The ECHELON-1 study was a large open-label clinical trial. Basically it compared two arms: one arm with brentuximab and AVD versus ABVD which is the standard of care until now, for example. So this trial was basically for advanced stage Hodgkin lymphoma.
What we see from this updated data, this five year PFS, it was a consistent superiority over ABVD. So A plus AVD or brentuximab plus AVD still showed a large superiority independent of any risk factors like IPS risk factors or stage disease 3 or 4. Mainly what is very interesting for me is it is independent of the interim PET; although interim PET was done for all patients in both arms but this superiority was independent of this interim PET.
Basically, the number that received a difference between these two arms when you talk about PFS per investigator was around 7%, which is a little bit higher from the two year release that they released about three years ago, which shows that the introduction of this new drug sustained a very good response with a very manageable safety profile. If you compared the two year data with the five year data what we see is basically a 30%, 31% reduction of death and progression due to ABVD when you compare A plus AVD versus ABVD.
What do we know about using brentuximab for stage 3/4 Hodgkin lymphoma?
Usually we all know that Hodgkin lymphoma is a highly curable disease but the curability is really related to stage. If you talk about stage 1 and 2 you are able to cure about 90-95%. If you talk about stage 3 and 4 there is an unmet need because we see a higher rate of relapse, around 25-30%. So with this study they really put a light in the end of the tunnel that it’s possible to decrease the relapse rate and, if I say so, I can easily say increasing curing rate by adding Adcetris to AVD.
So this analysis was done around five years ago, exactly 55.6 months. When you talk about relapse rate you see at least 31% decrease which is great because you are talking basically about young patients who we really have to cure them and to send them back to work, to university and to marriage etc. So it’s really something that gives me pleasure to say about this data because it’s really ground-breaking. When you see this maintenance of response it really ratifies, it shows that the brentuximab with AVD is really a valuable option for this kind of advanced stage patient.
Interesting in this data that we are going to see in the ASH meeting they also compared pregnancy and there was no difference between pregnancy in both male and female patients between these two arms. So we didn’t have much doubt about it but it’s good when you see this data comparing this very good phase III trial showing that there was no difference in pregnancy and any birth defects. So highlighting the safety of Adcetris plus AVD versus ABVD.
What methodology was used in this study?
The first paper released about three years ago used a modified PFS which means that basically the modified PFS is the progression when you stop, the stop is due to progression, death or basically the receipt of an additional therapy for patients not in CR. What does it mean? You take out radiotherapy as a consolidation therapy just to focus on the real benefit of the addition of brentuximab to this protocol. But the next release, three years, four years and now the five year release PFS, it’s not about [?] any more, it’s just by investigator which takes this idea of radiotherapy or any additional therapy from our analysis. I can say that this is an exploratory analysis, a post-hoc analysis but it still shows a great advantage of adding this new drug to the standard of care.
Together we are also able to take out bleomycin from this protocol and we all know that bleomycin is very toxic, both for young patients and mainly for old patients. So it’s good because we see a consistent superiority and you are able to take bleomycin from this treatment protocol.
Another thing that I want to emphasise, and I just said it before but it’s good to highlight that, because they are very types of treatment guided with interim PET. So if you have an interim PET positive you can escalate therapy and this, of course, can bring more cure but also can bring more toxicity and side effects, etc. mainly [?], acute secondary early and late onset toxicity and neoplasia. But with this protocol, the addition of brentuximab with AVD, there is no need to escalate therapy when the patient has an interim PET positive.
Of course we are not able statistically to compare every study that uses this escalation based on interim PET. But if you look just with the numbers we can easily say that there is no need to escalate therapy. This means increased chance of side effects when using this protocol. So I know that I just said it before but it’s good to emphasise that this protocol still shows a high efficacy versus ABVD independent of the interim PET.
What is the impact of this study on the future of Hodgkin lymphoma treatment?
For the last ten years what we are trying to find is a clinical protocol that’s at least as efficient as ABVD and/or less toxic than BEACOPP. So the future, mainly for these stage 3 and 4 patients, is very hopeful because we are not adding more toxicity but we are adding more efficacy.
But I must say that the addition of brentuximab with AVD, of course, there is a higher rate of neuropathy. But what this extended follow-up data from three, four and five years told us and showed us is that at least 85-86% of all patients in both arms, because we must remember that ABVD also had neuropathy, mainly due to vinblastine. But what we can say is that around 85% of all patients had this neuropathy result. So although it’s not a non-side effect protocol, but it’s really manageable and, of course, when you talk about the younger patients that are looking forward to starting work again and having their life back, of course it’s just a small side effect compared to the higher response rates that this group has.