2018 ASCO Annual Meeting Research Round Up: Brain Tumors, Sarcomas, Pancreatic Cancer, Liver Cancer, and Kidney Cancer

July 17, 2018
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The ASCO Annual Meeting brings together physicians, researchers, patient advocates, and other health care professionals to discuss the latest in cancer care. The research presented at this meeting frequently leads to treatment advances and new ways to improve the quality of life for people with cancer. In today’s podcast, Cancer.Net Associate Editors share their thoughts on the most exiting and practice-changing news to come out of the 2018 ASCO Annual Meeting.



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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

The ASCO Annual Meeting brings together physicians, researchers, patient advocates, and other health care professionals to discuss the latest in cancer care. The research presented at this meeting frequently leads to treatment advances and new ways to improve the quality of life for people with cancer. In today’s podcast, Cancer.Net Associate Editors share their thoughts on the most exiting and practice-changing news to come out of the 2018 ASCO Annual Meeting.

First, Dr. Vicki Keedy, the Cancer.Net Associate Editor for sarcoma, will discuss 1 study on treatment for osteosarcoma, a type of bone sarcoma that is most commonly diagnosed in children and young adults, and 2 studies on chemotherapy for older adults with soft-tissue 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.

Dr. Keedy: Hello, this is Vicki Keedy. I'm an Associate Professor of Medicine and the Clinical Director of Sarcoma at the Vanderbilt-Ingram Cancer Center in Vanderbilt University Medical Center. I have the pleasure of talking about some exciting research that was presented at ASCO in 2018. And the class of cancer was called sarcomas. Sarcomas are a class of rare connected tissue tumors that are made up of different types of cancers and they can affect patients at any age. I'd like to briefly discuss 2 topics that are at somewhat opposite ends of the age spectrum.

First, I want to discuss a trial presented by Dr. Duffaud in osteosarcomas. Osteosarcomas are a rare bone sarcoma that most frequently occur in pediatric and younger adults, but can actually present at any age. This particular study presented the data of a drug called regorafenib which is an oral therapy that primarily targets blood vessel development in cancers and patients with osteosarcoma. And it was studied in patients who had their cancer grow or return after they received their initial treatment.

Patients were randomized to either regorafenib or a placebo or a sugar pill. The study was not designed to formally compare these 2 groups but instead, the placebo group provided information on how osteosarcomas behave when they do not receive treatment. These data showed that 2 out of 3 patients receiving regorafenib did not have their tumor grow in 8 weeks, and 1 out of 3 patients did not have their tumor grow after 24 weeks. This is a particularly significant finding as all the patients receiving the placebo had their tumor grow at that first 8-week mark. What's so exciting about the results of this trial is that no study has shown improved outcomes in osteosarcoma patients once their initial treatment fails. We have to keep in mind that regorafenib is not FDA-approved for sarcomas, and these results are preliminary, thus a larger study will be required to confirm the results, but they are still quite promising.

Next, I'd like to move on to the opposite end of the age spectrum where a group of trials were presented evaluating chemotherapy in elderly patients with sarcomas. These are particularly important given sarcomas can occur just as frequently in older patients as younger patients. Two studies were presented that were specifically designed to evaluate treatment options in elderly patients with soft-tissue sarcomas.

The first trial presented by Dr. Hartmann evaluated a chemotherapy called trofosfamide compared to doxorubicin. The second trial presented by Dr. Grünwald compared an oral targeted drug called pazopanib to doxorubicin. Doxorubicin has long been considered the standard of care in the treatment of soft-tissue sarcomas and until recently no treatment regimen has proven to be better than it. The idea behind both of these trials is that doxorubicin as an IV chemotherapy can be relatively toxic, particularly, in older populations.

These studies were not meant to prove 1 drug was better than the other but rather to try to give us an idea whether there could potentially be a safer alternative that may be just as effective as doxorubicin. Ultimately, what I take from both of these studies is that the older patients actually did tolerate doxorubicin quite well with only a small portion of patients coming off due to toxicity. And if we're careful in selecting our patients based on their overall health and medical issues, patients can tolerate it well and that this chemotherapy is effective in our older populations. And therefore it's important for us to not make treatment decisions, particularly, to not hold chemotherapy in patients purely based on their age.

Thank you very much for listening. And I hope that was helpful.

ASCO: Thank you Dr. Keedy.

Next, Dr. Jeffrey Meyerhardt will discuss 2 new studies on the treatment of 2 different types of pancreatic cancer, and 1 study on a new treatment for cancer that begins in the liver. Dr. Meyerhardt is the Clinical Director and Senior Physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. He is also the Cancer.Net Associate Editor for gastrointestinal cancers.

Dr. Meyerhardt: Hi. My name is Jeff Meyerhardt. I'm a gastrointestinal oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. And today I'm going to discuss 3 studies that were presented at the recent Annual Meeting of the American Society of Clinical Oncology. All of them relate to what are considered non-colorectal GI cancers, so cancers that originate in other organs besides the colon and the rectum. In particular, I'm going to focus on 2 studies that originate in the pancreas from 2 different type of cancers, and 1 that originates in the liver called hepatocellular carcinoma.

Let me start with the first study. The first study is the PRODIGE Study which was a study conducted in France with also participation of sites in Canada. It was for patients with pancreatic cancer—the more common type of pancreatic cancer, what's called an adenocarcinoma—who were able to undergo a resection, a surgery for their pancreas cancer, and the question was looking at therapy after surgery to try to prevent recurrences. Before this study, there had been several studies that have looked at adjuvant—which is therapy after surgery—to try to prevent recurrent disease, and there have been some mixed results. There's been studies that've looked at chemotherapy alone and there's studies that have also looked at chemotherapy with radiation. And really, over the several years, there have now been multiple studies that showed that several chemotherapy regimens, the prominent 1 was a regimen with a single drug called gemcitabine or a combination of gemcitabine and another chemotherapy called capecitabine. Both showed an advantage for patients who had resection compared to doing nothing to reduce the risks of recurrent disease.

This study, which was a fairly large study of nearly 500 patients, compared a regimen called FOLFIRINOX which is actually 4 drugs—5-FU, leucovorin, irinotecan, and oxaliplatin—and compared that to gemcitabine which was 1 of the standard regimens prior to this study. The reason that they did the study was because FOLFIRINOX was shown in patients who had spread pancreatic cancer, metastatic disease, to be advantageous over gemcitabine alone. It significantly improved overall survival and patients overall tolerated it reasonably well—though there are some increased toxicities—and had a better progression-free survival which is the time until they had to switch to a different therapy.

So in this study, the logical next step was to see if it's more beneficial in metastatic disease, would it help in this setting? And you may think, obviously, it would but it lands up there's multiple examples of things that've worked in the metastatic setting that don't help to try to prevent recurrences in this, what's called, adjuvant, setting. But in this study of almost 500 patients that took about 4 and a half years to enroll, they showed that there was really a significant advantage to patients receiving adjuvant therapy with FOLFIRINOX if they had resection of their pancreas cancer. There was improvement in disease-free survival, in overall survival, in the amount of patients who were disease-free at 3 years, in the amount of patients who were alive at 3 years.

And so it really is a study that showed a real significant and sizable difference in all those endpoints, and has really become a standard of care now even several months since the completion of ASCO Annual Meeting. Now, it is a more toxic regimen and so there will be some patients that that would not be appropriate for, for toxicities, and the question is whether modifications of that regimen would be as beneficial as doing the sort of full doses that were studied in this individual trial.

There are also 2 upcoming trials that will also help understand what are the different options for patients who have pancreatic cancer and have surgery. The first trial is a trial that's comparing gemcitabine to gemcitabine and another chemotherapy called nab-paclitaxel, so combining gemcitabine and nab-paclitaxel. That's looking at a very similar population of patients who had surgery for pancreatic cancer resection and are looking to see if giving that combination over gemcitabine alone would improve the amount of patients who were main disease-free several years later.

And second, there is a study looking at radiation, because it's been a little back and forth in studies over the past several decades whether or not radiation adds benefit to patients after resection of pancreas cancer, or is there a sub-group of patients, particularly patients who may have higher risk disease or where the margin may be positive that would benefit from radiation, and that's currently a study going through the national cancer treatment network through the NCI, to try to look at that question. And again, it's going to be a little bit until we get those results.

The second study that I'm going to talk about is also related to pancreas cancer but it's actually a different pancreas cancer sub-type. It's what's called a neuroendocrine tumor. Neuroendocrine tumors are a smaller percentage of pancreas cancers. They're different than adenocarcinomas, different cell of origin, and have a different behavior. And they are a cancer that really haven't had any treatment options up till several years ago, and now there's actually 4 FDA-approved options for this disease: a drug called sunitinib, a drug called everolimus, a drug called lanreotide, and most recently the approval of a radioactive isotope 177 Lu-dotatate.

This was a study that was conducted through the national cancer treatment network of the NCI, the National Cancer Institute, that looked at patients who had metastatic—so spread—pancreatic neuroendocrine tumor, a sub-type called low or intermediate grade, which are actually the more common of the pancreatic neuroendocrine tumors, and comparing 2 drug regimens. One was giving alone a drug called temozolomide, a drug that has shown activity in multiple trials, though not yet FDA approved in this setting, versus adding capecitabine with temozolomide.

Capecitabine is a drug that has been approved in several different cancer types including colorectal cancer, including breast cancer, it's actually a drug that has activity in multiple type of gastrointestinal cancers and it was looking if this combination would be improved compared to temozolomide alone. The study was conducted for patients with low- or intermediate-grade neuroendocrine tumors and its primary endpoint was to look at progression-free survival. And it showed, again, a significant improvement in progression-free survival for these patients, which is defined as patients requiring another treatment. So people who have growth on their CAT scan of their disease, that then would be requiring another treatment.

It also ended up showing a significant improvement in overall survival for patients with the combination arm. It is a combination that is generally well-tolerated. With 2 drugs versus 1, there's going to be some increased toxicities, but overall, people have improved tolerance. And it adds to the armamentarium for patients who have neuroendocrine tumor where again, about 6 or 7 years ago really, there was no drugs that were FDA-approved and now there's a variety of drugs. And this adds another setting of drugs that could have activity of these patients' disease. In general, these are fairly slow-growing diseases but they are slow-progressive growing diseases and having multiple options for these patients is really quite important.

The third and final study I'm going to talk about is not in the pancreas. It's about liver cancer, or what's called a hepatocellular carcinoma. Now to avoid some confusion, there's a lot of different cancers that can affect the liver. Most common cancer people get in the liver are actually spread from another type of cancer - so whether it be breast cancer, or lung cancer, or colorectal cancer—that goes to the liver. If that's the case, those are treated like breast, lung, or colorectal cancer. They're treated like the cancer they start.

But there are cancers that can actually start from the cells in the liver and when that occurs—these what are called hepatocytes, which are the cells of the liver—people what's called a hepatocellular carcinoma. It's a cancer that has several risk factors including certain viruses like hepatitis B and C. It also can increase risks from alcohol cirrhosis. People who have high alcohol intake over a lifetime who get cirrhosis can have a higher risk of hepatocellular carcinoma, and then there are several other risk factors.

Again, it's actually a disease also that did not have many treatment options up till several years ago. Several years ago, there was a trial called the SHARP trial which led to the approval of a drug called sorafenib. It's a drug that affects a particular pathway called the vascular endothelial growth factor or angiogenesis, the blood vessels that form around tumors. And that has really been a standard of care for now several years for patients as initial therapy for hepatocellular carcinoma. Fortunately, really in the past 2 or 3 years ago, we've gotten data from multiple other drugs that can add to the armamentarium for patients with hepatocellular carcinoma. There's a drug called regorafenib, there's a drug called lenvatinib, and most recently, there was an approval of an immunotherapy called nivolumab for patients with hepatocellular carcinoma.

At this year's Annual Meeting of ASCO, there was a trial that looked at a drug called cabozantinib. It's actually also a VEGF, or vascular endothelial growth factor—affecting the angiogenesis, the blood vessels around the tumor—drug, and it was compared to placebo in patients who already had sorafenib in the past. So they had a hepatocellular carcinoma, they were treated with sorafenib, they either didn't tolerate sorafenib or their disease progressed, and it was an opportunity to have a second-line treatment to see if it can control their disease. It was a fairly large study of over 700 patients and they were randomized to cabozantinib versus placebo, and it showed a significant improvement in overall survival for patients who received cabozantinib and that also translated to a significant improvement in progression-free survival, time till you had to stop therapy because of growth of your tumor.

So this study showed another drug that could be beneficial to hepatocellular carcinoma. It's a drug that actually has a very similar pathway to the currently approved drug sorafenib, and so it shows that trying to switch it up a little bit but even within the same pathway, can have benefit for these patients. And again, now we have a disease that several years ago really had no therapies that were effective against it, where there's now multiple treatment options, some of which are FDA-approved and some are currently being evaluated by the FDA, the Federal Drug Administration, to be able to give opportunity to try to keep people with hepatocellular cancers disease under control over time.

So these are 3 exciting trials that were presented at the Annual Meeting of the American Society of Clinical Oncology. In my mind, these are all trials that are going to lead to change of care for patients with these individual diseases. They're clear advancements in adding to the armamentarium for all these diseases to help patients have control of their disease and improve their quality of life and overall survival.

This is Jeffrey Meyerhardt with Cancer.Net and the Dana-Farber Cancer Institute in Boston, Massachusetts. Thank you very much.

ASCO: Thank you Dr. Meyerhardt.

Next, Dr. Brian Rini will discuss 3 studies on different treatment options for advanced kidney cancer. Dr. Rini is a Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a staff member of the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Institute. He is also the Cancer.Net Associate Editor for genitourinary cancers.

Dr. Rini: Hi, my name is Brian Rini. I'm a Professor of Medicine at Cleveland Clinic. I run the GU oncology program here, and I'm going to talk today about some data that was presented at the 2018 ASCO Annual Meeting focusing on kidney cancer.

There were 3 studies that I'll briefly present. One was presented in the plenary session called CARMENA, which has to do with the role of nephrectomy in patients with metastatic disease. Another one was about pembrolizumab when given as monotherapy, or given by itself to patients with kidney cancer. And then a third regarding a drug called axitinib, which is approved, but there was a study reported using this drug after immunotherapy.

So first focusing on CARMENA, this was a plenary discussion, so very important data. And the basic background is that historically, when patients with metastatic kidney cancer have walked in the door with what we would say is primary in place, meaning they have the primary kidney tumor, it has not been previously removed, and they have distant metastatic disease. Historically, we've taken many, to most, patients like that to nephrectomy. Even though it's not curative, old studies showed that those patients lived longer, and that was an established standard of care for the past several decades. Now that we have more active drugs, kidney cancer patients and doctors have questioned that paradigm and whether or not surgery is really needed for all these patients. CARMENA was a study that randomized patients such as this to either get nephrectomy or not, and then get sunitinib, which is a common initial antigenic drug given upfront to these patients. This study didn't show a difference between the arms, and that's really what it was designed to do is so-called non-inferiority, or to not show a difference. And so the authors concluded that maybe surgery is not necessary in such patients.

I think it's important to know that, as I think about these data, I think that there's 3 groups of patients when it comes to making the decision about getting upfront kidney removal. There are patients who certainly should never go to surgery, patients who are older, more frail, whose surgeries are going to be very extensive, and especially who have a lot of disease outside the kidney. And historically, we've never taken those patients to surgery, and that remains so. There are also patients who should go to surgery, so young, healthy patients with the bulk of their overall tumor in their kidney, and very little outside the kidney. And then there's a middle group of patients who have sort of an even balance of tumor inside and outside of the kidney, and it's really that group of patients that CARMENA enrolled. And I think the data tell us that maybe we shouldn't be so fast to take those patients to surgery. So to me, CARMENA sort of reinforces at least what we've been doing here, and my personal philosophy that there's really very select patients that we should be sending to surgery in this circumstance. And so I think you'll see the practice shift a little bit to hopefully better select patients and lead to better outcomes.

The second study that I would like to highlight was presented by Dave McDermott, and had to do with pembrolizumab, which is a PD-1 inhibitor, a so-called checkpoint inhibitor as a standalone therapy in first-line kidney cancer. And the background is that immunotherapy agents are taking over oncology, and kidney cancer is no exception. Nivolumab, sort of a cousin of pembrolizumab was approved in the second-line setting a couple years ago, and a combination immune therapy was approved in the front-line setting a couple months ago. So many, many combinations are being developed of all our available therapies.

But this was important data because it asked a simpler question of what if we just give immune therapy as a standalone drug to initial metastatic RCC? And what was seen was a surprisingly high response rate. About 40% of people responded. That number was higher in patients whose tumors expressed this PD-L1 protein. And there was a number of complete responses as well, and so it was a surprising amount of disease control for this drug by itself. The other important part is that it's really well-tolerated. So compared to combining drugs, certainly a single drug will be better tolerated.

So while the study wasn't designed to lead to FDA approval, I think it's an important bit of data to tell us that there's probably a group of patients who can get away with less intense therapy upfront. As oncologists, we like giving people more and more drugs, and more intense therapy, and sometimes it's worth it, but it's not always necessary. So we need to see some more follow-up from these data and some more data, but I think there's going to be a place in a subset of patients to get away with just giving a single-agent immune therapy. And perhaps not forever. The other advantage to immune therapy is that it can be given for a period of time, patients can respond, and then potentially stop. And figuring out when to stop and in whom we can stop is a whole other area of research that we don't yet have answers to, but I think these data were important to at least start asking the question.

The last data that I'll comment on was some from our group that looked at axitinib after treatment with immune therapy. So as I mentioned, immune therapy has become standard in the second-line setting and is becoming increasingly standard in the front-line setting, and I think will be a front-line standard of care over the next 1 to 2 years. An open question was how to treat people after the immunotherapy had failed, whether it's in the front- or second-line setting. Another one of our interests has been altering the dose of these oral drugs, the oral antigenic inhibitors, especially axitinib, and how to achieve an optimal dose for each individual patient.

And so we combined these interests and looked at a novel way of titrating this axitinib oral drug after patients had been on immune therapy. And this was about 40 patients. It was done across 5 centers. And what was seen is that the response rate, which was nearly 40%, and the progression-free survival, or duration of disease control was nearly 9 months, both of which I think were surprisingly good in this circumstance. So it's good news in that it shows us that there are active drugs after immune therapy that patients can respond. The tolerability was very good using this titration scheme. And so we're starting to put together the building blocks of how we're going to sequence therapy for patients now that we have this new immune therapy.

And if I could sort of put all the abstracts together, it means that we need to carefully select patients for surgery or not upfront: it's still a very individualized decision. We are moving towards immune-based therapies, including combinations in the front-line setting, although the data presented at ASCO tells us that single-agent immune therapy may have a significant role for patients, and there are active drugs after immune therapy. The study was presented with axitinib, but any of the VEGF receptor inhibitors are likely to be active in this setting.

And so we're sort of rearranging the way we approach patients with this sequence of therapies. And I think the data presented at the ASCO 2018 Annual Meeting helps us to sort of move forward and reconstruct, if you will, that sequence of therapy for metastatic kidney cancer patients. Thank you.

ASCO: Thank you Dr. Rini.

Finally, Dr. Susan Chang discusses the importance of precision medicine in the treatment of brain tumors such as glioblastoma. Dr. Chang is the Director of the Neuro-Oncology Division at the University of California, San Francisco, and the Cancer.Net Associate Editor for central nervous system tumors.

Dr. Chang: My name is Susan Chang. I'm the Medical Director of the Division of Neuro-Oncology at the University of California in San Francisco. I also serve as an editor for Cancer.Net for the central nervous system area. I am pleased to present this overview of some of the advances that were delivered at the 2018 Annual Scientific Meeting of the American Society of Clinical Oncology.

Now this year's overall theme for the meeting was “Delivering Discoveries, Expanding the Reach of Precision Medicine.” And this is an important topic for primary brain tumors like glioblastoma where we are challenged with an aggressive disease with very limited effective treatments. But over the last few years, we have learned how the molecular and cytogenetic makeup of tumors can serve as important predictors of outcome and response to treatment. And several of the scientific abstracts this year demonstrated how improved understanding of the biology of disease can translate into personalized treatment strategies and novel approaches.

A couple of studies leveraged the discovery of one of the very early initiating events: low-grade glioma. This is the mutation in the isocitrate dehydrogenase gene or IDH gene. Patients with tumors having this mutation have a better outcome than those where the mutation is not present. One study evaluated a reversible brain penetrant inhibitor of the mutant IDH1 and 2 enzymes. This is AG-881, and what they showed was there was good evidence of tolerance and also a delay in progression of the disease.

Another study described the development of a peptide vaccine that targeted the neoantigen IDH1 R132H protein which is formed as a result of the mutation. Patients whose tumors harbored this specific mutation were vaccinated following radiation and chemotherapy. The study showed that the vaccine was safe and that this induced mutation-specific and sustained antibody responses. Correlative studies are ongoing to characterize the peripheral immune response and to determine if this can serve as a biomarker of their immune response within the tumor.

The majority of glioblastoma, however, do not have this mutation IDH, and so these strategies would not be relevant. One of the major challenges with treating glioblastoma is the heterogeneity of tumor cells within the tumor itself.

And another approach for personalizing treatment is the development of affected T cell responses that we can orchestrate and initiate with specific [inaudible] with those that are targeting multiple tumor antigens. One study evaluated the safety and feasibility of integrated, actively personalized immunotherapy in patients with newly diagnosed glioblastoma. And in this study, the tumor was resected, and a vaccine was produced by assessing the expression of specific proteins unique to the tumor. Laboratory testing for immunogenicity of the proteins were performed, and as a result of that testing, patients received up to 7 active peptides. Now there was a second vaccine that was produced after much more detailed sequencing of the tumor and delineation of specific mutations, and patients received up to 2 targeted peptides. By using this approach, the study showed that the vaccines were safe and that, again, mutation-specific sustained reaction to the vaccine was demonstrated.

So these early studies do demonstrate the safety and feasibility of future approaches. But what the next step is for these studies is to launch trials where the drug, or the vaccine, will be administered prior to a resection of a tumor, and then this will allow for the evaluation of drug delivery as well as the biological effect of the agent or vaccine. And in cases where a vaccine was administered prior to resection, we'll be able to characterize the immune cell response within the tumor and to see if this correlates to response.

Another biological hallmark of glioblastoma is the formation of neovessels within the tumor, and bevacizumab is a humanized monoclonal antibody targeting the vascular endothelial growth factor ligand, and that is approved by the FDA for patients with glioblastoma. Combining this agent with an immunotherapeutic strategy with a checkpoint inhibitor, pembrolizumab, was the focus of 1 study that tried to capitalize on multiple approaches to treat glioblastoma. And although the combination did not appear to be more effective than pembrolizumab alone, the immune-correlative laboratory data may be informative regarding the selection of patients who may actually benefit from this combined approach.

So in summary, these studies encompass approaches that are being explored to deliver precision-based medicine for patients with brain tumors, and they highlight the importance of the basic science discovery, and the translation of these discoveries to the clinical arena to try to improve patient outcome. Thank you.

ASCO: Thank you Dr. Chang. If this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

To learn more about all of the science presented at the 2018 ASCO Annual Meeting, visit www.cancer.net/ascoannualmeeting. If you have questions about whether new research may affect your care, be sure to talk with your doctor.

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