As many people know, there have been decades of research done on trying to identify better up-front therapies for patients with peripheral T-cell lymphoma. For years since the National High Priority study was published in The New England Journal of Medicine, CHOP became a de facto standard of care only because that study, which was focussed on patients with aggressive lymphoma, had included a very small number of patients with T-cell lymphoma, albeit that number is actually not specified in the patient population description of the trial, but CHOP became a standard.
The next biggest step that emerged was retrospective data from the German Large Cell Lymphoma Study Group published by Norbert Schmitz. In that study they did a retrospective analysis that explored all the different regimens they’d studied over decades and identified that the addition of etoposide might be associated with some clinical benefit in patients with T-cell lymphoma up front. So, in fact, statistically it really didn’t show any improvement in overall survival; there was a suggestion, perhaps, in some small subpopulations that maybe it did a little better but because the field is desperate for something people embraced this retrospective data. In all probability if this was in any other malignancy they would have ignored it. So for decades since the field has been oriented towards trying to make advances and the primary philosophy has been one of CHOP addition studies. So if there’s an mTOR inhibitor or an antibody we’ll talk about these trials. But for years and years these were all single agent trials and none of them in single arm, uncompared trials demonstrated that they had sufficient promise to warrant moving on to a randomised trial. In fact, one could reasonably make the statement that most of those trials were associated with significant untoward toxicity.
Along comes brentuximab. Brentuximab is an antibody drug conjugate that targets CD30. CD30 is really one of the defining hallmark features of anaplastic large cell lymphoma; it is sparingly expressed on all other forms of peripheral T-cell lymphoma. In fact, 50% of most of the other subtypes have 0-5% expression of CD30 but it was really the first drug to come along that was a biologic that targeted a rational component of the T-cell biology and it got very readily approved in anaplastic large cell lymphoma with very high overall response rates, very high complete response rates because anaplastic large cell lymphoma is that disease defined by 100% expression of CD30.
So, as part of a fulfilment for regulatory agencies in Europe and around the world, there was a requirement to look at randomised clinical trials with that particular drug. In fact, the trial ECHELON-1 was looking at these concepts, integrating brentuximab for Hodgkin lymphoma, and ECHELON-2 looked at integrating brentuximab with CHOP in patients with peripheral T-cell lymphoma. So the trial is a randomised study of CHOP against cyclophosphamide, doxorubicin, brentuximab and prednisone. Now, it’s actually the largest trial randomised ever conducted in patients with peripheral T-cell lymphoma up front and it’s a Herculean effort to be able to pull this off. It basically involved every major key opinion leader in the world.
The trial had two important features to think about as you try to put this data into context. The first is the trial required everybody, all patients, to have a 10% or more level of CD30 expression. So the debate and controversy around what is the level of CD30 expression that correlates with clinical activity is really one that’s still under massive debate. There’s some CTCL data to suggest that maybe the level of CD30 is important but there is data in other diseases like diffuse large B-cell lymphoma where there was a subset of patients with CD30 positive that had some response and patients who were CD30 negative who also had some but lesser response. So it is completely unknown what that is but for the sake of the trial it required everybody to come in at 10% expression.
The other feature of the trial is that it required 75% of the patients accrued to have anaplastic large cell lymphoma. So that could be viewed one of a couple of ways. In fact, that feature of the eligibility criteria was designed in in response to regulatory considerations where in order to secure the approval of brentuximab abroad there needed to be randomised studies showing benefit in that population. So ECHELON-2, in fact, became in part a regulatory study to represent that phase IV commitment on brentuximab in a randomised way. So it’s for that reason that, in fact, the patient population was stacked towards anaplastic large cell lymphoma. So only 25% of the remaining patients had all the other subtypes of T-cell lymphoma; that included patients with angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and some others. There were plenty of subtypes that were allowed in the inclusion criteria for which there were no accruals for those subtypes because they’re incredibly rare.
The really good news is that ECHELON-2 was positive across all the obvious clinical trial metrics that one would look at. That included both progression free survival and overall survival. Some have even questioned as to whether there might not be a plateau on the progression free survival curve and the overall survival curve in the treatment arm. There are a couple of things to think about – one is the applicability of this to all patients with T-cell lymphoma up front and it’s important to realise what the FDA indication was that was granted to Seattle Genetics for this trial. The indication actually from the FDA did not specify a certain amount of CD30 on the expression of the cells even though the trial said 10%. The FDA kind of said, ‘Well, any level of CD30 expression will be taken as sufficient to make you a candidate for the clinical trial.’ So that’s interesting; that’s a very generous move, probably, on the part of the regulatory agency. So when you’re looking at patients with other types of T-cell lymphoma where CD30 may not be prominently expressed at all the debate amongst practicing clinicians will be, ‘Well, is this something I want to do for somebody that has, say, 3% CD30 expression?’ So to help decision-makers be confident that it might be a good thing to add brentuximab the good news is, at least at the first cut, it looks like there’s no difference in neuropathy. So the one reason people might have for not choosing brentuximab might be the neuropathy. We’ve done plenty of studies with brentuximab over the years and neuropathy is an issue. In fact, in all these clinical trials, whether it’s ECHELON-1 or it’s ECHELON-2, the vincristine or vinblastine is actually omitted to try to reduce that risk of neuropathy in combination with brentuximab. So if you’re worried about that factor at least the first cut of the data says it may not be an issue. To the company’s credit what they did do is they did do a detailed instrument to actually look at neuropathy. That data is not presented here at ASH and I’m not sure if it’s going to be in the publication; the paper looks like it’s accepted for publication.
Really quite astoundingly and, I believe, a testament to the FDA’s responsiveness to try to improve options for patients, the application at the FDA was approved in under two weeks. That’s remarkably fast. So it implies that there is regulatory support for this and when you see the data and you finally see those curves move – progression free survival, overall survival – it’s definitely a positive step.
The trial does allow us to ask a lot of other questions, for example, is the observation going to hold up if we just put patients with non-anaplastic large cell lymphoma on these regimens, that’s a question that remains to be answered. What is the level of CD30 expression that’s really important? For the moment, at least from the community practice point of view, if your patient has CD30 expression and you feel that’s the right therapy you’re allowed to go ahead and do it. So it’s a major advance in a field where we have not had a lot of advances.
Some might say being addicted to this CHOP-based combination chemotherapy backbone is something we’ve done for a while. It’s taken us two decades to identify a trial that finally showed a benefit. So many people, including our group in New York, have suggested maybe we’ve learned a lot more about the biology of these diseases and that we might be able to leverage many new drugs approved for the disease in recent years like HDAC inhibitors and pralatrexate and create novel, non-CHOP based backbones. In fact, there’s going to be data presented at this meeting, one will be an oral presentation from Lorenzo Falchi from my group who will be sharing phase I data of a combination of azacitidine and romidepsin, a pure epigenetic-based therapy in a very heavily treated phase I patient population is producing overall response rates of 80-90% and 100% in patients with angioimmunoblastic T-cell lymphoma.
So actually I’m the optimist in the field. I actually think this is a good time for patients with T-cell lymphoma, that we have new concepts emerging that are biologically predicated on perhaps replacing chemotherapy and we finally have insights on new ways to leverage conventional chemotherapies that are FDA approved in a way that we can now demonstrate data-wise is going to help patients long-term.
