Joshua Brody discusses ECHELON-1 and its subanalyses, the results of which are anticipated to change the management of Hodgkin lymphoma.
Ahead of our coverage of the 2018 annual American Society of Clinical Oncology (ASCO) meeting, being held June 1–5 in Chicago, we are today speaking with Joshua Brody, MD, about some of the important studies of lymphoma that will be presented at the meeting. Dr. Brody is a medical oncologist with Mount Sinai Health System in New York City and an assistant professor at Mount Sinai’s Icahn School of Medicine. He specializes in the care of patients with lymphoma, and his research laboratory focuses on translation of basic science in tumor immunology into novel clinical trials.
-Interviewed by Anna Azvolinsky
Cancer Network: Are there any key presentations of clinical trial data at the meeting that you are looking forward to in Hodgkin lymphoma?
Dr. Brody: Absolutely. For Hodgkin lymphoma, I think the most exciting recent area of progress has been in the treatment of advanced-stage [disease]-[namely] frontline therapy, and specifically the results of a largest-ever, multinational trial that randomized patients to either a standard chemotherapy called ABVD [adriamycin, bleomycin, vinblastine, dacarbazine] vs a combination that swaps out the bleomycin for this targeted therapy, an antibody-drug conjugate called brentuximab vedotin, an antibody that targets CD30. That medicine, brentuximab, has been the standard therapy for late-line Hodgkin lymphoma, but this study is what has been bringing that targeted therapy into first-line treatment.
The trial, ECHELON-1, of more than 1,300 patients, has been ongoing for years, and we got the initial results from the trial in late 2017. The study was published in the New England Journal of Medicine, but now subanalyses of that trial are being reported at ASCO for the first time that we are excited to see. Specifically, [we can expect to learn] the results of a preplanned analysis looking at the North American patients and their outcomes, focusing mostly on the primary outcomes of the trial. [These were] a modified PFS [progression-free survival]-which is similar to PFS with some subtle but potentially important distinctions-and also looking at the conventional 2-year PFS readout.
What we got from the published abstract was already provocative, since the results in patients from the US were even more [dramatic] than the study results overall. The study results overall, I think, people would call positive, meaning that there was a significant difference between treatment with AVD plus brentuximab vs treatment with ABVD, with fewer people recurring or going onto a second therapy within 2 years in the AVD-plus-brentuximab arm. But in the United States sub-cohort, which is still a lot of patients (250 patients in each arm, [and] already bigger than most clinical trials we do in lymphoma), the difference was even greater.
Instead of a 5% difference, it was more than a 10% difference, and that is an exciting and provocative piece of information already. I think we will learn even more at the presentation about the details of how those patients did, and also maybe start to see hypotheses as to why patients did even better in the United States cohort on the new therapy.
Towards that, there is another presentation on a subanalysis of the same trial, assessing one of the more obvious hypotheses. It’s hard to guess why patients in the US would have a greater benefit from AVD + brentuximab, but the first thing that we might guess is that patients in the US, compared with patients in other countries, might have more commonly [received] growth factor primary prophylaxis-meaning [they had been given] these newer medicines, Neupogen [filgrastim] or Neulasta [pegfilgrastim], prior to developing the initial problem of febrile neutropenia.
The secondary problem is that these bad infections just delay a patient’s ongoing therapy, or could even prompt dose reduction of the therapy; so, those infections have a secondary bad effect, where [affected patients] get less therapy, and the chance that the lymphoma is not being adequately treated becomes greater. [A] subanalysis being presented by Dr. David J. Straus showed that patients who did get primary prophylaxis with growth factor also did seem to have superior outcomes. This was a post-hoc analysis, so we have to be careful, cautious about those; to use a metaphor, in [the game of] pool, if you don’t call the eight ball before you hit it, it can randomly go in some pocket and that doesn’t mean that that is meaningful. So we have to be very cautious about the interpretation of post-hoc analyses, but at the very least they can help us to generate and partly substantiate hypotheses that could be better tested in future trials.
But certainly, the take-home of ECHELON-1 is that [if] AVD + brentuximab is going to be considered the new standard of care for patients with Hodgkin lymphoma, it probably should always be given with primary prophylaxis. [This means] that patients should get Neupogen or Neulasta with every cycle, even before they have any problems [such as] fevers or infections, and that take-home was already incorporated into the last part of the ECHELON-1 trial.
Cancer Network: There are also several cost-effectiveness analyses that are being presented on brentuximab vedotin, which also, prior to this newer first-line approval, has been used in later lines of therapy for Hodgkin lymphoma patients. Can you talk briefly about how use of this agent is evolving in the care of these patients?
Dr. Brody: Let me say that most therapies that we discuss at ASCO attempt to achieve the gold standard of prolonging survival in our patients. The gold standard that we are talking about in this disease, and in this ECHELON-1 trial, is a platinum standard, really. Our intention is to increase the cure rate and that is not an elongation of survival, it’s letting people live their full lives.
Hodgkin disease is largely a disease of 20-year-olds. There is bimodal age distribution, so a large peak in the early 20s and then a smaller peak in older patients. But it’s mostly a common disease of [very young adults], and if we can cure these patients then they can go on with pretty much normal lives, and hopefully…be productive until they are 90 years old. In my mind, it is extremely difficult to put a price on that, and therefore any cost-effectiveness analysis has to first take into account what has been our increase in the cure rate.
I don’t think that is really possible yet with the ECHELON-1 trial, because we follow these patients for a median of 2 years and it is not yet really clear if the overall 5% increase in PFS-or as I mentioned, the almost 11% increase in PFS the US-will translate into an 11% increase in cure rate. And if it did, it would be difficult for us to put a price on that, curing patients and letting them go on and live another 80 years. But we have to actually see if that does pan out from this trial.
And if it doesn’t pan out-let’s say the patients did not get cured with their initial AVD + brentuximab-then many [patients] would go on to standard second-line therapy; this is an aggressive platinum-based chemotherapy followed by myeloablative chemotherapy with a stem cell transplant. So maybe we will not have cured an additional 11 people out of 100, but maybe we will have just saved 11 from having to go onto an autologous stem cell transplant. I even think that that would be a pretty big deal.
An autologous stem cell transplant is effective but potentially really toxic therapy. It is sterilizing-difficult to think that people will be fertile after that aggressive therapy-and again, if we are talking about 20-year-olds, that is a big deal. So even if we don’t cure 11 more people but save 11 more people from having to go through an autologous stem cell transplant, I am also a little hard-pressed to put a price on that. So, these cost-effectiveness analyses are very important in oncology, and I think when we are talking about curing people, [the study results] have to be interpreted differently.
Brentuximab vedotin is expensive therapy, but here it is given in a somewhat limited way. The normal way we give that therapy is for at least 1 year if people are doing well, or potentially for as long as they are getting benefit and tolerating it, which can be for many years. However, in this frontline setting, they are getting 12 reduced-dose treatments, so it’s a finite number of cycles and at a reduced dose [compared with] the prior standard use of the drug. So, I think that we have to be thoughtful about how we interpret cost-effectiveness analyses in this kind of setting. In terms of its utilization, I believe in the results of this trial and I think that the difference between the two arms is profound. I have moved over to using this therapy for the majority of my patients in this setting.
Cancer Network: In Hodgkin lymphoma, what do you think are the major clinical research questions that still need to be addressed, and are there trials now addressing any of these questions?
Dr. Brody: To be fair, we are doing so well with Hodgkin lymphoma, it’s hard to say that there is so much unmet need there compared to some of the worst types of non-Hodgkin lymphoma. However, since we are treating mostly young people, a lot of the questions [are related to] how we can give these patients less toxic therapy. That has been a big focus in many of the early-stage Hodgkin trials, [that is, scaling back] from greater numbers of cycles [of therapy], from greater doses of [radiation], and from larger fields of radiotherapy-so, minimizing all of these. And also using risk-adaptive therapy (meaning patients get a PET scan after 2 cycles or 3 cycles), and when we see an excellent result, doing a trial and randomizing patients to even less continued therapy to minimize the toxicity for these young patients. That is an area of active focus, and probably an unmet need is not only curing these patients but also curing them as gently as possible.