Brentuximab vedotin prolongs post-transplant survival in hard-to-treat lymphoma patients in phase III study

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Published: 7 Dec 2014
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Dr Craig Moskowitz - Memorial Sloan Kettering Cancer Center, New York, USA

At a press conference at ASH 2014, Dr Moskowitz presents the findings of a phase III trial which compared brentuximab vedotin (BV), an antibody targeting the CD30 protein on Hodgkin lymphoma cells, with placebo in 327 patients at risk of post-transplant disease progression.

Read the news story and watch the interview for more.

As far as some background information, we’ve been transplanting Hodgkin lymphoma now for almost thirty years and unfortunately the progression free survival is fairly stable between 40-55%. In fact, we’ve done a host of random assignment trials in all the aggressive lymphomas since I’ve been practising comparing A versus B and all of these studies are negative.
Brentuximab vedotin, as you know, was recently approved for the management of patients who are stem cell transplant fails and is standard of care in that setting. The AETHERA study is a random assignment placebo-controlled study, in fact the only placebo-controlled randomised study ever done in Hodgkin lymphoma, comparing brentuximab vedotin consolidation versus placebo after an autologous stem cell transplant to prevent relapse in patients at risk to do poorly.
We enrolled 329 patients in 78 sites in the United States and Europe, quite a challenging study to do. Patients were randomly assigned to receive 16 doses or one year of brentuximab vedotin or placebo given every three weeks. The patients were seen at that time. Imaging studies were done quarterly for the first year and then at 18 months and 24 months; thereafter imaging studies were not required.
It’s important to understand that this is a study where patients were allowed to cross over to standard brentuximab vedotin if they relapsed and were found to receive placebo. So if you think about it, the likelihood of having an overall survival difference at two years is not expected. When we wrote this study in 2009 our group and others had published that the median survival of Hodgkin lymphoma patients who are stem cell transplant fails was between 24-28 months. In 2015 the median survival of a patient who fails a stem cell transplant is between 42-48 months, that’s because of all the novel agents that are available, including brentuximab, the HDAC inhibitors and the checkpoint inhibitors and I’ll discuss some of those later today.
The primary endpoint of this study is progression free survival based upon independent review. The secondary endpoints are as written. I’ve highlighted two aspects in the patient characteristic slide; these two are probably the most important. Number one, half the patients needed to receive more than one salvage regimen to achieve chemosensitive disease to actually get to a transplant. In itself, patients who need more than one salvage regimen have about between a 20-30% chance of actually being a long-term survivor. Second, and probably the most important risk factor in relapsed and refractory Hodgkin lymphoma, is patients who actually have primary refractory disease. In this study 60% of the patients did not achieve a remission with up-front chemotherapy such as ABVD or BEACOPP.
Here’s the slide, the progression free survival slide. The left panel is based upon an independent review and the right panel is based upon investigator review. One can see that the hazard ratios are 0.57 on the left panel and 0.5 on the right panel. Both of these are obviously statistically significant. The major difference in the curves are where I put the dotted line in. At 24 months imaging studies were not required so almost all patients, based on independent review, are censored at that point. On the right panel patients can be imaged, the patients are a seen on a quarterly to every six months basis and are evaluated. So therefore you can see that pretty much the survival curves are flat in this study at 24 months and that’s seen across the board in all relapsed Hodgkin lymphoma transplant studies; relapses almost never happened after two years. So if you’re in remission at two years after a stem cell transplant for Hodgkin lymphoma you are likely to be cured. The bottom line is there’s a 20% difference in progression free survival at two years based upon investigator review. This has never been in seen in patients with relapsed or refractory lymphoma let alone Hodgkin lymphoma.
This is the forest plot; pretty much everything is better if you sprinkle a little brentuximab in. The next slide is the overall survival slide, I’ll just take you through this in a minute. Obviously at two years the overall survival is the same. The obvious reasons are fairly straightforward – patients were un-blinded, they could get brentuximab vedotin, 85% of the patients on the placebo arm crossed over to brentuximab. We know that brentuximab alone, by itself, post-auto transplant failure improves outcome by at least a year.
Second, more than twice as many patients who failed placebo in this arm underwent a second transplant, either a second auto or an allo. I’m not going to argue whether that’s good or bad, personally I don’t think it’s a good thing to get two transplants, but some of those patients were salvaged in that setting.
In the bottom panel I want everybody to understand what kind of patients we were taking care of. So these are five factors here which I feel are important in this disease: primary refractory disease, whether or not you have a complete response to salvage chemotherapy, whether or not you have disease outside of the lymph node system, for example a lump in the middle of your lung, whether or not you have active symptoms at the time of relapse and lastly are you heavily pre-treated or not. In this particular study nearly half the patients had at least three of these risk factors. We and others have published that if you have this many risk factors the likelihood of being cured with an auto transplant is about 25%.
As expected when you get placebo there are not a lot of side effects; when you get a study drug there are more side effects. The most common side effect with brentuximab vedotin is neuropathy; interestingly with dose reductions or stopping the drug 85% of the patients had resolution of their peripheral neuropathy.
So in conclusion, early consolidation or maintenance, whatever your word of choice is, with brentuximab vedotin after an autologous stem cell transplant in patients at risk to fail met its primary endpoint of progression free survival at two years. It sustained across all subgroups of patients. At this time interim analysis does not show an overall survival difference and I’ve explained the reasons why. I think the treatment is well tolerated. There were two deaths on study, both fairly expected. In my opinion I think that once this study is published in patients who met eligibility criteria to be on this study, once again I’ll remind you this is remission duration of less than a year, disease outside of the lymph node system or primary refractory disease, in my opinion this treatment will be standard of care.