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May 28, 2020

In today’s episode, Dr. John Sweetenham, Editor-in-Chief of ASCO Daily News and associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, discusses key abstracts on hematologic malignancies and advances in cancer care featured at the #ASCO20 Virtual Scientific Program.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today to highlight presentations on hematologic malignancies that will be featured at the #ASCO20 Virtual Scientific Program is Dr. John Sweetenham, editor-in-chief of the ASCO Daily News. He is also associate director for clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center and professor in the Department of Internal Medicine. Dr. Sweetenham specializes in treating lymphomas and other hematologic malignancies.


My guest today reports no conflicts of interest relevant to this podcast. Full disclosures can be found on our episode pages. Dr. Sweetenham, welcome back to the ASCO Daily News podcast.


Dr. John Sweetenham: Thanks, Geraldine, I'm very happy to be here.


ASCO Daily News: Dr. Sweetenham, tell us about the abstracts that have really caught your attention this year.


Dr. John Sweetenham: Yes, in the hematologic malignancies field, there are several abstracts this year, which I think are of particular interest. And I'm going to start out with some abstracts related to CAR-T cell therapy. This, of course, has been a huge buzz in the hematologic malignancies world for probably three or four years now. And there have been a rapidly increasing number of studies. And some of these are going to be presented at the Virtual Meeting this year. And I picked out one or two, which I think are of particular interest.


So starting out with abstract number 8008, this is a report of the interim analysis of the ZUMA-5 study. So this is looking at a well- established CAR-T cell therapy now, which is axicabtagene ciloleucil, also known as axicil, which targets the CD19 antigen on B cells. This particular CAR-T cell therapy has been demonstrated to have significant activity in some aggressive B cell lymphomas, as well as in B ALL.


This study has asked a separate question of this particular CAR-T cell platform, which is its activity in relapsed and refractory low-grade lymphomas. There are, of course, many emerging therapies for indolent lymphomas, such as follicular lymphoma and nodal and extranodal mantle zone lymphoma. So in this study, the investigators have taken patients with relapsed and refractory low-grade lymphomas who have failed at least two prior lines of therapy, including an anti-CD20 monoclonal antibody and an alkalizing agent and have applied the use of CAR-T cells to these patients.


So far on the interim analysis, they include a report of 94 patients with a median followup which is now just approaching a year. The median age is 63 years old in this study, which is highly relevant in this group of patients and close to the median age for the population as a whole. So not apparently a highly selected group. And interestingly, the upper age on the study was 79 years old.


And these were all relatively high-risk patients, either by virtue of a high FLIPI score or high tumor bulk according to Guelph criteria. And the patients that had a median of three prior lines of therapy, and 66% of them had progress within two years of their last line of therapy. In terms of results so far, the overall response rate was 94%, with a 79% complete response rate. If you look specifically at those patients with follicular lymphoma, the overall response rate was 95% and the CR rate was 80%.


So these are really very encouraging and impressive results in a relatively heavily pre-treated a group of patients with follicular lymphoma. It is at the moment a little too early to comment too much on the relapse rates and remission duration in this group of patients. Overall, the toxicity of the CAR-T cells was very comparable with what has been reported previously in patients with aggressive lymphoma. So I think one can say at this point that this is a very interesting result and a promising intervention for this group of patients who have a relatively limited number of treatment options and are generally regarded as being incurable.


Moving on to other CAR-T therapies there are two abstracts, numbers 8503 and 8504, which report comparable experiences for patients with multiple myeloma who are relapsed and refractory. So these two abstracts reports on different CAR-T cell platforms, both of which target BCMA, the B cell maturation antigen, a common target now for immunotherapy in multiple myeloma. And in both of these studies the group of patients who is included are those with relapsed and refractory multiple myeloma, patients who have progressed on three different classes of drug, all of the patients included in both these studies had progressed on regimens, which included immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies.


So in the first of these studies abstracts, 8503, patients that received three or more prior regimens and it being refractory to their last regimen, 140 patients were enrolled on this study, and 128 actually went on to receive treatment on study with a median age of 61 years and a median of 6 prior regimens. And most of these patients were refractory to multiple prior lines therapy. The median followup on the study at this point is just approaching a year. And the overall response rate was 73%, with a median progression-free survival of 8 and 1/2 months.


What they were able to show in this study was that there was an apparent association between the CAR-T cell dose the patient received and the response rates and progression-free survival. A similar trend was shown in the other study, abstract 8504, using a different CAR-T platform but with the same targets and a very similar patient population, patients with relapsed and refractory multiple myeloma having had at least three prior regimens. Again, they were able to demonstrate high overall response rates, which approached 90% in this study.


Once again, they were able to show that there was the relationship between the efficacy of the CAR-T cell therapy and the number of CAR-T cells infused. And overall, what they demonstrate in both of these studies was that with manageable toxicity, there were relatively high objective response rates in multiple relapse treatments. So I think that along with a number of other ongoing studies, the CAR-T cells and multiple myeloma, this demonstrates that this appears to be a very highly active intervention, which will require more follow-up obviously since these are relatively early results. But I do think that it shows some significant promise for the future.


The other particularly eye catching study from the hematologic malignancies group is late breaking abstract number 3. So that's abstract LBA3. This is a very important, large, randomized study, which was a comparison of two front line regimens for patients with multiple myeloma, known as the so-called ENDURANCE phase III trial. This was a study which compared two combinations for frontline therapy, a standard combination comprising bortezomib, lenalidomide, and dexamethasone, which was compared with the same regimen, but substituting bortezomib for carfilzomib a second generation proteasome inhibitor, which in some studies has shown higher efficacy and a different toxicity profile from bortezomib, the first generation proteasome inhibitor.


So the randomized phase III trial was designed to determine whether the carfilzomib-based regime improved progression-free survival compared with the standard regimen. There is also a secondary objective of the study based on a lenalidomide maintenance. The results of that are not reported in this abstract. Overall, just over 1,000 patients were accrued to this study, 1,087 patients randomized in a one-to-one fashion for 36 weeks of frontline therapy and then a second randomization to lenalidomide maintenance or not.


At the time of the report, the median age of the patients on the study is noted to be 65 years. And this represents the second of three planned interim analysis. The progression-free survival in the study shows a hazard ratio of 1.04 with no difference in progression-free survival noted between the two arms of the study. In the bortezomib-based arm, it was 34.4 months compared with 34.6 months in the carfilzomib-based arm of the study.


And when they analyzed by subgroup, the investigators were not able to find any group where there was a superior survival for one arm versus the other. So at the second interim analysis the futility was met for this study. The authors conclude that the randomized phase III trial demonstrated that the carfilzomib-based regimen didn't improve progression-free survival compared with the standard bortezomib-based regimen. What's more, there was a higher rate of cardiac and renal toxicity with the experimental arm, while the neuropathy rates were somewhat higher with the bortezomib-based arm. And the authors conclude that the combination of bortezomib, lenalidomide, and dexamethasone remains that a standard induction arm for patients with multiple myeloma.


ASCO Daily News: Staying in the hematology field, what are some of the most practice changing abstracts this year in your opinion?


Dr. John Sweetenham: Yes, in addition to the one I just mentioned, I draw the listeners' attention to another important study, which is abstract number 8005. And this is switching gears a little and looking at the issue of relapse and refractory classical Hodgkin lymphoma. So the background to this study is that there have been a number of active agents demonstrated to be useful in patients with relapsed and refractory Hodgkin's lymphoma. And in recent years, brentuximab vedotin has been widely used in this context. This is a antibody drug conjugate, which is targeted to CD30, commonly expressed on classical Reed-Sternberg cells in Hodgkin lymphoma.


This study describes the results of the so-called KEYNOTE 204 trial. This is a randomized phase III study of PD1 blockade with pembrolizumab versus a standard approach of brentuximab vedotin in patients with relapsed and refractory classical Hodgkin lymphoma. Patients were either patients who had previously received an autologous stem cell transplant for relapsed and refractory Hodgkin lymphoma. All were ineligible by virtue of age or comorbidity. Patients could enter the study if they had previously been exposed to brentuximab vedotin, which is now relatively widely used in patients with Hodgkin lymphoma.


So 304 patients were randomized onto this study. And in all 300 were treated. The median followup on the study is now just over two years. Of note, 15 of the patients had previously been exposed to brentuximab vedotin. The results of this study show a statistically significant improvement in progression-free survival for pembrolizumab versus brentuximab vedotin. The median progression-free survival was 13.2 months for pembrolizumab and 8.3 months for brentuximab vedotin for a hazard ratio of 0.65. And the 12-month progression-free survival rates were around 54% and 36% respectively. And the benefit was observed in all of the subgroups tested, including those who'd had a prior transplant and those with primary refractory disease, as well as those who had had prior brentuximab vedotin or not. The duration of response was notably significantly longer for those patients who received pembrolizumab.


So the conclusion of this study was that pembrolizumab was certainly superior to brentuximab vedotin based on progression-free survival across all subgroups. And the safety of the drug and the side effects were very consistent with previous reports of checkpoint inhibitors. So I think this is a report which is likely to change the practice of how patients with relapsed and refractory Hodgkin lymphoma manage moving forward.

ASCO Daily News: Well, thanks very much, Dr. Sweetenham for sharing some really interesting highlights with us today.

Dr. John Sweetenham: Thank you very much for the opportunity, Geraldine.


ASCO Daily News: And thank you to our listeners for joining us. If you're enjoying the content on the podcast, please wait and review us on Apple Podcasts.

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.

COI Disclosure: 

Dr. John Sweetenham

Honoraria: Seattle Genetics