fatigue, affecting 16.9% of patients, while the most common side effects for the LAG-3 drug alone were fatigue and nausea, hitting 20% and 15% of patients, respectively. 

Merck and other companies are developing LAG-3 antibodies to make PD-1 blockers like Keytruda work in more people.  

“When you look at preclinical models in patients exposed to anti-PD-1s, the LAG-3 pathway is upregulated, suggesting that it might be a compensatory pathway for tumors to evade anti-PD-1 treatments,” Rubin said. 

Like PD-1, LAG-3 is an immune checkpoint receptor that acts as a “brake” to stop T cells from attacking tumors. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer. 

Fevezelimab isn’t the only checkpoint inhibitor that Merck is combining with Keytruda. In September, the company presented data at the annual meeting of the European Society for Medical Oncology showing that Keytruda, along with its TIGIT-blocking antibody vibostolimab, shrank tumors in 29% of patients with non-small cell lung cancer. That combo did even better—as expected—in a subset of patients whose tumors expressed high levels of PD-L1, shrinking tumors in nearly half (46%) of them."

Anti-LAG-3, in at least some of it's machinations!  The more you know. Be well. ~ 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

ASCO 2017: Anti-LAG-3 plus nivo, for melanoma already treated with anti-PD-1/PD-L1

Here is what I have on LAG-3:
2014:  How to make anti-PD1 work better with a new player...LAG-3????
2016:  The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

Now, there's this ~ anti-LAG-3 with Nivo:

Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.

ASCO 2017. J Clin Oncol 35, 2017. Ascierto, Melero, Bhatia, et al.

Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity. Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] greater than 12 wk), and duration of response. Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had greater than/ = to 3 prior therapies, and 15 (35%) had BRAFmutations. In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts.  Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109

43 melanoma patients with progression on or after treatment with anti-PD-1 or anti-PD-L1, 30 of whom had also been previously treated with ipi - were treated with nivo and BMS-986016 (anti-LAG-3).  In the end, 31 patients were evaluated.  ORR = 16%.  DCR (disease control rate) = 45% "with benefit observed even in some patients refractory to prior anti-PD-1".  Median treatment duration = 10 weeks. 

Small numbers. Patients who had already been through a lot.  Fingers crossed. - c

How to make anti-PD1 work better with a new player...LAG-3????

Our immune system is a wonder of cell function with checks and balances.  Cells can be turned on to help fight germs and tumors and other yuck we encounter, but can also be turned off so we don't suffer from the body attacking or hurting itself through too much of an inflammatory process (as it does in autoimmune diseases like lupus, arthritis and even asthma).  Here are some terms that might help in understanding the presentation and article below as it relates to how anti-PD1 works, why it might not, and what might be done to make it work better for folks when their cancer/melanoma rears its ugly head again.

Definitions:
YOU HAVE:
1. T-cells - a type of lymphocyte (white cell) with a "T-cell receptor" on the surface.  There are several types of T-cells.
     i)  CD4-T cells - (T helper cells)- express the CD4 protein on their surface and become activated when  exposed to peptide antigen, which is expressed on the surface of an antigen-presenting cell (like bacteria and tumor cells).  When active they increase in number and secrete cytokines that regulate/trigger the immune response to attack the invader.
     ii)  CD8-T cells - (cytotoxic T cells)- express CD8 on their surface and can destroy virus cells, tumor cells, and are implicated in transplant rejection.  They can be "inactivated" so that autoimmune diseases are prevented or decreased. (Many meds to decrease transplant rejection as well as the signs and symptoms of rheumatoid arthritis, ankylosing, and other autoimmune diseases work to do this.)
     iii)  Memory T cells - persist after an infection or vaccine to create immunity.
     iv)  T reg cells - (suppressor T cells)- these cells shut down T cell mediated immunity at the end of an immune reaction.  There are 2 types of the these CD4T reg cells:  Naturally occurring cells that begin in the thymus gland (CD4, CD25, and FoxP3 T regs) and Adaptive T regs that originate during a normal immune response.
     v)  Natural Killer T cells - These T cells recognize a different molecule from other T-cells.  (Instead of peptide antigens, they recognize a glycolipid antigen.)  When active, they can eliminate some tumor and invasive viral cells.

2.  PD1 - also called programmed cell death protein 1, is a membrane protein and a member of the extended CD28/CTLA-4 family of T cell regulators.  PD1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or engulf/digest 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.

3.  CTLA-4 - another T cell regulator, also called Cytotoxic T-lymphocyte Antigen 4, is a protein receptor that down regulates (can "turn off") the immune system.  It is found on the surface of T-cells.

4.  LAG-3 - a molecule on T reg cells that contributes to their suppressor activity.

MEDICINE:
5.  Anti-PD1 - Nivolumab by BMS and Pembrolizumab (MK-3475) by Merck - are monoclonal anti-bodies that block the switch on T cells so that PDL1, produced by tumor cells, can NOT bind with them and turn them off.

6. Anti-CTLA-4 - Ipilimumab/Yervoy - a monoclonal antibody created by BMS that works to activate the immune system by targeting CTLA4, a protein receptor that down-regulates the immune system in melanoma patients, thereby turning ON the T cells.

FROM TUMORS:
7.  PDL1 - a ligand produced by the surface of melanoma tumors that can bind to infiltrating T-cells and turn them off.

Attached here is a presentation by Charles Drake MD, PhD from John Hopkins, from the Perspectives in Melanoma XVII meeting in Baltimore in September 2013, where he gave a review of PD1 biology, and how anti-PD1 works, as well as factors that might make it more effective:
The Basic Biology of PD1 and thoughts about LAG-3

Primary points:  
Anti-PD1 (a PD1 blockade) causes -
    1.  An increased number of CD8 T-cells
    2.  Increased function of those CD8 T-cells
LAG-3:
Alone, anti-LAG-3 is not very effective.  However, when anti-PD1 is combined with a LAG-3 blockade, the effectiveness of the CD8 T-cells is even greater than when either is used alone.  Unfortunately, there was a high death rate in the mice given both.  However, that particular mouse population was genetically engineered to have NO LAG-3, not a normal circumstance.
When does Anti-PD1 work?  In the priming or the effector phase????
This remains somewhat unclear...or perhaps there is action in both phases.  In this data, it seems that when anti-PD1 is on board with the initial antigen exposure....it leads to not only increased discrete numbers of CD8 T-cells, but even greater T-cell function per individual cell.  Therefore, it may be that earlier treatment (prior to advanced disease) is more effective because more T-cells with greater function may be produced.  Additionally, in advanced disease, the addition of anti-LAG-3 (to anti-PD1) seems likely to create more effect.

We already have data indicating that patients who are taking anti-PD1 (MK-3475 for this data set) and are ipi naive have about a 40% response rate while patients who are ipi refractory have a lesser response (28%).  data as discussed by Ribas and Weber
We also know that data shows that with smaller tumor size, there is increased overall survival in melanoma patients treated with anti-PD1. Baseline tumor size as an independent prognostic factor
(Now, on that point, you have to bear in mind that no matter how active ones white cells may be, they can be overwhelmed...with infection (in cases of sepsis)...or with cancer cells....BUT....)
Both these issues may be addressed in a continuation of the ideas presented in the lecture...studied  specifically here:


Restoring Immune Function of Tumor-Specific CD4+ T Cells During Recurrence of Melanoma
Goding, Wilson, Xie, et al.  The Journal of Immunology, March, 2013.
   "Recurrent solid malignancies are often refractory to standard therapies....adoptive T cell transfer may benefit select individuals, the majority succumb to their disease.  ...developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence.  During recurrence, Foxp3 tumor-specific CD4 T cells became PD-1+ and represented more than 60% of the tumor-specific CD4 T cells in the host.  Concomitantly, tumor-specific CD4 T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1...and LAG-3 inhibitory molecules.  Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibody or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.  Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 antibodies overcame the requirement to deplete tumor-specific Tregs.  In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or antibody therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer."

Primary points:
    Initially, blocking just PD-1 with anti-PD1 drugs will allow T cells to kill melanoma cells.  When relapse occurs, the immune response has been further suppressed by CD4 suppressor cells (T regs).  In relapse, reducing the number of T regs (Remember! These are the T cells that shut down the immune response!!) through drugs like cyclophosphamide or radiation...as is done before TIL therapy...plus the combination of anti-PD-L1 OR using anti-PD1 combined with anti-LAG3....showed the restoration of effective tumor killing by T cells.

So....all of this seems a good way of thinking about how to GET THOSE T CELLS FIRED UP!!!!  Initially AND in later stages of cancer progression.  I hope I was able to make it somewhat comprehensible.  Keep it up, you smart and enthusiastic research guys.  And you ratties....both the 4 and 2 legged sorts....hang tough!!!
Love - 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

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

The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

This interview/report is pretty cool and clear.  I'll just let the Wizard break it down - 

Novel Immunotherapy Combinations May Be the Future of Melanoma Treatment

By Caroline Helwick December 10, 2016  The ASCO Post

Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies. — Jeffrey Weber, MD, PhD

The future treatment of melanoma may rely on combinations of immunotherapy agents beyond the current checkpoint inhibitors, and they are entering clinical trials, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, who has spearheaded clinical trials in melanoma. At the 2016 European Society for Medical Oncology (ESMO) Congress, Dr. Weber gave attendees a taste of what’s to come in this tumor type.

“It’s become obvious that multiple checkpoints exist that are both antagonistic and agonistic molecules controlling adaptive immunity and innate immunity,” Dr. Weber said. He counted more than 50 members of the immunoglobulin or tumor necrosis factor (TNF) receptor superfamilies that could act as controlling or regulatory molecules.

In other words, the pipeline is rife with drugs that will target far more than cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). T cells also express TIM-3, LAG-3, GITR, and other factors, which, if agonized or antagonized, could boost an immune response and yield potential clinical benefit. They include many receptor agonists, “which press on the gas pedal,” he added, and receptor antagonists, such as CTLA-4 and PD-1, which “release the brakes.” In addition to antibodies in development, up to 15 new indications could be approved for the current CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) inhibitors, Dr. Weber predicted.

A High Bar to Surpass
The best results so far in advanced melanoma have been achieved by the combination of the anti–PD-1 agent nivolumab (Opdivo) and the anti–CTLA-4 agent ipilimumab (Yervoy). Nivolumab/ipilimumab yielded a 2-year survival rate of 63.8%, vs 53.6% for ipilimumab alone, in the CheckMate-069 trial.²

“In developing new checkpoint inhibitors, that’s the number we will have to be beat. If you want to add an inhibitory or agonistic molecule, you must at least match this, with less toxicity, and that’s a daunting challenge,” admitted Dr. Weber. “The fact that anti–PD-1 was developed early on sets a very high bar, which ironically could be a significant barrier to the successful development of other checkpoint inhibitors.”

Dr. Weber expects all new checkpoint agents to be tested in combination. Although 64% survival at 2 years is “fantastic,” he said, “at the end of the day, at least half the patients will need other therapy.” In all the tumor types for which these agents are important, “there is space for improvement,” he added.

Rationale for Novel Combinations
Immunotherapy combinations, with anti–PD-1/PD-L1 agents as backbones, will be driven by four key aims:

1. To bring T cells into tumors and overcome suppression of the immune system: For this, anti–PD-1/PD-L1 agents can be combined with anti–CTLA-4, immune-activating antibodies of cytokines, Toll-like receptor agonists, oncolytic viruses, indoleamine 2,3-dioxygenase (IDO) inhibitors, macrophage inhibitors, and targeted therapies.
2. To generate de novo T cells: This might be accomplished by vaccines, T-cell receptor–engineered adoptive-cell transfer, and chimeric antigen receptor–engineered adoptive-cell transfer.
3. To increase immune recognition: Stimulators of interferon genes (STING) agonists and interferons may help here.
4. To facilitate T-cell infiltration: This will be especially important for “cold” tumors that are deficient in T cells; the aim is to turn these “cold” tumors into “hot” ones. T-cell suppression, which occurs via multiple active and passive processes, must also be overcome.
These aims will be the mission of novel agonists, including anti-ICOS, anti-GITR, anti-OX40, anti-41BB, and anti-CD27, and novel antagonists, including anti–LAG-3, anti–TIM-3, anti-VISTA, anti-A2AR, anti-TIGIT, and IDO inhibitors.
“With T-regulatory cells, M2 macrophages, myeloid-derived suppressor cells—each a different lineage that requires a different maneuver to overcome—it’s amazing that any of this works at all,” he commented.

Sampler of Novel Combinations
Novel immunotherapies are not expected to be particularly potent as single agents, but in combination with other checkpoint inhibitors or targeted drugs, they are showing promise. More than a dozen combinations (including some triplets) are in phase II and phase III trials, including the following agents:

• Ipilimumab plus IDO inhibitors, talimogene laherparepvec (also known as T-VEC), interferon, and nivolu­mab/histone deacetylase (HDAC) inhibitor
• Nivolumab plus anti-CD137, TRAIL-R2 antibody, and LAG-3 antibody
• Pembrolizumab (Keytruda) plus IDO inhibitor, talimogene laherparepvec, BRAF/MEK inhibitors, interferon, and JACK/STAT inhibitor
• Atezolizumab (Tecentriq; anti–PD-L1) plus BRAF/MEK inhibitors
• Durvalumab (anti–PD-L1) plus BRAF/MEK inhibitors.
  

“Looking at all the mouse data from almost every antibody, results are better with combinations than with single drugs alone,” he said. “Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.”

Promising Early Data
Early data suggest that, for mutated patients, checkpoint inhibition plus BRAF and MEK inhibition is a powerful approach. In a study of the anti–PD-L1 antibody atezolizumab plus vemurafenib (Zelboraf) and cobimetinib (Cotellic), all patients in a 16-patient study had a reduction in target lesions; 3 patients had complete responses.³ The anti–PD-L1 antibody durvalumab plus a BRAF and MEK inhibitor produced a 69% response rate in another study, and all responses were ongoing at the time of analysis.⁴ In KEYNOTE 022, pembrolizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) produced tumor regression in almost all patients.⁵

Novel Combinations in Melanoma

• The future treatment of advanced melanoma may involve combinations of agents, with anti–PD-1/PD-L1 and anti–CTLA-4 as backbones.
• The pipeline is replete with agonistic and antagonistic molecules that target new checkpoints.
  

Pembrolizumab plus the IDO inhibitor epacadostat produced responses in 56% of 61 patients (63% of treatment-naive patients), and a disease control rate of 78% (and 75% of treatment-naive patients).⁶ Hepatotoxicity can be an issue with epacadostat, but it was not concerning in this study, he said.

One of the “more innovative” compounds targets OX40, an agonistic molecule that is expressed on activating T cells. An antibody against OX40 has shown significant and long-lasting antitumor activity in a mouse model of ovarian cancer when paired with an anti–PD-1 antibody.⁷ “This combination looks very impressive,” Dr. Weber commented. “You see very long survival [mean of 80 days, vs < 40 days for either agent alone], and, in fact, many of these mice were resistant to re-challenge. It’s clear that an adaptive immune response is promoted by the combination.”

An OX40 antibody (MOXR0916) was also combined with the PD-L1 inhibitor atezolizumab in a phase Ib study in solid tumors, but only 2 responses were observed among 51 patients, which he considered “disappointing.” However, this regimen will be further tested in melanoma and in other histologies with demonstrated responses to atezolizumab.

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

Wishing strength and peace to all my fellow melanoma ratties and fighters.  We've come a long way, baby!!!  And though there are miles to go...We Will GET THERE!!!! - love, c  

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

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

My synopsis:

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

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

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

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

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

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

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

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

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