In the annual Research Round Up podcast series, Cancer.Net Associate Editors share their thoughts on the most exciting scientific research to come out of this year’s ASCO Annual Meeting and what it means for patients. In this podcast, Dr. Vicki Keedy will discuss 2 different studies in soft-tissue sarcoma, and explain how the results of these studies have lead to important conversations in the field of sarcoma, and Dr. Ryan Sullivan will discuss 2 studies in melanoma, including 1 that looked at treatment for melanoma that has spread to the brain, and 1 that is a long-term follow-up on targeted therapy for melanoma with a BRAF mutation.
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The 2019 ASCO Annual Meeting, held May 31 to June 4, brought together physicians, researchers, patient advocates, and other health care professionals from around the world to present and discuss the latest research in cancer treatment and patient care. In the annual Research Round Up podcast series, Cancer.Net Associate Editors share their thoughts on the most exciting scientific research to come out of this year’s ASCO Annual Meeting and what it means for patients.
First, Dr. Vicki Keedy will discuss 2 different studies in soft-tissue sarcoma, and explain how the results of these studies have lead to important conversations in the field of sarcoma.
Dr. Keedy is an Assistant Professor of Medicine in the Division of Hematology/Oncology and the Clinical Director of the Sarcoma Program at the Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center. She is also the Cancer.Net Associate Editor for Sarcoma.
Dr. Keedy: Hello. My name is Vicky Keedy, and I am a medical oncologist who specializes in the treatment of sarcomas at Vanderbilt University Medical Center. Today, I'm going to talk about 2 important studies discussed at the 2019 ASCO Annual Meeting.
The first study I would like to discuss is called the ANNOUNCE trial. This study looked at whether adding a targeted therapy called olaratumab to the standard treatment, doxorubicin, was better than doxorubicin alone for patients with adult soft tissue sarcomas. In 2016, this combination was approved by the U.S. Food and Drug Administration, or the FDA, based on the results of a smaller phase II trial. This was approved in what is called an Accelerated Approval Program, which requires a larger study to confirm the findings.
The final results presented unfortunately showed the larger phase III trial did not confirm that the combination of olaratumab and doxorubicin was better than doxorubicin alone, meaning there is no benefit to adding olaratumab to doxorubicin. The reasons for the different outcomes between the 2 studies are not completely known and is likely due to a combination of factors. An important finding, however, was that survival in patients with adult sarcomas continues to improve over time. And for patients receiving doxorubicin alone, overall survival was an average of approximately 20 months, showing that doxorubicin is an effective treatment for patients with adult soft tissue sarcomas.
Based on these results, olaratumab will be withdrawn, and no new patients should start on this treatment. For patients already receiving olaratumab for the treatment of their sarcoma, they should have an open discussion with their oncologist about stopping the drug. For patients who their doctors feel they are receiving benefit from olaratumab, there is a program to allow continued access to this drug.
What I think is most important about this trial is the focus it has drawn to clinical research and sarcoma. Because sarcoma is made up of a large number of very different and very rare cancers, advancements in treatments has been relatively slow. The results of this study have led to a larger discussion about how we think about and design trials for patients with sarcomas. It also highlights how important it is for patients to be seen at centers that have trials for their specific type of sarcoma.
Several trials reported at the meeting exemplify how the sarcoma community can successfully complete trials in rare sarcoma and make potentially substantial advancements. One example is the phase II trial of tazemetostat in patients with epithelioid sarcoma. Epithelioid sarcoma is a rare sarcoma sub-type with disappointing results from standard sarcoma treatments. One of the hallmarks of epithelioid sarcoma is the loss of a tumor-suppressor gene called INI1. When INI1 function is lost in a cell, a tumor-enhancer molecule called EZH2 becomes too active. Tazemetostat blocks the action of EZH2. The trial included patients with several types of cancer that have lost some INI1. This trial reported the results of the cohort of patients with epithelioid sarcoma. The results showed 15% of patients had a partial response, meaning their tumors decreased by about a third, with an additional 56% of patients having a minor response or stable disease. Importantly, in many of the patients whose tumors decreased in size, the response lasted for a relatively long time compared to what we typically see with sarcoma-based chemotherapies. The drug was relatively well-tolerated, with the most common side effects of low-grade tiredness, nausea, loss of appetite, and tumor pain. The company who developed tazemetostat has submitted an application to the FDA for consideration of an accelerated approval for patients with epithelioid sarcoma. If approved, this will be the first drug approved specifically for this type of sarcoma.
Again, the study is just 1 example of how we can make substantial improvements for patients with a rare cancer by collaboration amongst the sarcoma community, both nationally and internationally. Although it will not be possible to have a trial for every sarcoma sub-type, when available, it is important for patients with a metastatic sarcoma to go to centers that have trials for their specific disease. With this approach, I believe we will see even more advancements in the future for patients with sarcoma. Thank you very much for your time, and I hope I have more exciting findings to discuss in the future.
ASCO: Thank you, Dr. Keedy.
Next, Dr. Ryan Sullivan will discuss 2 studies in melanoma, including 1 that looked at treatment for melanoma that has spread to the brain, and 1 that is a long-term follow-up on targeted therapy for melanoma with a BRAF mutation. Dr. Sullivan is a medical oncologist and Attending Physician in the Division of Hematology/Oncology at Massachusetts General Hospital. He is also the Cancer.Net Associate Editor for Melanoma and Skin Cancer.
Dr. Sullivan: Hello. My name is Ryan Sullivan. I'm the Associate Director of the Melanoma Program at the Mass General Hospital Cancer Center in Boston, Massachusetts. Today I'm going to discuss research that was presented at the 2019 ASCO Annual Meeting in the Melanoma Program. There are 2 presentations that I'm going to highlight.
The first is a presentation by Dr. Hussein Tawbi from MD Anderson in Houston, Texas, who presented a follow-up of the safety and effectiveness of a combination of 2 treatments called nivolumab and ipilimumab given together in patients with melanoma who had brain metastases. This trial is also known as the CheckMate 204 study and initially, was presented in 2017 at the ASCO Annual Meeting and was subsequently published in 2018 in 1 of our prestigious journals called the New England Journal of Medicine.
This is an important study because it truly is the largest and most relevant clinical data that we have in how to most effectively treat patients with melanoma who have brain metastases. Brain metastases, unfortunately, are very common scenario for patients with metastatic melanoma. While the majority of patients probably do not develop brain metastases a significant minority do, and brain metastases can certainly complicate the treatment of patients with melanoma. Furthermore, they are also commonly and traditionally very commonly then a cause of death for patients with metastatic melanoma.
The CheckMate 204 trial built upon a number of emerging clinical trials that were showing that some of the newer treatments for melanoma, specifically drugs called immune checkpoint inhibitors which are therapies that alter the way that the immune system interacts with the cancer, have been increasingly effective in patients with metastatic melanoma, and furthermore have actually been moved forward into earlier stages, for example, stage 3 melanoma. And a logical question was whether or not these treatments would be effective in patients with brain metastases.
A common problem with therapies in patients with brain metastases is they may not get into the brain or the tumor to effectively treat that tumor and that was specifically a concern with these types of therapies. However approximately, it was almost 10 years ago when the trial was run and probably 8 years ago when it was published was the trial of ipilimumab in patients with brain metastases. Which the summary of it was that that drug worked about as well in patients who had disease in the brain particularly if that disease was asymptomatic and didn't require treatment for symptoms—it worked about as well in patients who were in that situation whereas patients who didn't have brain metastases but were treated with that medicine and about 20% of patients had long-term control of disease.
Moving forward, the last few years there's been clinical trials that have been published and presented about PD-1 blocking drugs called pembrolizumab and nivolumab which seemed to work a little less well in patients who have disease in the brain, and specifically these drugs probably, in patients who present with metastatic melanoma and are treated and don't have brain metastases, probably about 40 to 45 percent of patients have disease control in response and maybe a third of patients have control that's long-standing. In patients who have disease in the brain, it appears that that number is about 20 or 25 percent with response and durable control of disease, so effective, but not as effective in patients who do not have brain metastases.
So one logical question with emerging data about the combination of ipilimumab plus nivolumab, so ipilimumab plus a PD-1 blocking drug, was whether or not there would be a higher effectiveness. In patients without brain metastases, there's a clear improvement in response rate and maybe a delay in progression of disease and maybe even a slightly better overall outcome in terms of living longer for that combination, but that combination has side effects and those side effects can limit the effectiveness of the treatment.
So it wasn't clear whether or not combining these drugs would be the best scenario for patients with brain metastases. However, this clinical trial, the CheckMate 204 study, looked to study just that. The initial data that had been presented and published was based on 101 patients who were treated. These patients did not have any symptoms of brain metastases but were identified to have these brain metastases on imaging that was done probably just prior to starting therapy for recurrent and/or newly diagnosed metastatic disease. And amazingly over 50% of patients had responses to this combination on this trial, so of the 101 patients, 55 had a response and 59 had control of disease. And perhaps more amazingly, over time, the control of disease rate, which we call progression-free survival which basically just measures whether or not patients are alive and that their disease hasn't progressed, remained pretty stable at about 60%. So 60% of patients at 6 and 12 months had disease that hadn't progressed in the population of patients that previously had very bad outcomes. And that was really better than anything we've ever seen in these patients.
More importantly, the great majority of patients were alive. So almost over 90% of patients at 6 months, over 80% at 12 months, about 75% of patients at 18 months, and it seemed like that was pretty stable thereafter. And so a therapy that had shown effectiveness in patients with melanoma who don't have brain metastases seem to be even more effective in patients who did have brain metastases, at least when you compare that to outcomes that had previously been presented or published with just a single drug of nivolumab or the similar drug called pembrolizumab. So that data that was previously presented and published really set the new standard of care for patients who were diagnosed with metastatic melanoma who were unfortunate enough to have brain metastases, for us as providers who are treating these patients to say, "You need to be on this combination."
At the ASCO meeting, in addition to sort of the update that I just provided, they also presented the data from the cohort B. The second part of this study was in patients who actually had symptoms, and in those patients with symptoms they could be on medicines called steroids. Steroids often will reduce swelling in the brain around a metastasis and can make the symptoms better, however, the challenge with that is these medicines tend to be suppressive of the immune system and so they theoretically could counteract immune therapy like ipilimumab and nivolumab.
In any event, there were 18 patients that were treated on this part of the study. 4 of those 18 patients had responses, so that was over 20%. And importantly, of those patients who responded, 3 of the 4 were not on steroids. That baseline, again, suggesting that potentially patients who are on steroids may have worse outcomes than patients who aren't on steroids, may do a bit better. There's certainly going to be a bit longer follow-up needed to truly understand how effective this approach is in patients who have symptoms and who may be on some steroids. But the bottom line is it's clear that patients who are having symptoms, this is still the best regimen for patients with metastatic melanoma with disease in the brain and that it's possible to have responses even in the situation where those symptoms require patients to be on steroids. And so this is really important information for the field. And again, though it doesn't change the standard of care—our standard of care changed a year-and-a-half or two years ago with the initial presentation of this data, but it solidifies the standard of care and expands it a bit out to patients who also may have some symptoms and/or who may be on steroids and that this is an approach that's possible.
The second study that I wanted to talk about was a presentation. It was the first presentation of very long-term follow-up on BRAF-targeted therapy. So BRAF-targeted therapy for patients with melanoma is only appropriate for about the 40 or 50 percent of patients who have a BRAF mutation that's identified in their tumor. BRAF is a gene that leads to a protein that ends up being a very important part of the signaling pathway that leads to tumor growth and metastasis and evasion of the immune system. And as I stated, about 40 or 50 percent of patients who have melanoma will have an identifiable mutation in BRAF and that BRAF mutation drives tumor growth in those patients.
There are now three combinations of inhibitors that block BRAF and its subsequent signaling to a protein called MEK. And so our standard BRAF-targeted therapy is a BRAF inhibitor and a MEK inhibitor. There are three combinations: dabrafenib plus trametinib, vemurafenib plus cobimetinib, encorafenib plus binimetinib. So there are 3 regimens that are FDA approved for patients with BRAF mutant melanoma that's metastatic or unresectable.
Now, we know that these drugs are very effective. About 70% of patients have significant regression of tumors, and we know that when we compare these to single BRAF inhibitor treatment that combination is better, that patients live longer, have more responses, are less likely to have their disease progress. We know that BRAF inhibition versus chemotherapy is better on all those same parameters. And so what we don't know, however, is whether BRAF-targeted therapy’s better than immune therapy, and the purpose of the study I'm going to describe doesn't address that. There are a couple of trials that are still being enrolled to across the world that are answering that question, but we don't have that data to make any definitive statements about what's the best first therapy for a patient with BRAF mutated melanoma. However, we haven't had very long-term data with these combinations.
So this presentation by Dr. Paul Nathan was a combination of patients that were enrolled to either the COMBI-d study which compared dabrafenib, trametinib versus dabrafenib and the COMBI-v study which is dabrafenib, trametinib versus dabrafenib. And the data that was generated was looking at the 211 patients who got dabrafenib and trametinib in the COMBI-d and the 352 patients that got dabrafenib, trametinib in the COMBI-v study, and they just pooled all of that data together and followed to see how well those patients did.
The 3-year data was presented and published a few years back. This was the 5-year data, and I think the most important points are that about 20% of patients are still alive and without progression at 5 years. BRAF-targeted therapy was thought to be something that would be a temporary help and that wouldn't lead to durable benefit, but in fact, it seems like we're seeing durable benefit in these patients and more importantly, over 30% of patients were alive at 5 years. That number being 34%.
When the investigators broke that down, we know that a protein that we can measure in the blood called LDH is associated with poor outcomes, and we know that patients who have a normal LDH tend to do better with these types of therapies. And in fact, over 30% of patients who had a normal LDH and limited number of metastatic sites were alive and progression-free at 5 years. And when you looked at that same bit of data with regards to whether people were alive or not, the great majority, 55%, were still alive at 5 years. So this is proof that some patients can have long-term benefit and disease control with BRAF-targeted therapy who are started on BRAF-targeted therapy as their first treatment for metastatic melanoma, and that if you select patients just by very easily and readily available criteria, like this blood LDH measure and how many sites the melanoma has traveled to, that you can identify a population of patients where the majority will be alive at five years.
Now, we have more work to do. We still need to learn a little bit more about who those 30% of patients are that may have long term disease control in addition to the LDH measure, in addition to the number of metastatic sites. And we and others are working on trying to develop better tests to identify who those people are so that when we have a patient with metastatic BRAF mutated melanoma in front of us we can best offer them the option of BRAF-targeted therapy or immunotherapy and be smarter about making that decision. But I think that this is really an important piece of information because it does prove the concept that long-term control with disease is possible with a therapy that 10 years ago we didn't think long-term disease control was going to be possible. And so it's really exciting data to finally see it. We obviously have a lot more work to do. It's not acceptable to only have 30% of patients alive five years later. We need to get that number to 100% and along the way get it to 50 and then 60, and 70, and 80 percent, etc. But the fact that this data demonstrates that long-term control is possible with these therapies really does make us feel better about offering this to some patients in the front-line setting, and more importantly, inspires us to do additional research to truly figure out who those patients will be.
And with that, I'd like to thank you for your attention today, and it's been a pleasure discussing these 2 presentations at the 2019 ASCO Annual Meeting. Thanks.
ASCO: Thank you Dr. Sullivan.
Learn more about these topics and other research presented at the 2019 ASCO Annual Meeting at www.cancer.net.
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