Consensus or Controversy? Clinical Investigator Perspectives on the Current and Future Management of Chronic Lymphocytic Leukemia
Consensus or Controversy? Clinical Investigator Perspectives on the Current and Future Management of Chronic Lymphocytic Leukemia
Faculty presentations from an independent satellite symposium during the SOHO 2019 Annual Meeting. Featuring perspectives from moderator Dr Christopher R Flowers and faculty members Drs Jennifer Brown, William Wierda and Jennifer Woyach.
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Evolving Therapeutic Algorithms for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia (CLL) DR WOYACH: During this very short talk, I’m going to be discussing data from the 4 initial Phase III therapy studies, E1912, AO41202, iLLUMINATE and CLL14. These are all ones that came out within the past year or so. I’ll discuss how these studies fit into our current practice and what I think are some of the most pressing open questions in front-line CLL right now. Moving directly into the study, so ECOG-1912 was a Phase III trial comparing chemoimmunotherapy to ibrutinib-based therapy in younger, previously untreated patients. These patients had to be under the age of 70. And then they were randomized 2:1 to receive either ibrutinib plus rituximab or FCR. The primary endpoint of this study was progression-free survival. And we can see that progression-free survival is indeed longer with ibrutinib plus rituximab compared with FCR, with a hazard ratio of 0.035, and about 90% of patients were still progression free at about a year. Probably most interesting about this study and a little bit unexpected is that even at this short point, overall survival actually favored ibrutinib plus rituximab as well, with a very small hazard ratio of 0.17. As we’ve been pointing out, in the groups of patients that had very favorable disease characteristics, including those with IgVH mutated disease, there doesn’t right now appear to be a difference between the arms. Like I mentioned before, that’s predominately because people haven’t relapsed in either of the arms. I think that’s still a very open question for those patients. For each of these studies I’m going to show you some select Grade 3 or higher adverse events. You can kind of see the toxicity profiles between the regimens. For FCR compared with ibrutinib, we can see that most of the hematologic toxicities are higher in patients receiving FCR, as well infections and febrile neutropenia were a little higher in FCR patients. Atrial fibrillation and hypertension, which are 2 known toxicities associated with ibrutinib, were indeed higher in the I/R arm. I want you to note, in this young patient population, 3.2% of patients had Grade 3 or higher atrial fibrillation and about 18% had Grade 3 or higher hypertension. And we’ll look at that compared to the older patients in just a second. The Alliance study, AO41202, took patients that were age 65 or older –– stratification based upon Rai Stage and the presence or absence of the high-risk abnormalities. I didn’t mention before, but the ECOG study actually did not include patients with 17p deletion. This study did. And patients were randomized to 1 of 3 arms in a 1:1 fashion –– bendamustine plus rituximab, ibrutinib or ibrutinib plus rituximab –– and then there was a crossover for patients on the bendamustine/rituximab arm who experienced disease progression. Similar to the ECOG study, we saw an advantage in progression-free survival for ibrutinib-based regimens when compared with chemoimmunotherapy. Median follow-up on this study is 38 months, and at 24 months progression-free survival with BR was 74% compared to 87% and 88% for the ibrutinib and ibrutinib plus rituximab arms. The other important outcome of this study is that ibrutinib plus rituximab was no more effective than ibrutinib alone. Overall survival at this time is no different among the 3 arms. And we’ll have to see with longer-term follow-up whether that remains the same. And a study with our planned crossover, we don’t necessarily expect that there will be a survival advantage though. The Grade 3 or higher adverse events, similar to –– with the ECOG study with FCR, we saw that hematologic adverse events were a little bit higher in the chemoimmunotherapy arm. As well, febrile neutropenia was higher with chemoimmunotherapy. However, infections in general were fairly similar across all arms. All 9 hematologic toxicities were a little bit higher with the ibrutinib arms, specifically atrial fibrillation and hypertension, like we saw before. In older patients there was a higher incidence of both of these toxicities. And we can see about 6% to 9% of patients had Grade 3 or higher A-fib. Grade 3 or higher hypertension was recorded in about 30% of patients. What do these tell us? Ibrutinib-based regimens are more effective than chemoimmunotherapy in the front-line setting. Ibrutinib is probably more toxic in older patients than in younger, and rituximab does not improve PFS. iLLUMINATE was a similar study to Alliance in terms of the patients that were enrolled, although younger patients with higher comorbidities or lower creatinine clearance or high-risk features could be enrolled. They were randomized to either chlorambucil plus obinutuzumab or ibrutinib plus obinutuzumab in a study that chemoimmunotherapy was also 6 months, and it did have a crossover. And as you would expect, ibrutinib plus obinutuzumab had a higher progression-free survival than chlorambucil plus obinutuzumab. And at 30 months, 77% of the ibrutinib/obinutuzumab patients remained in remission. Grade 3 or higher adverse events, like we’ve been seeing, the hematologic AEs were more common in the chemoimmunotherapy arm, atrial fibrillation higher with ibrutinib/obinutuzumab. Hypertension on this study was a little bit low, and I don’t know if it’s how they’re recording it or capturing that data or whether it was just lower here. Ibrutinib/obinutuzumab as well is more effective than chemoimmunotherapy. The PFS for IO doesn’t appear to be a lot different than ibrutinib alone, but we don’t have head-to-head data on that comparison. These trials establish ibrutinib as one standard of care. CLL14 is the most recent of these Phase III studies. These were untreated patients, predominately older population because of the entry criteria of a SEER score comorbidity index greater than 6 or low creatinine clearance. Patients were randomized to chlorambucil plus obinutuzumab or venetoclax plus obinutuzumab. And both of these treatments went for about 1 year and then stopped. Progression-free survival favored venetoclax plus obinutuzumab. Like I had mentioned previously, median follow-up is about 2 years or 28 months. There are 24 months progression-free survival, which is about 1 year off therapy, was 88.2% with venetoclax plus obinutuzumab. AEs for venetoclax and obinutuzumab are a little bit different than we see with the ibrutinib-based regimens. And we can see that the hematologic adverse events, relatively low among all of the groups except for neutropenia, which was seen in about half of the patients at Grade 3 or higher, but similar between chemoimmunotherapy and venetoclax. Infections as well were pretty similar, febrile neutropenia similar between the 2 groups. But notably, despite the relatively high rate of neutropenia, the rate of febrile neutropenia is very low. Diarrhea was more common in venetoclax plus obinutuzumab. And I put in here that benign or malignant neoplasms, which is really a catchall and not necessarily meaningful at this time, was a little bit higher in the venetoclax/obinutuzumab arm. This tells us venetoclax plus obinutuzumab is indeed more effective than chemoimmunotherapy. Toxicity seems fairly similar between these regimens, which is good, and chlorambucil plus obinutuzumab is a very tolerable regimen, as is venetoclax/obinutuzumab. At 2 years the PFS for venetoclax/obinutuzumab is similar to what was seen in the Phase III studies with ibrutinib-based regimens. And I think the long-term results are really going to be critical to determine the place for this regimen in clinical practice. I think the most pressing open questions for front-line therapy right now, first is, where will acalabrutinib or acalabrutinib plus obinutuzumab fit in? There’s a completed Phase III study that hopefully we’ll hear the results sometime soon to let us know what the efficacy of those regimens are. And it still remains a little bit up in the air the efficacy and toxicity differences between ibrutinib and acalabrutinib. How does venetoclax plus obinutuzumab compare to ibrutinib in the long term? And again, that just goes to follow-up on these studies. Is venetoclax plus ibrutinib better than all of these therapies? And I think that there’s a lot of data to suggest that that is as well a very interesting regimen. Again, need more long-term follow-up and head-to-head comparisons. And then finally, what we had talked about previously, what do we do with these IgVH mutated patients who are young and fit and would do very well with chemoimmunotherapy or our novel regimens? In conclusion, novel agents have consistently now been shown to be superior to chemoimmunotherapy in terms of progression-free survival and in some cases overall survival. I think many patients with CLL will never receive chemotherapy for their disease. Long-term follow-up will be critical to determine whether one specific therapy is best or whether all are really appropriate. And that these prospective clinical trials remain extremely important to help us determine what is, indeed, the optimal front-line therapy for our patients. Acalabrutinib and Other Promising Strategies Under Investigation DR BROWN: If we consider the spectrum of BTK inhibitors in clinical development, we can divide them broadly in 2 groups, between the covalent and the noncovalent inhibitors. Ibrutinib we know is our first-in-class molecule which inhibits BTK but also inhibits quite a large number of other kinases. And so the 2 next-generation covalent inhibitors that target the same cysteine, one is acalabrutinib, which we’ve been talking about at length. It’s more specific for BTK. You can see it does not inhibit ITK at all. And it inhibits TEK less than ibrutinib as well. The other one is zanubrutinib, which is also in registration trials, I’ll make a comment about briefly, also more specific than ibrutinib. And so both of these are hoped to have better adverse event profiles. The noncovalent inhibitors have been largely developed to target the cysteine 481 mutation that develops in the context of ongoing therapy in relapse on ibrutinib. And so vecabrutinib, ArQule 531 and LOXO-305 are all in the clinic in Phase I studies with data that has been or will soon be presented. And they have a range of different profiles. Vecabrutinib and Arqule 531 do inhibit a variety of other kinases other than BTK but are more specific in general than ibrutinib. LOXO-305 is very selective for BTK. I encourage you to keep your eyes open for more data on these drugs over the fall. Now if we consider the pharmacokinetics of the covalent inhibitors, you see ibrutinib in the middle, which is given daily, and drug levels are quite low by 12 hours and gone by 24 hours when the next dose occurs. Comparing that to acalabrutinib, on the right, acalabrutinib has a very short half-life and so peaks higher but is cleared very rapidly from the blood. Zanubrutinib, on the left, has a half-life more similar to ibrutinib but is dosed BID, twice a day, so that you actually maintain drug exposure throughout the 24-hour dosing interval. The newer-generation drugs were very carefully optimized for BTK occupancy. These are data with acalabrutinib in the treatment-naïve setting comparing the 200-mg daily dose to 100-mg twice-daily dose. And you can see the 100-mg twice-daily dose that has been selected maintains trough levels significantly higher than the 200-mg daily dose. Zanubrutinib has also been optimized for BTK occupancy, in the top panel, across multiple doses, a Phase I. As you can see with ibrutinib, on the bottom, there is some splay downward at the 420-mg dose. Acalabrutinib reported results of its first Phase III registration trial earlier this year. This was the ASCEND trial in relapsed/refractory CLL, where patients were randomized to either acalabrutinib or investigator choice of idelalisib/rituximab or bendamustine/rituximab. Median age in the late sixties, 1 or 2 prior therapies and about 16% had 17p deletion, 80% unmutated IGHV. The study met its primary endpoint of IRC-assessed progression-free survival. You can see the acala arm had a 1-year estimated progression-free survival of 88% compared to median PFS on the order of 16 months between BR and idelalisib/rituximab. We’re of course very interested to look at the toxicity profile in the setting of a randomized trial. You can see for atrial fibrillation there were 8 events with acalabrutinib compared to 5 in the combined control arm, so no definite signal of an increase there. Hypertension was 5 and 5. Low-grade bleeding is increased with acala, but the major hemorrhage is not. Infections were high across the board, as we expect in a relapsed/refractory study. And there were 10 second malignancies with acalabrutinib, 6% rate, which does look like it may be a bit higher than the control arm, but it’s not dissimilar from what’s been reported with ibrutinib at about 10% rate of second malignancies. Acalabrutinib has also been studied up front. We had some long-term follow-up data in treatment-naïve CLL at ASH last year, where the 36-month event-free survival rate in this cohort of 99 patients was 92%. This includes discontinuation for adverse events as well as disease progression. You can see that the great majority of patients were able to remain on the drug for that 36-month interval. ELEVATE treatment naïve is a second registration trial for acalabrutinib, which has been reported to be positive by press release, with acalabrutinib superior to obinutuzumab/chlorambucil and acalabrutinib/obinutuzumab superior to obinutuzumab/chlorambucil. And we hope to see that data this fall some time. But the combination of the ASCEND study and the ELEVATE treatment-naïve study should lead to a broad approval for acalabrutinib in CLL, hopefully early next year. The ELEVATE-relapsed/refractory study is the head-to-head comparison of acalabrutinib to ibrutinib in previously treated high-risk CLL, which will obviously give us the best data on comparative toxicity and efficacy. The study enrolled 17p- and 11q-deleted patients but is not expected to read out until 2021. Now turning our attention to some other molecules, zanubrutinib I already mentioned –– is also doing a head-to-head registration trial comparing zanubrutinib to ibrutinib in relapsed/refractory CLL. That study is an ongoing accrual. They also have done an up-front registration study, which completed accrual but we have not seen data. In terms of other classes of molecules, we know that the PI3K gamma delta inhibitor duvelisib was approved last year. And umbralisib has been billed as the next-generation PI3 kinase inhibitor, which has completed Phase I study and actually also completed enrollment to a registration trial I’ll show you in a minute. It’s attracted a lot of attention because its toxicity profile, shown here, appears to be improved compared to idelalisib or duvelisib, with less transaminitis, less colitis and less discontinuations due to adverse events. We haven’t seen any updated efficacy data in some time, but we’re currently awaiting the results of this Phase III trial comparing ublituximab with umbralisib, or TGR-1202, to obinutuzumab with chlorambucil. What about CAR T cells in CLL? After the initial splash from UPenn, some of the subsequent studies had lower response rates and lower complete remission rates in CLL than in other diseases, you can see ranging from 8% to 30% to 50%, on the right. Two recent studies adding ibrutinib to CAR T have suggested that perhaps the addition of ibrutinib improved response rate of CR. At ASCO this past year, we heard updated data on JCAR017 from the TRANSCEND study. This study enrolled very high-risk, ibrutinib-exposed patients, half of whom were also venetoclax refractory, and the CR rate was 46%, with 65% undetectable MRD by next-gen sequencing in bone marrow. It looked quite encouraging. And the CRS was common, but Grade 3 CRS was less than 10%, so that was reasonably good. Neurotoxicity, Grade 3 or higher, was about 20%. There were no deaths due to AEs. There will be ongoing emerging data from CAR-T trials in CLL, which I encourage you to look out for, particularly as we get more patients refractory to both BTK and BCL2 inhibitors. In summary, acalabrutinib has received a breakthrough designation for CLL based on the results of ASCEND and ELEVATE treatment naïve. The data to date suggest at least similar efficacy to ibrutinib with improved tolerability, but ultimately the head-to-head trial will really define that spectrum for us. Zanubrutinib has ongoing registration trials in front-line and relapsed CLL. Umbralisib with ublituximab has been evaluated in the UNITY registration trial, awaiting results. And interest is again alive in CAR T in CLL, with JCAR017 looking promising in ibrutinib-refractory/venetoclax-refractory patients. Thank you. Existing and Recently Approved Approaches for Patients with Relapsed/Refractory CLL DR FLOWERS: I will turn and talk a little bit about existing and recently approved approaches for patients with relapsed/refractory CLL and some of those particular situations that we just discussed in the cases. Let’s first talk about the recent data from John Seymour that was in The New England Journal of Medicine now a little bit more than a year ago, looking at venetoclax and rituximab in the relapsed/refractory setting. And you’ve heard bits and pieces of this through our discussion about the cases. The MURANO data really are data that compared the combination regimen of venetoclax and rituximab given in a time-limited basis in the relapsed setting for patients who had progressed on front-line therapy for CLL compared to bendamustine/rituximab. And here you see in the progression-free survival curves shown at the top, venetoclax and rituximab compared to bendamustine/rituximab shown here in the green, with a progression-free survival in the venetoclax and rituximab group that had not been reached at the time of publication compared to 17 months for bendamustine and rituximab. And we see that while bendamustine/rituximab has some role perhaps in older patients in CLL, its role in CLL really has fallen by the wayside compared to many of these newer combination regimens with novel targeted therapies. And when we look at the overall survival curves here, impressively we can see with a 3-year overall survival rate for venetoclax and rituximab at nearly 88% compared to 79% for bendamustine/rituximab, that we actually were seeing separations in the overall survival curves for these 2 approaches, suggesting that in the relapsed/refractory setting with the number of approaches that we have that chemoimmunotherapy really has a limited or no particular role for patients in the modern era. This shows the adverse events that were seen in this particular trial comparing the 2 approaches, and when you look at the Grade 3/4 adverse events, although this is an anti-CD20 antibody combined with an oral agent, there still is a fair amount of neutropenia seen in this particular population that relatively uncommonly transitioned into infectious manifestations, about 17% in this group that had venetoclax/rituximab versus about 22% in the group with bendamustine/rituximab. And you see other cytopenias also occurred: anemia in about 11% and thrombocytopenia in about 6% of individuals and only about 4% of individuals who had febrile neutropenia in the group that had venetoclax/rituximab compared to bendamustine/rituximab chemoimmunotherapy in that situation. We did see slightly less infusion-related reactions. Now, it’s unclear whether that’s really a statistical anomaly or something that’s different about the suppression of cytokines when you use the Bcl-2 inhibitor venetoclax in this particular situation. And you can see here in this combination setting the tumor lysis syndrome was relatively uncommon in the relapsed/refractory setting. Although it’s something that we spend a lot of time talking about and thinking about with the modern ways that we manage that, it is less common to see that in practice. That has been followed up by another study that was just recently published in the Journal of Clinical Oncology looking at minimal residual disease in the patients in the MURANO trial. We talked a little bit about the role of minimal residual disease in patients who were receiving venetoclax at the outset. And I think that these data really help us to solidify the role of this regimen and the potential use of minimal residual disease for these patients. And you heard from Dr Brown earlier about the ways that minimal residual disease testing can occur in this particular setting. And so when you look at the comparisons and the timing of minimal residual disease, these are for only the 194 patients who had venetoclax/rituximab on the trial. And you look at various time points across the trial. This here in the yellow shows those patients who had progressive disease or died or withdrew from the study, but you can see across the trial those who had a high level of minimal residual disease, what was defined as a low level of minimal residual disease by the definitions that Dr Brown discussed and those who had undetectable minimal residual disease, shown here in the blue. Obviously at the screening time point when patients were starting on therapy, there was no one with undetectable minimal residual disease. And you can see here now at cycle 4, day 1, at the end of the induction therapy and then at time points 9 months, 12 months, 15 months and so on on therapy and then following the end of therapy the levels of undetectable minimal residual disease across patients. And what this follow-up to the MURANO study showed us is that this was quite high and much higher than in the patients who received venetoclax in this particular study compared to those who had chemoimmunotherapy –– and this continued benefit was observed for the patients in terms of an enduring — and predictably, there was longer progression-free survival for those patients who had undetectable minimal residual disease. The other thing that we alluded to in our discussion is the role of the management of tumor lysis syndrome in patients who are receiving venetoclax. While that’s something that was a considerable concern when this drug was first developed and in Phase I clinical trials where we saw tumor lysis syndrome rates as high as 13% in those particular patients, that typically involved a shorter ramp-up period, with higher starting doses across the Phase I trial, or at least in some of those patients. And there we saw about 10 of 77 patients in the Phase I trials had tumor lysis syndrome, including evidence of clinical tumor lysis syndrome and some fatal events early on. What we’ve seen in practice and in clinical trials, both in the use of venetoclax as a single-agent therapy and in these combination therapy studies with rituximab or with obinutuzumab, those rates tend to be much lower. This tends to predominately be laboratory tumor lysis syndrome, and in many cases there was no clinical consequence of that. But that requires the longer ramp-up period and very carefully following this tumor burden approach that you heard earlier from our panel of experts as a way to be able to monitor patients and to give hydration, either in the outpatient setting or in the inpatient setting, when necessary. Next I’ll turn to the role of duvelisib in this setting for relapsed/refractory CLL. There’s been a press release that looked at the role of duvelisib, and it was granted regular approval for adult patients based on the trial data that I will talk to you about. This trial, published in Blood last year, the Phase III DUO trial, looked at duvelisib versus ofatumumab in relapsed/refractory CLL. Ofatumumab is an anti-CD20 antibody that’s approved in this space but one that we really spend little time talking about anymore, given the panoply of options that we now have for patients with relapsed/refractory CLL. In this trial, patients were randomized on a 1:1 basis to either duvelisib, given as a 25-mg dose twice daily continuously, or ofatumumab, given IV with the option of crossover to ofatumumab or duvelisib. And what we see here is that there was an improvement in progression-free survival of 13 months for the duvelisib arm versus less than 10 months for the ofatumumab arm in this particular trial. When we look at the response rates, there are also higher response rates, both in terms of the overall response rates and response rates in lymph nodes for the group that received duvelisib compared to ofatumumab, albeit a little bit of a straw man, since this is an approach that we uncommonly use in this setting. And here shows the adverse events, which are typical of some of the adverse events that we talked about earlier for PI3 kinase inhibitors. Diarrhea is prominent as a nonhematologic adverse event. Neutropenia did occur in about a third of patients, as well as other cytopenias seen in this setting. This is now a new approach that is approved for use in patients with relapsed/refractory CLL who have failed prior lines of therapy. Available Data with and Potential Role of Novel Combination Approaches DR WEIRDA: I’m going to talk about some of the data with regard to the combination therapy, then I’ll review our data that Nitin Jain has recently published in the New England Journal. We’ve covered this I think quite a bit this morning in terms of goals of care and where we’re at with treatment. It’s been exciting to see that this new standard of care and the standards have changed and evolved. And we have a number of Phase III studies now available. I think maybe the main comment to make is that the first treatment that a patient gets is the best opportunity to achieve whatever that goal that you have for that patient is, whether it’s long-term management of the disease with a BTK inhibitor-based therapy or deep remission with chemoimmunotherapy or deep remission with a combination or venetoclax-based therapy. When we’re talking about relapsed disease, we’re really talking about keeping our options open and long-term management of the disease. This is sort of my approach to first-line therapy now, and we’ve talked about FCR for patients who have a mutated V gene and no 17p or TP53. And we have options between the BTK inhibitors and Bcl-2 small molecule inhibitor, as we’ve talked about. I don’t see benefit to rituximab with a BTK inhibitor in the front-line setting, and we did a randomized trial with rituximab and ibrutinib in the relapsed setting and didn’t see benefit. The question will be if obinutuzumab is a different antibody in that regard and there is benefit. And we may have insights into that with an update or, actually, the initial presentation of the data with the acala 3-arm randomized study. The BTK inhibitors, particularly ibrutinib and venetoclax, have clinically complementary activity. Ibrutinib is very effective at shrinking lymph nodes. Most patients achieve a partial remission. Those partial remissions are partial remissions because there’s usually persistent disease in the bone marrow and patients may have a persisting lymphocytosis. Venetoclax, very effective front line and relapsed disease. Patients will achieve a complete remission in the front-line setting more commonly than the relapsed setting. And residual disease with venetoclax is usually in the form of persistent lymphadenopathy. It’s very effective at clearing disease from the blood and the bone marrow. Clinically complementary between the 2 agents. And our laboratory collaborator, Varsha Gandhi, has looked at and shown that patients who are on ibrutinib will have decreased expression of MCL1, which is a resistance mechanism or resistance mechanism for patients on venetoclax, and so that was one of the rationales that led to the testing of this combination. We had a study, a Phase II study that we initiated several years ago now, where patients received 3 months of ibrutinib monotherapy to debulk their disease prior to initiating and ramping up with venetoclax. And patients were intended to receive a total of 24 cycles of the combination therapy. And we were looking at responses, including minimal residual disease status in the bone marrow. We did frequent bone marrows, and we have a lot of data that gives insight into responses and the kinetics of responses. Now, the trial had 2 cohorts. It was a front-line cohort and there was a relapsed cohort. The front-line cohort enrolled patients who were over 65 or who were younger than 65 and had a high-risk feature –– 17p deletion, mutated TP53 or an unmutated V gene or 11q deletion. We’ve reported on both cohorts. We’ve published on the front-line cohort and will update on the relapsed cohort at this ASH. I’m going to show you the data for the front-line cohort of 80 patients. This was the first 80 patients –– the trial started out with 40 patients in each cohort, front line and relapsed. It expanded to 80 in the front-line cohort and then 120 in the front-line cohort. We now have 120 patients who’ve enrolled on that front-line cohort and a total of 80 who have enrolled in the relapsed cohort. These are the characteristics for the first 80 patients who were enrolled on the front-line cohort. And these are the responses that we’ve seen so far. Looking from left to right, you can see responses after the first 3 months on ibrutinib monotherapy –– most of the patients responding, most of those responses are partial remissions, as reflected in the purple portion of this bar. After the first 3 months on the combination therapy, you see the complete remission rate goes up to 57%. And we’re starting to see patients who are MRD-negative in the bone marrow even after 3 months of combination therapy. So the complete remission rate continues to go up here as patients remain on treatment. And this shows you the first 26 patients that reached out to 18 months of combination therapy who had a complete remission rate of 96% and a bone marrow undetectable MRD rate of 69%, which is very high for a regimen. And as I mentioned, it’s 24 months of combination therapy. These patients are continuing on therapy and we’re continuing to get follow-up from these patients as well as the relapsed. But we were impressed with this rate of complete remission and the rate of undetectable MRD in the bone marrow on this trial of a group of patients who would otherwise be considered a high-risk population. We saw responses, as you see in this slide, even including among patients in the older age group, although there were few patients in this analysis. And these are undetectable MRD in patients who had high-risk features, including 17p deletion or complex karyotype. Patients did come off treatment, and that’s shown here. Five patients came off when they were on the ibrutinib monotherapy for various reasons, and we’ve had a few patients come off while on combination. We see similar toxicities that would be expected if using 1 drug alone or the other. Ibrutinib-related toxicities we’ve seen. We didn’t see higher incidence of toxicities or any signals of new toxicities with the combination. It’s a safe combination, and we’ve used that to justify using the combination when ramping up the venetoclax, as I mentioned before, in patients who are developing resistance to ibrutinib. Progression-free survival and overall survival shown here. And as I mentioned, the toxicities are consistent with what we would expect with monotherapy for either of the drugs, including atrial fibrillation with ibrutinib. I just wanted to touch on what our next trial is. This trial is enrolled. One question is if a CD20 antibody makes a difference in this combination. We’re going to embark on a randomized trial –– it’s a Phase II randomized study that has a similar population for enrollment, and patients will be randomized to receive early obinutuzumab or no obinutuzumab for 6 cycles. We’ve swapped out acalabrutinib, ibrutinib with acalabrutinib and the venetoclax continues. And we’ll be looking at MRD status as our primary endpoint in each cohort –– at 6 months for the front-line cohort and at 12 months for the relapsed cohort. This is the CLARITY study. The CLARITY study is a similar-designed study as our study with the combination of ibrutinib plus venetoclax, and these patients were previously treated. And these patients –– the other feature that’s different from our study is that these patients could stop treatment early if they’re MRD-negative. This trial has recently been published. And I didn’t show you our relapsed data yet. But we see a similar rate of undetectable MRD in patients after 12 months of combination therapy. About 40% of our relapsed patients are MRD-negative in the bone marrow following a year of combination therapy. Complete remission is about 50% in this experience. And durable and impressive progression-free and overall survival. And I’m not going to show you the data for this trial. This is the trial that’s been done by Jennifer Woyach’s group at the Ohio State. This trial was a triplet of venetoclax/ibrutinib, and patients received obinutuzumab. And they had a 25-patient cohort of previously untreated and previously treated patients on this study. And the data were intriguing. And so again, the question remains, does a CD20 antibody add to this combination? And that was the rationale for us designing the randomized Phase II trial that we’re doing. There’s a lot of exciting stuff going on. The combinations are very well tolerated and are achieving deep remissions that are appearing to be durable, with a high rate of undetectable MRD. And I think we’ll be able to get many of our patients in a deep remission and off treatment for extended periods of time. |