2-Minute Drill: Experts Highlight Surprising, Practice-Changing Findings in Leukemia and Lymphoma Following 2022 ASH

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EP: 1.2-Minute Drill: Experts Highlight Surprising, Practice-Changing Findings in Leukemia and Lymphoma Following 2022 ASH

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Ryan McDonald: Hello, and welcome to 2-Minute Drill, a video series where no subject is off topic. We'll talk about the latest clinical research—whether it's good, bad or ugly—from the most recent cancer conferences. Either way, we'll get to the point, but we'll do it fast. Bringing together some of the leading and most engaging voices in cancer care, CancerNetwork®, home of the journal ONCOLOGY®, will offer unbiased, unscripted thoughts and opinions from our panel about the 2022 ASH Annual Meeting and Exposition.

I'm your host, Ryan McDonald, associate editorial director of CancerNetwork®. And today I am joined by Dr. Nakhle Saba, a hematologist-oncologist at Tulane Cancer Center; Dr. Lindsey Roeker, an assistant attending physician at Memorial Sloan Kettering Cancer Center; Dr. Javier Pinilla, a senior member and head of lymphoma section in the department of malignant hematology at Moffitt Cancer Center; and lastly, but certainly not least, we have Dr. Catherine C. Coombs, associate professor in the division of Hematology Oncology at University of California, Irvine School of Medicine.

Before we jump into today's topics, let's go over some ground rules. First, while many shy away from talking about themselves, on this show we actually want you to. If you have a trial you presented, we want to hear about it. Do you have a drug you're investigating? If so, what's the name? And for my own sake, if it has more than 3 syllables, how do you pronounce it? Two, we don't want or need your financial disclosures. We're limited on time, and we all know that some of those disclosure slides could take about 20 minutes alone, so just skip it. Three, this is meant to be fun. Obviously, bullies are not welcome. But we agree to disagree here. So speak up and tell us your thoughts. But again, let's do it fast.

And with that, please be mindful of the clock. The last thing I want to do is cut you off, but I will. Each question will be allotted a certain amount of time to be answered. So please keep your eye on the timer. Let's jump right into it. You will each get 1 minute to tell us what was the biggest surprise that came out of ASH. I’m going to start [with] Dr. Coombs.

Catherine C. Coombs, MD: So for the biggest surprise at ASH, we saw a very nice session combining BTK inhibitors with venetoclax. And the CAPTIVATE [NCT02910583] trial had really good outcomes. But I would say the thing I was surprised by was the GLOW [NCT03462719] trial. So in the earlier analyses of that trial, there were a good amount of deaths on treatment. But the thing that surprised me is actually with just around four years of follow up, we're actually now seeing an overall survival benefit of the I plus V-treated patients compared to chlorambucil plus obinutuzumab. With all studies, I do think we still need more follow up to see what happens over time, but I would say I was pleasantly surprised based on [those] results.

McDonald: Dr. Coombs, rapid fire right there. You came in with 15 seconds to go. Dr. Roeker, I’m going to go with you next.

Lindsey Roeker, MD: The biggest surprise is the ALPINE [NCT03734016] data. So that was looking at zanubrutinib versus ibrutinib in the relapsed refractory setting. And it's the first time we've ever seen a PFS benefit of one covalent BTK over the other. Now, I think there are some caveats here. The ibrutinib arm underperformed in this study. So we saw that it was an open-label trial design. And certainly I think providers are aware of the limitations of ibrutinib and maybe a little bit more willing to pull people off of that drug. But certainly, the PFS difference is huge, because it's the first time we really have reason to use one of these covalent BTK inhibitors over [the] other that isn't just driven by toxicity.

McDonald: Dr. Roeker, you beat Dr. Coombs in terms of time. Congrats on that one. Now over to Dr. Saba.

Nakhle Saba, MD: Well, I second both of what you said guys, [these are] really both surprising; very well said. But my biggest surprise is actually not a piece of data, it's actually rather the amount of novel agents that were presented. So for instance, if you look at the BTK alone, you have the covalent you know, ibrutinib, acala, zanu ... and then the BTK degraders. So, it feels like somewhat industrial fishing in a way, a lot of stuff going on. So, this could cause a problem. You know, just imagine the combination of any of these novel agents you'll find it. So, trial recruitments will be a problem, how to get these drugs to be approved and available [will] be a problem and then the knowledge burden on community oncology. So now that drugs are approved, how can we fast educate the community to adapt the latest and greatest of these combinations or drugs?

McDonald: We’re going to close out question 1 with Dr. Pinilla.

Javier Pinilla, MD: I don't think I will be able to really add much more to my colleagues. But I want to really, really turn around and say that I think one of the interesting things, but maybe not surprising is how the evolution of all these new therapeutic strategies alone and combination, maybe start to really give you a glimpse of where and how we're going to use different combinations in which genetic subgroups as we really discuss the I plus V, may be more [effective] in certain subgroups, and we still don't know at the end is going to really have a benefit of PFS. But I think once again, all these combos and everything at the end of the day may be more useful in certain genetic markers versus others. And we'll have to see more data to really corroborate this this point.

McDonald: Once again, everybody hit that one minute mark, great job. We're going move on to the next topic. You'll each get 2 minutes to tell us what trial do you think will be the most practice changing in the space of CLL and lymphoma that you heard out of ASH? Dr. Pinilla, I’m going to start with you.

Pinilla: Well, without any type of doubt, [the] ALPINE trial is going to be a really fundamental change. It's a trial done in the second line, really comparing ibrutinib versus zanubrutinib in [a] relapsed/refractory population. Obviously, everyone is comparing and trying to really bring criticism to the trial in terms of how it was designed, how it was done, but at the end of the day, as Lindsey said very well, the PFS is there.

[This is] the first time in history that 1 BTK won [over] another BTK. [And] we have the previous experience with ELEVATE relapsed refractory where a particular population at high risk, they were not really different between ibrutinib and acalabrutinib, although we now better tolerance of acalabrutinib in this case, the tolerance is better for zanubrutinib but also the PFS, something that definitely is going to really change many, many minds about these drugs. Side effects may really be slightly different from acala in terms of hypertension. But besides that, I think it's going to really change the game.

McDonald: Dr. Saba any change there or are you're going to follow with Dr. Pinilla.

Saba: Oh, absolutely. This ASH was really rich in a lot of stuff that we can apply to our clinic. So as a stem cell transplanter—including in lymphoma—the two abstracts that caught my attention and have major impacts are the TRIANGLE [NCT02858258] and BMT CTN 1703 [NCT03959241] trials. So the TRIANGLE study that was presented by Dr. Dreyling as a plenary session showed that in frontline young [population with] mantle cell lymphoma, the addition of ibrutinib to induction and maintenance with the standard of care, which is basically a high dose cytarabine-based induction followed by transplant and maintenance rituximab, that strategy was superior to standard of care alone.

Whether we can omit the transplant altogether, that remains to be determined and more follow-up is needed there. So that was pretty interesting to see that yes, we can probably alter the outcomes in mantle cell lymphoma yet to be a curable disease. A second abstract that was presented as late breaking was BMT CTN 1703, which compared post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate as the historic standard of care for GVHD prophylaxis. In this case, they used a matched-donor reduced-intensity conditioning allogeneic stem cell transplant. So this strategy was considered the standard of care of mismatch transplant and haploidentical transplant. It should also be termed the standard of care for the matched ones as well.

McDonald: Thank you, Dr. Saba. Dr. Roeker, I'm going to switch things up and head your way to follow that.

Roeker: So in CLL, definitely ALPINE is going to be practice changing, totally agree with that. The pirtobrutinib data [BRUIN, NCT03740529] that was presented isn't necessarily new, but we got longer follow up and in terms of agents that I think are going to have huge clinical impact in the treatment of CLL and other lymphomas, I think pirtobrutinib is it. You know, this is a trial of a noncovalent BTK inhibitor in a multiply relapsed/refractory population, accrued [approximately] 700 patients; a huge phase 1/2 study.

Most patients were CLL, but also shows activity in mantle cell. And then also we saw data in Richter's transformation, which has historically been a really hard population to treat. We know that chemoimmunotherapy doesn't work great for these patients. And it looks like the response rates with pirtobrutinib as a monotherapy in Richter's transformation—large cell lymphoma—look really good like 50-plus percent with some very durable responses. So I think in terms of data that's going to impact our clinical practice moving forward, having [an] option for these patients who are the double refractory, so those who have seen a covalent BTK inhibitor and progressed [and] those who have seen venetoclax and progressed, those are the patients that are really going to benefit from this trial, and that's definitely an area of unmet need in the care of CLL. So I think it wasn't necessarily new data. We've seen BRUIN before, but we've definitely got even more confidence that this is a really active, really well-tolerated agent.

McDonald: And Dr. Coombs, we're going to end with you. We've been hearing about some added follow up data, right, and the ALPINE trial and everything else out there. So I'm going to shift over to you to see what you're thinking.

Coombs: Yeah, so going last is tough. I have to agree that ALPINE is the most practice changing trial for all of the reasons stated. Also very surprising to see superiority of one BTKi over another. However, just to shake things up a bit to talk about something else. I would say the other study that profoundly impressed me relates to acute lymphoblastic leukemia. So this was also in the late-breaking session, the E1910 [NCT02003222]. This trial randomized patients to receive blinatumomab as part of their consolidation treatment in adults with B-cell ALL who are in a [complete response] and had undetectable MRD.

And it showed an overall survival benefit, that was not even questionable. A lot of times they say, “oh, there's an OS benefit,” and you have to squint to see the curve separate. This was a profound benefit to blinatumomab and was just such a surprise to me. And that's a really challenging disease to treat. So a huge cooperative group effort, and I would say that would also be practice changing, though outside of the CLL world. I have no arguments with respect to ALPINE being the most practice changing in CLL, though.

McDonald: For the next topic, you’ll each get 1 minute. We just heard most practice changing, but before all of that—and I have a feeling I know what your answer might be—but what trial is going to lead to the next FDA approval the soonest following ASH? I’ll start with Dr. Roeker.

Roeker: ALPINE. I think [zanubrutinib is] actually slated for January 2023. So we're just around the corner for the approval in CLL.

McDonald: Dr. Pinilla?

Pinilla: ... definitely the next in line is zanubrutinib in front line and second line.

McDonald: Dr. Coombs, any outside winners that we can expect?

Coombs: So those are actually my two answers. Relevant to CLL? Definitely ALPINE. But I have heard titterings that there may be a mantle cell approval on the horizon for pirto. And it is what it is, but sometimes there's off-label use. So I do think a pirto approval may affect the CLL population through that mechanism, not saying it's right or wrong. But I have nothing outside of those two.

McDonald: Alright, Dr. Saba, I'm kind of leaving you out to dry here as the fourth person to go. Do you have any outside information or is this what you're expecting?

Saba: It would be really funny if I win this section because I think I think one of the bispecifics might make it earlier. I think that mosunetuzumab, which is a bispecific antibody that's out there; a CD20 bispecific that A). is under priority review in the FDA and could actually, we could reach a decision before the end of [December]. We'll see; I think it's in relapsed/refractory follicular lymphoma after two or more lines, based on the data presented with a very high ORR nearing a little less than 80% [and a] high CR rate nearing 60%.

McDonald: Well, I think we kind of have a general idea of what's perhaps coming down the pike. Obviously, everybody was talking about ALPINE. So that'll be interesting to see moving forward. We're going to keep it going, and this is actually going to be still 1 minute each. What CLL trial maybe requires more follow up as a next step. And I'm going to start with Dr. Saba on this one.

Saba: I know you guys talked about ALPINE and I'll leave that discussion for later. But I was a little intrigued by the data ... mentioned earlier with the combination of I plus V. This most extensively studied combination of BTKi plus venetoclax—FLARE, GLOW, CAPTIVATE—some of them showed some plateauing of the curve, particularly in the ICP-mutated subgroup. We would love to see a longer term follow-up to see whether those MRD negativity are maintained on the long run and perhaps maybe talking of a cure in a subset of patients on the long run. And that will also help us determine what's the best third agent to add on top here.

McDonald: Dr. Pinilla, I will switch gears to you.

Pinilla: There is no doubt that even the fantastic data [out of] ALPINE; everyone wants to see more data. … At the same time, we continue to really see how these curves really come together [and] continue to separate. So from that point of view, I really want to see that, and I definitely agree with Nakhle that we need the follow-up of I plus V.

McDonald: Dr. Coombs.

Coombs: I was going to say I plus V as well. I think CAPTIVATE in particular; the thing that I would like to see more follow up on is whether there is a role for MRD-directed treatment prolongation or not, it doesn't seem to be the case yet. I do think the curves will separate in a statistically significant fashion. However, is that enough to justify prolongation? And I would say even if they did, maybe not, because for patients that stop, I think they'll likely be resensitive upon rechallenge. For patients that continue, they may develop a resistance mutation. But my 2 friends here said I plus V, so I want to be special and say something different. I was kind of excited about the epcoritamab data [EPCORE CLL-1, NCT04623541] in Richter's, but 10 patients [and] very short follow up. So I really want to see more on that to see if that's going to be a promising approach.

McDonald: Dr. Coombs, just made it on the time. And we're going to conclude on this topic with Dr. Roeker.

Roeker: I was going to say I plus V too. But to diversify, we'll try something different. So we saw the first data for BTK degraders. So NX-2127 [NCT04830137] kind of a cool mechanism of a drug, a new way to think about how to deal with BTK. And the follow-up on that study is relatively short, the toxicity profile, I think we're still figuring out, but I think more follow-up on that agent, and that class of agents is going to be really helpful to figure out where those fit in our treatment paradigm.

McDonald: Now we're going to shift gears a little bit. So aside from studies, this next topic can honestly be on anything out of ASH—trials, data, a certain drug, presenter, meeting itself, you name it—but the kicker is you only have 30 seconds each. Who, or what, was the biggest winner out of ASH. And I'm going to start with Dr. Pinilla.

Pinilla: We really keep saying the same thing, but ALPINE and zanu I think is the winner by far. Everyone was expecting the data since it was a press release and I think, really definitely has been the highlight in my opinion of ASH.

McDonald: Dr. Roeker.

Roeker: Nirav Shah presented Richter's data with 20 minutes of notice, like somebody got stuck on a plane. That's bananas. He got asked at the last minute and went up and did a beautiful job.

McDonald: OK, Dr. Coombs.

Coombs: I’m going to see if I can do this in 30 seconds. No. 1, the Miami Party—best live band I've seen; so much fun to network with friends. Two, Nirav Shah, I second that and it's funny because the other thing I really liked was the ability to watch presentations from bed, so I got a bad blister [and] I watched that session from bed, but I thought, “oh my god, if I was there could that have been my time to shine because I also enrolled patients on that study.” Nirav did a great job.

McDonald: You did a good job too, you met the 30-second time limit. So we're going to close with Dr. Saba.

Saba: I'll stay classic here, I guess bispecifics. Yeah, really, without exceptions. I'm so excited about all the data. Really, highly efficacious. Heavily pretreated relapsed/refractory lymphoma; in general high CR rates. Some even fixed duration. So again, this will compete clearly with CARs for sure, although it's a different target. But just for their availability, off the shelf, ease of use, sub q, less CRS and ICANS and probably community [oncologists] will be able to use it.

McDonald: Just on the dot, Dr. Saba. Earlier I mentioned [that] we encourage you all to talk about yourselves. But before we close out the day, 1 minute each; [again I’m] giving you 1 minute each, give us your shameless plug from the meeting. I will start with Dr. Roeker.

Roeker: We presented some cool data from the Flatiron database, which is a big community center-based database and looked at basically—in the frontline setting and then in the relapsed refractory setting—BTK monotherapy versus BCL2 inhibitor with obinutuzumab in the frontline setting; so the CLL14 [NCT02242942] regimen and then in the relapsed refractory setting, then with any CD20. In the frontline setting, there's pretty much equipoise between the regimens, which is always kind of nice.

We don't have any head-to-head data. And obviously there's all of the limitations of real-world data and retrospective cohorts, but I think [it] gives us a good sense that as the first novel agent, these regimens are performing both very well. In the second line setting there was a hint that BTK inhibitors had a longer time to next treatment, which is kind of a surrogate for PFS in that second line setting mostly a chemo pretreated population about 30% ...

McDonald: Unfortunately, we are out of time, but we'll move on to Dr. Coombs.

Coombs: As far as studies I participated on, I was an author on a number of the BRUIN papers. So one that we hadn't discussed yet was a poster presentation looking at the use of pirtobrutinib in patients who had discontinued prior covalent BTK inhibitor for intolerance. That study just further highlights the safety of that agent and supports its use for patients with CLL and SLL with intolerance as their reason for discontinuation.

I would also like to highlight one other aspect of the Richter's presentation. We've talked about that a bit, but Richter's is just such a hard disease to study [because] patients progress very rapidly or are often very sick. And the BRUIN substudy looking at Richter's was the largest prospective trial in Richter's transformation. So I think just a commendable effort.

McDonald: 3 seconds left, you just got it in. Dr. Pinilla, we’ll go with you.

Pinilla: I have [a] very nice presentation from my lab at ASH. But the first thing is a trial in progress that we are really starting in my institution, really targeting in CLL, a new protein and Ror1 in a very, very cool methodology ... And obviously, I have to reach out to my very, very talented students and postdocs in the lab, who present our beautiful studies about the metabolomics of the cells in CLL. And how we in the future, we're going to hopefully, really reprogram these T cells to really be much more successful in immunotherapy strategies. And finally, another pathway, we try to refine new mechanisms to really treat CLL and we recharge it another very well-known protein is 109. And we have a drug that in the mouse model really works beautifully. So really are dealing with a microenvironment. And hopefully, maybe one day we will see a trial on those.

McDonald: 2 seconds left. Good job. I'll close out with Dr. Saba.

Saba: I’m still doing some work in COVID, lymphoma and CLL. And we have a poster that my fellow presented. We're still collecting samples throughout the time, although I feel like the interest is, is cooling down. So probably I'll be back with some more lab data. But it's interesting to see that how the CLL and lymphoma patients in general and multiple research showed that they take time to make this immune response. We're right now studying the T cell responses as well and the inhibitory activity of this antibody to see if they're able to basically shut down the virus. So that's ongoing. It's interesting, but you know, it's cooled down by the fact that the pandemic is overall over anyway.

McDonald: We touched on a lot today. I want to thank you all so much for joining us. But before we get to the end, 15 seconds each. I'm going give you your closing thoughts. So Dr. Saba, I'll start with you.

Saba: Very excited in lymphoma, a lot of drugs, a lot of agents all highly efficacious. We just need to find that magic combination. And hopefully we'll be talking about cure in a lot of patients.

McDonald: Perfect. Dr. Pinilla, we'll jump to you.

Pinilla: Sure, quite excited as very, very nice new drugs. Again, we still need to really figure out how we're going to combine, and which groups or categories of patients need one versus another. I think they will be challenged in the next years to come.

McDonald: Dr. Roeker

Roeker: An exciting ASH. I think we know that for a lot of patients, the future of CLL-directed therapy is going to be time-limited and figuring out for whom that's the right approach and how we should best use it.

McDonald: Alright. And lastly, 15 seconds; Dr. Coombs.

Coombs: Great meeting; I would say I'm most excited about the newer generation drugs with improved tolerability, but also all the new targets to help more effectively treat our double refractory and beyond CLL patients.

McDonald: Well, that is all we have time for today. Thanks for joining CancerNetwork® for 2-Minute Drill where we offer unscripted, rapid insight on the most recent cancer conferences. I'm Ryan McDonald. Have a great day.