Pivotal Studies in Double-Expressor DLBCL Yield Divergent Results

Pivotal studies testing new options in previously untreated double-expressor (MYC/BCL2) diffuse large B-cell lymphoma (DLBCL) yielded differing results, according to findings presented at the recent American Society of Clinical Oncology (ASCO) annual meeting.

The first study showed adding venetoclax (Venclexta) to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) offered no improvement in progression-free survival (PFS) and increased toxicity. In contrast, the second study demonstrated promising outcomes with R-CHOP plus tucidinostat, an investigational selective histone deacetylase (HDAC) inhibitor.

MedPage Today brought together three expert leaders in the field for a virtual roundtable discussion: Moderator Loretta Nastoupil, MD, from the University of Texas MD Anderson Cancer Center in Houston, is joined by Catherine Diefenbach, MD, from NYU Langone’s Perlmutter Cancer Center in New York City, and Mazyar Shadman, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle. This third of four exclusive episodes focusing on the two phase III studies in double-expressor DLBCL.

Click here to watch the other videos from this ASCO roundtable series in DLBCL.

Following is a transcript of their remarks:

Nastoupil: So we saw two randomized phase IIIs in frontline at this meeting, both in double expressor large B-cell lymphoma. So let’s start with the negative study. So we saw the combination of R-CHOP plus/minus venetoclax really didn’t result in improvement in efficacy, a bit more toxicity. What’s your takeaway on that study?

Shadman: So venetoclax is considered to be a chemo-sensitizing drug. So we are seeing combinations of venetoclax with chemo in different diseases. Large cell lymphoma, as we all know for a long time we’ve been trying to improve on the backbone of R-CHOP chemotherapy. And until recently when we had the polatuzumab vedotin [Polivy] combination really giving us some efficacy benefit, our experience has been that we are not improving the outcome.

So this study which looked specifically at double-expressor population added venetoclax to the R-CHOP backbone. And in the phase II study did not meet the endpoint that was required to move forward with the next study, which would’ve been a phase III study.

So another reminder that randomized trials are important, and this would be a great example of a negative study that we should definitely pay attention to and learn from. And first-line large B-cell lymphoma remains an unmet need until we cure all patients. So hopefully future combinations with more effective drugs including immunotherapy, bispecifics, or cellular immunotherapy will get us to the next level.

Diefenbach: And I just want to say I think this is really disappointing, right? Because chemotherapy treats everything like a sledgehammer and venetoclax is really a targeted therapy and BCL2 is one of the drivers of large cell lymphoma. So this was such a rationally designed trial, it took the population that it should be helping, right? Patients who are double expressors. You could argue that being a double-hit is different than a double-expressor. And should they have really targeted double-hits more than double-expressors, would that have changed this into a positive trial since it was really a mechanistically designed trial?

So I mean to me the question is we all knew that the venetoclax arm was going to be a little more toxic because venetoclax is not the easiest drug to give. And for our audience, in case you don’t know, venetoclax is a drug that targets BCL2, which is a survival protein in the apoptotic pathway that basically cancer cells rely on co-opting to stay alive.

And the one drug that worked in large cell, no overall survival advantage yet, but that had a large international phase III, polatuzumab, is really a better way to deliver chemotherapy, but it’s not a targeted therapy. And if we’re talking about personalized medicine, it would seem that in large cell where we’re really not doing well enough yet that we should have more not less personalized approaches. So to me it’s just so disappointing to see a really well-designed trial not succeed. But I completely agree with you. I think that’s why it’s so important to do these trials because we have to think what we can learn from this to be able to design the next one better and get a positive result.

Nastoupil: One surprising study to me was a positive phase III that was presented here looking at a sub-selective HDAC inhibitor in combination with R-CHOP versus R-CHOP is the control arm again in double-expressing patients. So Catherine, what’s your takeaway from that study?

Diefenbach: A couple of take home points. I mean I think we have seen some very intriguing preliminary data that HDAC may sensitize patients to immunotherapy or chemotherapy. And the group at Cornell actually did an AZA [azacitidine, Vidaza] R-CHOP study not long ago. That was a positive early-phase study and there’s an effort right now in the intergroup looking at AZA R-mini-CHOP in elderly patients. So I don’t think this is a novel idea. I think it’s just one where we haven’t seen the AZA R-CHOP elderly studies ongoing. And the earlier study was a small study that was the preliminary data for this. So this is a different HDAC.

So scientifically it’s certainly plausible that an HDAC could improve chemotherapy outcomes. So I will say that on the plus side for the study. When you look at the POLARIX study, which was the polatuzumab study that got R-CHP-pola [rituximab, cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin] approved compared to R-CHOP, that was an international study that was in 23 countries and there were stratification factors that were known and there were data trends. There were regulatory agencies in multiple countries that were parsing through the data.

This is a single country study, so one country, it’s not done outside of that country and they don’t really tell us any of the stratification factors or whether the patients who are double-expressors are balanced in the two arms with respect to their double-hit status or IPI [International Prognostic Index] status or any other high-risk feature.

And the thing that really jumps out at me with the data, and you can tell me what you think, is that the standard arm, the R-CHOP arm, had an extremely poor outcome. So if you think about the trials that failed in large cells, so R2-CHOP versus R-CHOP alone or R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin] versus R-CHOP, it’s always because the standard arm does so well that the experimental arm can’t do that much better. If Wyndham Wilson’s trial had had a 60% PFS in the standard arm, we would all be giving our EPOCH now. So I don’t understand why the standard arm in that study is doing so, so poorly. What are your thoughts?

Shadman: I totally agree. Looking at the performance of the standard arm is always important. As you mentioned, targeting epigenetic mechanisms in large lymphoma makes a lot of sense whether or not it’s hypomethylating agent or HDAC inhibitor, hopefully we’ll have either follow-up of the same study or designing a study that includes more centers and with more visibility to the design and the schedule will give us the answer.

The maintenance part of the study was also interesting. We are not used to seeing maintenance therapy in large B-cell lymphoma and I’m always worried about the added toxicity that may have when your efficacy is not necessarily or significantly improved, but down the road you may induce some added toxicity. So I think it would be important to look at the long-term data from the same study as well.

Diefenbach: I think it would be interesting if the drug was promising and became available for investigator-initiated studies … and you could sort of design small investigator-initiated studies to follow up on this. Or if the company decides to have a trial outside of ex-China and do a global study, I think the scientific rationale is strong.

If you think about in the POLARIX study, there’s a progression-free survival advantage, but there’s no overall survival advantage because everyone is salvaged with CAR-Ts or auto-transplants or bispecifics. So you wonder if this study was replicated in countries where there are more second- and third-line options, whether there still would be a survival advantage because the patients who relapse would actually get treated with something other than chemotherapy. And you also wonder if with supportive care, the outcomes in both arms would be better.

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