COMMENTARY

Venetoclax Shows Benefits Across a Range of Hematologic Cancers

Ann S. LaCasce, MD, MMSc; Jennifer L. Crombie, MD

Disclosures

December 27, 2018

Ann S. LaCasce, MD, MMSc: Hello. I'm Ann LaCasce, associate professor of medicine and lymphoma specialist at the Dana-Farber Cancer Institute in Boston, Massachusetts. I would like to welcome you to Medscape Oncology Insights, coming from the 2018 American Society of Hematology (ASH) annual meeting.

Today we will be discussing some of the highlights of the meeting and, in particular, developments with the BCL2 inhibitor venetoclax. Joining me in this conversation is a friend and colleague, Jennifer Crombie, who is a specialist in lymphoma and chronic lymphocytic leukemia (CLL) at Dana-Farber and instructor of medicine at Harvard Medical School. Welcome, Jen.

Could you start by telling us a little bit about the drug venetoclax and its target, and why it is so appealing in lymphoma?

Jennifer L. Crombie, MD: Venetoclax is an exciting new drug, and we're now finding a role for it in treatment across a variety of hematologic malignancies. We have been hearing the results from venetoclax trials across various diseases at this meeting.

Venetoclax is an orally administered, targeted, very potent, selective inhibitor of the protein BCL2. BCL2 plays a role in the intrinsic pathway of apoptosis, which occurs at the level of the mitochondria. When venetoclax is bound, it releases pro-apoptotic proteins that can then activate apoptosis and induce cell death, which is very appealing when we are thinking about drugs for the treatment of lymphomas and other cancers.

LaCasce: Right. It is effective in many different cancers, which is quite exciting about this particular drug. In addition, I believe it is easy to combine.

Crombie: That is what we are finding now. It is also active as a single agent in some diseases. In other diseases, it seems to produce improved responses, deeper responses, when used in combination.

LaCasce: Just briefly, venetoclax has a unique toxicity profile, and it is worth discussing a bit.

Crombie: When venetoclax first became available, it was initially studied in CLL. In the first phase 1 trial, the first three patients experienced tumor lysis syndrome. The investigators did reduce the dose, but even as they initiated the phase 1 trial, there was unfortunately a treatment-related fatality associated with tumor lysis syndrome.

Since the implementation of a dose ramp-up, starting at a very low dose and every week raising it gradually to the recommended phase 2 dose, patients have been able to safely achieve the recommended dose without tumor lysis. Going forward, and now that the dose ramp-up has been implemented, patients rarely have clinical tumor lysis; occasionally we see laboratory tumor lysis, which can be managed with close observation.

Tumor lysis syndrome seems to be most prominent only in diseases where the drug is very active—specifically CLL. We have also seen evidence of it in mantle cell where this ramp-up is also being used. It seems to be less of a concern in some of the other diseases with lymphoma subtypes, which may be because the activity is lower.

Otherwise, the drug seems to be very well tolerated. Patients may have some mild neutropenia or gastrointestinal toxicity, but otherwise patients are able to take this as a daily medication that they may remain on. It seems to be very well tolerated.

LaCasce: Switching to the specific disease entities, could you tell us about some of the updated venetoclax data, particularly in CLL, which was the first US Food and Drug Administration (FDA)-approved indication for the drug?

Crombie: As you mentioned, it was initially studied in patients with CLL and was FDA approved for CLL in 2016. The initial approval was only for 17p-deleted CLL in the relapsed/refractory setting. Approval has now been expanded to the relapsed/refractory setting independent of 17p status.

More recently, there have been trials of drug combinations with venetoclax for the treatment of CLL. Just this past year, the data from combining rituximab with venetoclax were published in the New England Journal of Medicine,[1] and those data were impressive. That was the MURANO trial, an international phase 3 trial comparing bendamustine and rituximab with venetoclax and rituximab in patients with relapsed/refractory disease.

At the ASH 2018 meeting, the investigators reported an update,[2] which included an additional year of follow-up. That was very interesting to see because that trial discontinued therapy after 2 years. This provided the first chance to see how patients did on a time-limited therapy with the targeted agent, venetoclax. The patients seemed to do really well, with very few patients progressing after an additional year off therapy. And it seems that those who did progress were able to restart venetoclax successfully in the event that the disease did recur.

The trial also looked at the minimal residual disease (MRD) status, which is becoming a more and more important marker in the CLL trials. The rates were quite high with the combination, and it seemed that the patients who did progress had MRD positivity at the time of discontinuation. That raises the question of whether those patients may not be as suitable for discontinuation and rather should continue treatment.

LaCasce: Are you using that combination as a second-line option in patients?

Crombie: Not yet, but we are starting more and more to add the rituximab in a few patients. Again, venetoclax seems to be very well tolerated, even with the addition of the rituximab.

LaCasce: Yes; I believe that is part of the appeal for patients. What about the combination in the frontline setting? Can you tell us about those trials?

Crombie: A few updates[3,4] have been presented from trials looking at the combination of ibrutinib plus venetoclax, in both the frontline and the relapsed/refractory setting. Both of those trials were impressive in terms of the degree of response and the rates of MRD negativity, and then the sustainability of the responses. You may expect that in the frontline setting, but in the relapsed/refractory setting, especially when patients may be heavily pretreated, the curves were quite impressive with that combination.

LaCasce: Then, adding in monoclonal antibodies as well will probably heighten the MRD negativity even further and really change the face of initial therapy.

Crombie: The big question with all of these trials will be how to sequence the various combinations in the frontline and the relapsed/refractory settings. We will have to see additional randomized trials to try to answer some of those questions.

LaCasce: Switching gears to mantle cell lymphoma, where responses typically have been shorter in duration, there was an update from Matt Davids[5] from our center. What did you take away from that data?

Crombie: He presented results from the mantle cell cohort, and although the numbers are quite small, he is reporting a longer follow-up of that subgroup, which again achieved a high overall response. We can see now with a longer follow-up that the patients who achieved a complete remission seem to have quite durable responses, although again the numbers are very small.

There have also been data to suggest that combining other targeted agents with venetoclax in this disease is a good strategy. Like CLL, ibrutinib, for example, particularly has activity in this disease. That has been published previously,[6] with very small patient numbers in that trial, but the responses look quite deep, with high rates of MRD negativity.

LaCasce: It will be interesting to see how that plays out.

Crombie: Yes, it will. We do need larger numbers of patients in the trial and longer follow-up, but I believe that it is another good strategy for patients with relapsed/refractory disease. Now more trials are also looking at combinations with CD20 antibodies, moving that to the upfront setting in patients who may not be good candidates for chemo.

LaCasce: Finally, I'd like to discuss the CAVALLI study[7] [of patients with non-Hodgkin lymphoma]. We have all been waiting to learn whether venetoclax can overcome the poor prognostic impact of BCL2 and the double-hit and double-protein expression. What were your impressions of that?

Crombie: Going back to the phase 1 trial of single-agent venetoclax in patients with non-Hodgkin lymphoma, it looks as though the response rate in diffuse large B-cell lymphoma in particular is very modest at best, with a less than 20% overall response rate.

If you look at the subgroups and the specific complete response rate, of the 18% who responded, 12% had a complete response. It raises the question of whether there may be biomarkers that could predict which patients would benefit from venetoclax.

The CAVALLI trial moves venetoclax to the frontline in combination with R-CHOP to see if that could improve the responses—again, primarily for those high-risk patients who may not be cured with R-CHOP alone.

From what I can tell so far, the responses seem to be higher. They compared these responses to historical data from the GOYA trial,[8] looking at the R-CHOP arm in particular, and it seems that [the addition of venetoclax leads to] a higher response rate. There is no difference in response rate overall, but when they looked particularly at BCL2 immunohistochemistry staining, there may be higher responses in patients who have overexpression of BCL2 in both the ABC and GCB subtypes, although more GCB-subtype patients were in the trial. This was also the case in double-hit patients, which is a major unmet need, so this may lead the way for improving studies going forward, in terms of trying to select the best patients who may be good candidates for venetoclax.

LaCasce: Yes, absolutely.

Crombie: Some work is [being done to] look beyond BCL2 protein expression. Recent data have dissected the underlying genomics of diffuse large B-cell lymphoma, identifying the heterogeneity of this disease. Exciting work from Margaret Shipp's group[9] at Dana-Farber has identified different subgroups that may be susceptible at a genomic level to venetoclax. That is something we are interested in and working on. We hope it will result in new targeted combinations for selected subgroups of patients with diffuse large B-cell lymphoma.

LaCasce: That is quite exciting. Jennifer, thank you for joining me today. This was a fascinating discussion. This is Ann LaCasce from ASH, San Diego, 2018.

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