Brentuximab vedotin for advanced Hodgkin lymphoma in the ECHELON-1 study

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Published: 10 Dec 2017
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Dr Joseph Connors - British Columbia Cancer Agency, Vancouver, Canada

Dr Connors presents, in a press conference at the 2017 ASH annual meeting, data from the phase 3 Echelon-1 study looking at brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine as frontline therapy in patients with previously untreated stage III or IV hodgkin lymphoma.

Read the news story or watch our interview with Dr Connors for more information.

It’s my privilege to be here to thank you for coming to hear about our study and for me to have a chance to describe for you this trial called the ECHELON-1 trial which is focussed on advanced stage Hodgkin lymphoma.

It’s important to understand that Hodgkin lymphoma is one of the success stories of modern oncology with a large percentage of the patients being cured with standard multi-agent chemotherapy. However, approximately a quarter to a third of patients wind up requiring secondary treatment to accomplish that goal and still some of the patients do die of progressive treatment refractory disease. A new agent was crafted and initially tested almost a decade ago, brentuximab vedotin, which is a targeted agent aimed at the CD30 antigen expressed on the surface of these cells. The material is internalised by the cell, digested, releasing monomethyl auristatin E which is a microtubular poison and leads to the cell death.

In a phase I dose escalation trial with co-investigators I was able to demonstrate a very high response rate, five year failure free survival and overall survival when the drug was combined with the three agents Adriamycin, vinblastine and dacarbazine in a four drug recipe. So we brought this forward to test this in comparison to the standard chemotherapy that’s used in much of the world for advanced stage disease. Ultimately a study with 218 study sites in 21 countries worldwide and so it’s a genuine international effort. The structure of the trial was straightforward – a comparison of standard ABVD versus the experimental regimen in which brentuximab vedotin, or Adcetris, was combined with three of the drugs, the AVD. At the end of the planned chemotherapy patients were reassessed with CT and PET scanning and then followed for success of the treatment. Patients had to have stage 3 or 4 disease, good performance status and be adults to participate in the study. A unique aspect of managing Hodgkin lymphoma is that you get an early look at how well the treatment is working after two cycles when a PET scan can be performed.

About fifteen minutes ago the results of our trial were published in The New England Journal and are available online now so greater detail can be found there. This is the independent reviewed response outcome data for the trial demonstrating on the blue line the superiority of the experimental arm using a specific endpoint that tested for the success of the chemotherapy at eradicating all of the disease which we entitled a modified progression free survival. The difference in the two outcomes at the two year mark is just shy of 5% and documents that about one quarter of the patients that otherwise would have had a failure of their primary therapy were successfully treated with the new combination, further reducing the likelihood that patients would experience eventual progression of treatment refractory disease.

It’s important to understand that the way the trial was conducted that we were able to examine which kind of therapy was used if the primary therapy failed and that’s summarised on this slide here. What I want to emphasise is the frequency with which patients required additional systemic therapy, a return to chemotherapy or even more intensive treatment with chemotherapy and high dose chemotherapy and autologous stem cell transplant. What we’re trying to do in this situation is to avoid the necessity for those secondary treatments to be used and accomplished that, as you can see the patients on the experimental arm, about a third of them more were able to avoid that secondary therapy than would have occurred with the standard ABVD recipe.

It’s important also to understand the kind of toxicity that occurs when one employs a new treatment and I’m going to focus on three of those aspects here. The first of them is what is called neutropenia, this is a lower than normal granulocyte count and it leaves the patient open to the failure of treatment and as manifest by secondary toxicity. It was necessary to explore the utility of GCSF primary prophylaxis for these patients. What we were able to demonstrate, although this circle has moved on beyond this slide, was that we were able to lessen the likelihood of this secondary and toxic side effect occurring when patients were given primary prophylaxis and were able to reduce the incidence of that toxicity to approximately the same level as is seen with the standard chemotherapy. This translated into a reduction in the toxicity as visited on the patients in terms of overall adverse events and led to the recommendation that such GCSF primary prophylaxis be used whenever the experimental arm is employed. Another important toxicity, because both brentuximab vedotin, which is the experimental agent, and vinblastine, which is included in the standard recipe, are neurotoxic is whether patients developed peripheral neuropathy. This does occur, as you can see, in excess in the patient who were receiving the experimental treatment but the good news is that over time this side effect resolves and with appropriate reduction in dose or change in scheduling the large majority of patients recover from the peripheral neuropathy.

Another toxicity that we focussed on was that of interstitial lung disease and you can see that this occurs asymmetrically more severely in the cases of the patients taking ABVD. This can prove to be a fatal toxicity for patients and we hoped that we would be able to avoid that by removing the bleomycin from the experimental arm of the trial, substituting in the brentuximab vedotin and seemed to have been able to accomplish that goal of reducing the risk of the patient developing interstitial lung disease.

We think that ECHELON-1 establishes that there is a significantly superior outcome for patients treated with brentuximab vedotin in combination with AVD, that this leads to a 23% reduction as measured by independent review, a 27% reduction as measured by the investigators themselves conducting the trial and leads to a superiority in the likelihood of remaining free of disease after the primary therapy, establishes that brentuximab vedotin in combination with AVD is more effective than ABVD. Bleomycin, the toxic drug that causes the interstitial lung disease can be omitted and we do recommend that primary prophylaxis with GCSF be given to all such patients. The most troublesome of side effects that can linger for patients, such as peripheral neuropathy, if managed properly sufficiently diminishes over time as to not remain troublesome for the patient. So I’ll thank you for your attention and I guess I’ll be answering questions later on. Thank you.

Video switches to panel Q&A

The question is focussing on the primary therapy of advanced stage Hodgkin lymphoma around the world and the regimen to which you are referring is often called BEACOPP or escalated BEACOPP. This is a different way of treating patients with advanced stage Hodgkin lymphoma and also leads to very high rates of complete response and cure of patients. The challenge with using that particular type of regimen has been the kind of irreversible toxicity associated with it such that virtually all male patients are sterilised, most older women also lose their fertility and there is an associated incidence, first of all, of hospitalisation and complications that also trouble the patients. Then finally the escalated BEACOPP recipe isn’t appropriate for patients over the age of about 50 which means about 20% of the patients with Hodgkin lymphoma aren’t appropriately treated.

So what is happening in both arenas, that is North America and in Europe, where escalated BEACOPP is popular, predominantly in the German speaking countries, is that the regimens are coalescing. Currently the German group is interested in figuring out how to integrate the use of brentuximab vedotin into the escalated BEACOPP recipe in a way that allows them to reduce the net toxicity. Here in North America and in the study that I showed you from around the world we’re interested in seeing how to integrate it with the ABVD recipe but we’re moving essentially towards the same goal, that is finding a way of treating the patient for their advanced stage Hodgkin lymphoma that carries with it as low as possible the level of irreversible troublesome toxicity that can stick with the patient and, at the same time, maintain the high levels of cure.