[music]

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer.

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.

Every year, the ASCO Annual Meeting brings together attendees from around the globe to learn about the latest research in the treatment and care of people with cancer. This year, attendees from 138 countries worldwide gathered virtually for the ASCO20 Virtual Scientific Program, held Friday, May 29 through Sunday, May 31.

In the annual Research Round Up podcast series, Cancer.Net Associate Editors answer the question, “What was the most exciting or practice-changing research in your field presented at the ASCO20 Virtual Scientific Program?” In this final episode of 2020, editors discuss new research in the fields of central nervous system tumors and lymphoma.

First, Dr. Glenn Lesser will discuss new research on a form of non-Hodgkin lymphoma that begins in the central nervous system, and research into a possible treatment for breast cancer that has spread to the brain. Dr. Lesser is the Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest University, with joint appointments in the Departments of Anesthesiology, Neurosurgery, and Public Health Sciences. He is also the Cancer.Net Associate Editor for Central Nervous System Tumors.

View Dr. Lesser’s disclosures at Cancer.Net.

Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and director of medical neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss what I think are 2 of the most clinically relevant research studies on brain tumors that were presented at this year's ASCO's Virtual Scientific Program. I should say right up front I have no disclosures or relationships that are relevant to the particular studies I'll be discussing today.

Unlike the progress we've seen in the treatment of many cancers over the past few years, patients with brain tumors and the physicians who care for them have not seen the same rapid advance in effective treatment strategies. Cancer that begins in the brain, so-called primary brain tumors, and the more common situation of cancer that spreads to the brain after originating elsewhere in the body, so-called metastatic or secondary brain tumors, still have relatively few effective treatment options available. However, I believe that the 2 abstracts we'll discuss today may impact the way that we treat certain primary and metastatic brain tumors in the future.

The first study I'd like to talk about was presented by Dr. Omuro on behalf of a group of international colleagues that described a randomized study of standard chemotherapy with or without low dose whole brain radiation in patients with a brain tumor known as a primary central nervous system lymphoma, which I may also talk about as a PCNSL for abbreviation. Non-Hodgkin's lymphoma is a relatively common cancer that involves the blood and lymph nodes throughout the body. Primary central nervous system lymphoma is the term used when patients develop a non-Hodgkin's lymphoma that's confined to the central nervous system which is really made up of the brain, the spinal cord, the spinal nerves, and the spinal fluid. This turns out to be a pretty rare diagnosis with only about 1,500 new cases of this cancer occurring in this country each year. This type of lymphoma is important, though, because it's very treatable in most patients, and a significant percentage of our patients can be cured with appropriate therapy. Because the disease is so rare, we really don't have the results of large clinical trials to help us determine the best treatment approach for patients with primary central nervous system lymphoma. And as a result, there are a variety of controversies over how to initially treat patients who develop this lymphoma, so-called induction therapy, as well as what type of treatment to give once the disease has been made to go away, or so-called consolidation therapy. In the past, radiation therapy to the whole brain was used to treat patients with PCNSL. And most of these patients who were treated with radiation-containing regimens had their tumors respond, although the cancer frequently returned within a year or 2. This approach has really fallen out of favor over the last few decades because of the very high incidence of neurotoxicity or brain damage from the radiation that was seen in surviving patients.

Unfortunately, a significant number of those patients who were treated with high doses of whole-brain radiation therapy developed a progressive irreversible dementia over the years following the radiation treatments, and a particularly high incidence of this toxicity was seen in patients who are over the age of 50. With current multi-agent chemotherapy regimens, a high percentage of treated patients are having their lymphomas go away. Unfortunately, a significant number of patients still have their disease come back within months or years of this treatment. And so strategies to consolidate or lock in that initial good result with treatment are being evaluated. These strategies may involve high doses of different types of chemotherapies, consideration of bone marrow or stem cell transplant, and even long-term maintenance treatment with oral chemotherapies. More recently, low doses of whole-brain radiation therapy have been explored as a way to try to prevent these lymphomas from coming back with a thought that the low doses of radiation might have minimal long-term brain toxicity as compared to the high doses of radiation given in the past.

So this study that was presented at ASCO involved about 91 patients with primary central nervous system lymphoma. Half of them received the low-dose whole-brain radiation therapy after their tumors were treated with several months of multi-agent chemotherapy, while the other half did not get the radiation. After a follow-up period of 4 to 5 years, the results of this treatment were that the patients who received the low-dose radiation in addition to chemotherapy lived longer and had a significantly higher rate of their tumor going away and staying away at least at the 2-year follow-up tie point. Now, data is not yet available on the neurocognitive outcomes in both groups of patients. That is how well their brains were functioning with tasks like memory, calculations, and personality. The improved results seen in this group of patients who got radiation suggests that this approach may be one effective way of helping to consolidate the treatment of primary central nervous system lymphoma after the induction chemotherapy.

These results, however, can only really be fully interpreted and applied once we have more long-term information on whether the patients treated in this fashion suffer from the high rate of neurotoxicity and dementia that was seen in prior studies using the higher doses of radiation. With further follow-up, this study should provide us with some definitive information on whether the strategy of adding low-dose radiation following standard induction chemotherapy is a good one for patients with primary central nervous system lymphoma.

The second study I'd like to talk about was presented by Dr. Nancy Lin, again on behalf of an international group of colleagues, and described the results of a trial adding a new drug called tucatinib to a standard chemotherapy regimen of trastuzumab and capecitabine in women with HER2-positive breast cancer involving the brain. Now, many common cancers have a tendency to spread to the brain if they recur after initial treatment. This metastatic or secondary involvement of the brain occurs in over 200,000 patients a year in the U.S., and new treatments for brain metastases are desperately needed. Women with advanced breast cancer are particularly susceptible to developing brain metastases, particularly if they have the subtype of breast cancer known as HER2-positive disease. In HER2-positive disease is defined that way because of the presence of the HER2 protein on the surface of breast cancer cells. Although a number of effective treatments have been developed for patients with HER2-positive breast cancer involving the body, including some common drugs like trastuzumab and pertuzumab, these agents have not been particularly effective in either treating breast cancer that has spread to the brain or preventing the breast cancer from spreading to the brain in the first place.

One of the main reasons why these chemotherapy drugs have not been effective in treating breast cancer metastases in the brain is that unlike the other organs in our bodies, the blood vessels of the brain are formed in such a way that they carefully restrict what substances in the blood are able to leave the blood and spread into the brain. Normal blood vessels in our body are somewhat leaky. And fluids, proteins, drugs can leak out of those vessels into the tissue with some freedom. The blood vessels of the brain, however, are lined by cells that tightly joined together to create a blood-brain barrier that is not leaky, and that barrier protects the brain from compounds that are circulating in our bloodstream which could adversely affect brain function if they were able to get into the brain in any concentration. Because of this barrier, most of our standard chemotherapy and anticancer drugs simply cannot cross the barrier to reach the cancer cells within the brain. In part, because of this, patients whose cancer had spread to the brain have typically been excluded from most of the clinical trials evaluating new drugs and treatments for breast cancer. The study reported by Lin at ASCO tested the ability of a new HER2-targeted drug, tucatinib, which because of its chemical structure has good penetration across this blood-brain barrier. Earlier smaller studies had suggested that this drug did indeed get into the brain at concentrations that could effectively treat breast cancer involving the brain. In this study, almost 300 patients with metastatic breast cancer involving the brain were treated with a standard chemotherapy regimen with or without the tucatinib. Serial brain scans were obtained in order to measure the response of the brain metastases to the treatment. These were typically MRI scans of the brain.

The study results showed that the use of tucatinib in patients with breast cancer involving the brain reduce the risk of the growth of their brain disease by about two-thirds and improve their overall survival by at least 6 months. These results have recently been published in a more complete form in the Journal of Clinical Oncology. And these results really strongly support the use of tucatinib in combination with the standard chemotherapy regimen of trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer involving the brain.

Although neither of the new approaches I've just described cure the majority of patients treated with either the primary CNS lymphoma or brain metastases from breast cancer, both describe new approaches that really potentially move us further along the road to having more effective treatments for patients with brain tumors. These studies are also outstanding examples of why well-done clinical trials that carefully test and evaluate the beneficial effects as well as the toxicities of new cancer treatments are critical to our goal of finding new therapies to treat our patients with cancer. Thanks very much.

ASCO: Thank you, Dr. Lesser.

Next, Dr. Michael Williams will discuss several studies that looked at new ways to treat different types of lymphoma. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center. He is also the Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. He is also the Cancer.Net Associate Editor for Lymphoma.

View Dr. William’s disclosures at Cancer.Net.

Dr. Williams: Hello. This is Dr. Michael Williams. I'm a professor of medicine at the University of Virginia hospital in Charlottesville, Virginia, where I'm chief of the hematology oncology division and the physician lead for cancer services here at UVA. I have a few disclosures, clinical trial grant support from Janssen and Pharmacyclics to the University of Virginia. I've received honoraria for medical education conferences from Xian Janssen, and I have been a consultant for Kite Pharmaceuticals in the past. So what we're going to talk about today are some of the highlights in lymphoma that were presented at the recent virtual meeting of the American Society of Clinical Oncology focused on lymphoma. So the field continues to move forward very rapidly. It's really a dynamic time for advances in treatment of lymphoma and related disorders. The exciting thing is that patients in the not-too-distant past may have had limited options, especially in the setting of recurrent lymphoma. We now have new approaches that are really quite interesting, quite effective, and I think are going to change the way we practice for these particular diseases.

So the first of these I'm going to talk about is for classical Hodgkin lymphoma, also called Hodgkin's disease. So the good news is here, that the vast majority of people with Hodgkin lymphoma are cured by their frontline therapy but not all do achieve a remission, or if they do, they may relapse a year or 2 or sometimes later after their initial therapy. And these patients, historically, have not had as good of a long-term outcome as those who remained in their initial remission. So investigators from an international team of lymphoma experts conducted the KEYNOTE-204 study that compared an immune checkpoint inhibitor - it's a form of immunotherapy called pembrolizumab - versus a standard agent brentuximab vedotin, which is a drug antibody conjugate that delivers a chemotherapy agent directly to the Hodgkin tumor cells. So these were patients who had either not responded to their initial treatment, in other words were considered to be primary refractory, or had relapsed later. Many of them relapsed within 12 months, which is, again, a worrisome timing for relapse in that those patients may be more chemotherapy resistant to traditional treatments.

So in this study, it was a 1-to-1 comparison of about 300 patients. And the study found that those who received the checkpoint inhibitor pembrolizumab had a better response in terms of their remission rate and a more long-lasting response than those patients treated with brentuximab vedotin. At 12 months, about 54% of patients remained in remission as opposed to about a third of patients on brentuximab. Although, there were some continued relapses over the next year, there were some patients who achieved more durable response. So it was a very encouraging finding. The side effects were as would be expected. There were some autoimmune problems with the immunotherapy checkpoint inhibitor and peripheral neuropathy in those who got brentuximab. So these investigators concluded that for patients with this form of relapsed and chemotherapy-resistant Hodgkin's lymphoma, that pembrolizumab should be considered the preferred treatment option and a new standard of care for these patients.

Now, the second trial that we'll talk about relates to a specific form of non-Hodgkin lymphoma called lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. This is a lymphoma where an abnormal immunoglobulin, a high molecular weight IgM, is produced. That can cause problems of hyper viscosity and headaches, vision changes, shortness of breath, in addition to some lymphoma-related symptoms. And what they did is compared 2 targeted agents for people who needed treatment, whether they were relapsed or had not had prior treatment at all for their Waldenstrom's. And the drugs that they chose were Bruton tyrosine kinase, or BTK, inhibitors. These are a very active class of drugs in B-cell lymphomas including Waldenstrom's. And the first of these that became available several years ago and was FDA approved is ibrutinib, and a second agent more recently approved is zanubrutinib. The latter being a bit more targeted to the molecule that we're trying to inhibit in the tumor cells. And it's similar in many ways to a third drug that's available called acalabrutinib.

But in this study, they're comparing ibrutinib with zanubrutinib. And what they found is that, in about 200 patients, that both drugs were very effective in achieving a response. Slightly higher response rates for zanubrutinib, but really no significant difference in the progression-free and overall survival for these patients. So both drugs were very active and very reasonable for treating patients. There were fewer side effects, however, with zanubrutinib, in particular toxicities such as the development of atrial fibrillation and diarrhea or bruising and bleeding, which happened in a small percentage of patients on ibrutinib. So those side effects seemed to be less with the more targeted drug zanubrutinib. So they appeared to be similar in efficacy but perhaps a better safety and toxicity profile with zanubrutinib. Now, ibrutinib is approved in the United States for relapsed Waldenstrom macroglobulinemia. Zanubrutinib is approved for mantle cell lymphoma, so not for Waldenstrom.

So the final entity that I want to discuss is really using a treatment that many of you no doubt have read about. There's been a lot in the news about the use of CAR T-cell, or chimeric antigen receptor T-cell therapy. So this is a form of cellular therapy. And by that, I mean that in patients who have relapsed aggressive lymphoma, usually diffuse large B-cell, a patient who has relapsed disease has T-cells. Those are part of their immune cellular defenses. And those T-cells are removed and they're genetically reprogrammed and then expanded and reinfused to patients. So they're reprogrammed so that the immune effects are targeted against the patient's lymphoma cells. So this is an approved therapy in aggressive relapsed large B-cell lymphoma. But at this meeting, investigators from a number of centers in the United States reported the interim results of a study using a CAR T-cell called axicabtagene ciloleucel, or Axi-cel, for patients with indolent or low grade lymphoma that, nonetheless, is recurring, needs treatment, and has been resistant to at least 2 or more prior therapies.

So I'm going to focus in this study on the results with follicular lymphoma. They did also study a small number of patients with another type of indolent low-grade lymphoma called marginal zone. But looking at the follicular lymphoma patients, they were heavily pre-treated. Most of the patients had had 3 or more prior therapies. Most of them were refractory or, in other words, resistant to the current and the most recent chemotherapy they had received. And about a quarter of the patients had had a prior stem cell transplantation for relapsed disease but had now relapsed even after that therapy. And what they found in the first 80 follicular lymphoma patients they studied is that 95% of them responded and 81% achieved a complete remission. The duration of response was really quite good. So with a follow-up of a little over a year, about two-thirds of patients were still in remission. Whether these patients may be cured of their follicular lymphoma or may experience a later relapse is going to require more follow up, but very promising early results for this treatment of patients with otherwise resistant follicular lymphoma.

There are significant side effects with this type of therapy, including something called cytokine release syndrome, which is like an intense inflammatory reaction. Fortunately, the severe forms of this occurred in a minority of patients, under 10%. There can also be neurologic events that can range from tremor or confusion, and rarely even patients becoming unresponsive. Fortunately, most everyone recovers from this. And in this trial, the more severe forms of these neurologic events occurred in about 15% of patients. So a very promising early set of data for another group of lymphoma patients, in addition to those with large cell lymphoma. So if you are in a situation of highly resistant and progressing follicular lymphoma, including follicular lymphoma that may have transformed from the lower grade into a higher grade large cell lymphoma, then considering a CAR T-cell therapy or a clinical trial of other novel approaches is certainly worth considering.

And I'll finish by just saying that it's a fast-moving field. There's a lot of benefit if you have a newly diagnosed or a relapsed lymphoma to talk with your oncologist and consider whether a second opinion may be in order and what clinical trials might be relevant for your situation because, nowadays, we often find that taking part in such a trial provides access to some of these very promising new agents and allows us to move the field forward and bring these newer treatments online so that they can benefit as many patients as possible. So a very exciting time in the field of lymphoma, lots of important new data presented at ASCO, and I'll look forward to updating you on future advances in another podcast.

ASCO: Thank you, Dr. Williams. Learn more about the research presented at the ASCO20 Virtual Scientific Program at www.cancer.net/blog, and subscribe to Cancer.Net podcasts on Apple Podcasts or Google Play to catch up on the other episodes in the Research Round Up series.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

[music]