Hillmen Analyzes Current and Upcoming Trials of BTK Inhibitors

Peter Hillmen, MBChB, PhD

During a Targeted Oncology Case-Based Peer Perspectives event, Peter Hillmen, MBChB, PhD, professor of Experimental Haematology, University of Leeds, Honorary Consultant in Clinical, Haematology, Leeds Teaching Hospitals NHS Trust, discussed the case of 61-year-old patient with diffuse infiltration by chronic leukocytic leukemia (CLL).

Targeted Oncology^TM: What would your next options for this patient be? What factors affect these decisions?

HILLMEN: In my practice, we tend to put patients into clinical trials. We now have some choice, but we’ve been limited because we’re a socialized system [National Health Service], so there’s some control over drug usage. But we’ve had access to everything for deletion 17p [del(17p)]—acalabrutinib [Calquence] for del(17p) and venetoclax [Venclexta] and obinutuzumab [Gazyva] for all patients now. So this patient could be eligible for that.

In terms of the [patient’s comorbidities], I would tend to be concerned about the atrial fibrillation and the cardiac history. Our experience is that the worst outcomes in terms of the cardiac history [are usually with] men more than women, but she has a history of atrial fibrillation and she’s on treatment for hypertension, so those are 2 things that make me concerned. Looking at the real-world data of hypertension [on ibrutinib (Imbruvica)] is significant. The majority of patients have high blood pressure, so that’s a concern [as well].

The good side, from a BTK [Bruton tyrosine kinase] inhibitor perspective, is del(11q) seems to be positive in terms of outcomes, so most of the trials we have in the front line suggest that patients [with del(11q)] do better on a BTK inhibitor than the ones without del(11q). So that would slightly [push] you toward a BTK inhibitor.

Where does acalabrutinib fit into this setting?

It has been approved in Europe and is now funded in the United Kingdom. We don’t have any head-to-head comparison [yet]. The comparison between ibrutinib and acalabrutinib, the ACE-CL-006 trial [NCT02477696]...will report out the next few months. So we’ll have that head-to-head data, which will give us the safety angle between the 2 BTK inhibitors. I think the choice in most places [is treating with] ibrutinib versus venetoclax/obinutuzumab.

What kind of testing would you order for this patient?

TP53 mutation testing would be important, particularly if therapy depends on it. Next-generation sequencing would be preferable because of the sensitivity of the test being better [than others]. We know from [previous data] that even patients with a small proportion of TP53-mutated cells do as poorly as the ones with a large proportion. So, if we just do Sanger [sequencing], we’re going to miss those between 5% and 20% mutated alleles that [would make] those patients in our practice [eligible] to [receive] more therapies. Then there’s cyclin D1 for mantle cell lymphoma, but she’s CD23 positive, so it’s unlikely she would have mantle cell. We generally would do a cyclin D1 translocation test, but it’s driven by the lab to a large extent.

What would you have chosen from these polling options?

I voted for acalabrutinib, although I don’t know the head-to- head difference—I think we have to accept that. No one went for chemoimmunotherapy; I think if we had this question a year or 2 ago, we would probably all have been using chemoimmunotherapy. It’s been an amazing change.

How do the European Society for Medical Oncology (ESMO) guidelines suggest treating these patients?

The latest ESMO guidelines [show] for the fit patients with unmutated disease, you have a choice of ibrutinib, chemotherapy, and FCR [fludarabine, cyclophosphamide, rituximab (Rituxan)].¹ In the United Kingdom, we have venetoclax/obinutuzumab available for those patients. [The guidelines] don’t help me decide which ones to use particularly; it’s just a shopping list of choices, whereas our British Society guidelines tend to be prescriptive.

Does the addition of a CD20 antibody to a BTK inhibitor help?

Obinutuzumab probably has some additive effect, but if you’re not stopping the BTK inhibitor, what is the gain of obinutuzumab to acalabrutinib? I think most people are not adding obinutuzumab to acalabrutinib at the moment, particularly in the COVID-19 [coronavirus disease 2019] era. We don’t want our patients going to hospital for infusions, and that I think has swayed a lot of people away from venetoclax/obinutuzumab combination at the moment because of the escalation in the obinutuzumab.

Can you discuss the trial that looked at the combination of obinutuzumab and acalabrutinib?

In the ELEVATE TN trial [NCT02475681], we did have an arm with that combination.2 We had a number of patients in that arm of that trial and there were [a few who were] minimal residual disease [MRD] negative on the combination—they continued on acalabrutinib. We kept them in the trial. In fact, one of our patients has been MRD negative for 3 years. So I’m talking about whether we should stop the acalabrutinib for him...as it’s used at the moment, probably not because I don’t think we have the evidence in the phase 3 trials that we stop the treatment.

Biologically, we have data where we’ve added obinutuzumab to ibrutinib in the IcICLLe trial. When we add it later on when there’s less disease, we see eradication of disease in the majority of patients. So I think we’re using it at the wrong time—using it at the beginning is not the right time to use obinutuzumab, but that’s the way the trial is designed. We’re not stopping the acalabrutinib; I think if we’re going to go through the inconvenience for the patient and the cost of adding obinutuzumab, we need to stop treatment. I think it’s probably a strategy that would work.

The one exception [with] the ELEVATE-TN data is, there is a separation [of Kaplan-Meier curves] in terms of progression-free survival [PFS]. Although it’s significant...we can’t compare them because of how the trial [was designed]. If that was to translate into an overall survival [OS] difference, then we may want to add obinutuzumab, but it hasn’t shown that yet.

I’ve been saying to my patients who are starting on acalabrutinib that I don’t know what the advantage of adding obinutuzumab is to acalabrutinib. But there is a possibility it will have a fundamental effect in outcomes. If that’s the case, then maybe after 3 years we would add obinutuzumab to eradicate the disease and stop the therapy, but we need evidence that that’s an appropriate way to do it.

What other phase 3 trials have been published in this setting?

RESONATE-2 [NCT01722487] was a small frontline study with 269 patients.³ We need much bigger numbers to really look at the subsets. [Fifty-five patients receiving] chlorambucil crossed over to the extension.

This has the longest follow-up [of these] randomized trials, so chlorambucil is not an appropriate comparator anymore, but 18 months is quite long as a median PFS. Now we’re out further than [18.4 months follow-up]. Five-year follow-up [was still not reached for the ibrutinib arm and 15 months for chlorambucil (HR, 0.146; 95% CI, 0.098-0.218)].⁴

The median age was 71 or 72 depending on the arm. The majority of patients are still on treatment; two-thirds are still progression free. The thing we should say about progression on BTK inhibitors is that they don’t always immediately require alternative therapy. We have patients who technically progressed [to] B-cell CLL who remain on therapy for over a year and still benefit. So we need to find the next treatment in that setting.

If you look at the risk groups, patients with del(17p) were excluded from this trial. With chlorambucil, the patients with del(11q) did worse than the patients without [median PFS, 9 months and 18 months, respectively], whereas in the ibrutinib arm, [the median PFS was not reached for either]. These are patients with big nodes generally, and maybe that’s why we see nodal responses with ibrutinib. That’s intriguing, and it’s seen in a number of trials now.

It was the same thing with [IGHV status]; the patients with unmutated disease do worse than those with mutated disease. There’s no difference until about 4 years, and then there’s some separation, but there are not many patients out beyond about 4.5 years.

Please discuss other trials that looked at ibrutinib in these patients.

The ECOG1912 trial had a 2:1 randomization of ibrutinib/rituximab versus FCR.⁵ The design of these trials is [historic] because we were trying it with a chemotherapy. We weren’t worried about rituximab, but now you wouldn’t have rituximab in the combination. But at the time we didn’t know. This is continuous until disease progression.

The outcomes altered the field. The latest [median] follow-up we have is 34 months, which is short. The median age in this trial was 58, so this is the youngest group of patients we ever put into a trial. At the same time the Alliance study [NCT03737981] was open, and the elderly patients could go into that 3-arm trial.

PFS was a primary end point, with a hazard ratio of 0.39 [95% CI, 0.26-0.57; P <.0001]. But what’s surprising was the difference in OS. For the [OS] in this young group of patients, when we looked at the data, 91.5% is normally where we are. It wasn’t that the FCR arm was doing worse than we expect, it was that the ibrutinib arm was doing better. We need more follow-up from this trial, but it was significant, and that’s led to a big change in practice.

Was crossover allowed on this trial?

Crossover wasn’t part of the trial, but it was in the United States, so these drugs were available. Most of the patients went to targeted therapy, and most of them went to BTK inhibitor; so, effectively, yes, [they did cross over]. But the deaths were too early for crossover to benefit. We’ve seen this with other FCR trials; a small proportion of patients do not do very well and die of treatments or the disease. They’re probably already preordained as being [poor risk]. There was a small number of deaths, so you have to bear that in mind, but it seems to overcome that issue.

The RESONATE-2 trial had crossover. There was a difference in survival, as well, but that was in [elderly patients]. They don’t tolerate ineffective treatment and active disease. I think there were a lot of data supporting using the best treatments first.

How did patients with mutated IGHV status do compared with patients without the mutation?

I think this is going to be key to go forward. The unmutated population receiving ibrutinib did better than [those in] the FCR arm. There’s a large number of patents; it’s 2:1 randomized, so there’s a total of 210 patients who are unmutated in the ibrutinib/rituximab arm and 71 in the FCR arm.

Looking at the mutated population...70 and 44 patients [on ibrutinib/rituximab and FCR], respectively, so it’s not powered to show a difference in mutated statuses. The mutated hazard ratio was 0.42 [95% CI, 0.16-1.16]. It’s not significant.

Would you use rituximab for your patients?

The only time I would consider rituximab is probably in active autoimmune disease—autoimmune hemolytic [anemia] and immune thrombocytopenic purpura [ITP] perhaps. We normally control those complications first, anyway, if we can. We don’t have any direct evidence of using ibrutinib or any of the new drugs in active hemolysis or active ITP, although we have used it in a lot of patients who had previous or active immune problems, without it causing [more issues]. I’ve seen 1 or 2 immune complications occurring in people on ibrutinib, but I don’t think it was caused by ibrutinib. That’s when I would put them on rituximab.

Please describe the ELEVATE TN trial in more detail.

ELEVATE-TN was a big trial for a registration trial.² You need that [high] number of patients to look at the subgroups. This had 3 arms [for patients] unfit for FCR. The data we have are relatively short still, with 28.3 months’ follow-up.

The outcome [favored] the combination or acalabrutinib alone [over] obinutuzumab/chlorambucil, which is no great surprise. It is consistent across all trials. We can’t look beyond about 30 months, probably. The hazard ratio doesn’t cross 1.00. It was significant, but we couldn’t test it because of the way the trial was designed.

Some subgroups [favor] obinutuzumab and acalabrutinib. It isn’t surprising that they’re all positive in terms of PFS. There are subtle differences. In terms of the obinutuzumab/acalabrutinib, it adds to [the treatment]. The bulky disease [population had better response to the combination], so it may be in bulky disease patients you’ll see a better response. But it’s across the board in terms of the advantage of acalabrutinib over chlorambucil and obinutuzumab, at least.

I’m becoming interested in the mutated group for BTK inhibitors. There aren’t enough patients in this trial; there were only 58, 59, and 74 [in the acalabrutinib/obinutuzumab arm, acalabrutinib- only arm, and obinutuzumab/chlorambucil arm, respectively] with mutated disease. But it’s interesting that the mutated population, in terms of PFS, was not significant [with acalabrutinib monotherapy]. It’s not a large number of patients. We know chlorambucil/obinutuzumab does better in those patients. To see a difference is going to take longer.

We don’t see many complete remissions with acalabrutinib monotherapy at 28 months, but it will increase over time. But in RESONATE-2, it was up to 9% in the last follow-up out to 5.5 years.³

We see complete remission...with the addition of obinutuzumab. Some of these patients are MRD negative, so that probably means we have faster response with the combination, I would say.

The OS [showed] no significant differences, but the follow-up is short. We’re living in an era of crossover to other therapies.

Atrial fibrillation was about 3% total in this trial in either arm, 3% to 4%, which compares favorably against ibrutinib trials.... All the BTK inhibitors cause bleeding. I don’t think there’s any difference; this is a BTK effect, and the rest of it was tolerated. Hypertension is quite low, which I think is important. There’s guidance [being issued] on cardiac monitoring with BTK inhibitors, including doing EKGs regularly in all patients because the cardio-oncologist said that’s what we should do.

What other trials have looked at obinutuzumab?

CLL14 [NCT02242942] was a reasonably large trial, [with] 12 months of therapy between the 2 arms for fixed duration.⁶ [The updated data are] now at 52.4 months follow-up. With this regimen, we stop treatment in both arms at 12 months. There was a difference at 4 years [with a 4-year] PFS rate of 74% versus 35.4% [for venetoclax/obinutuzumab and obinutuzumab/ chlorambucil, respectively]. The time to next treatment...was at 81% at 4 years as opposed to 60% for the obinutuzumab/ chlorambucil treatment. That’s a pretty good outcome with chlorambucil/obinutuzumab.

With the IGHV-unmutated patients at 3 years, we’re down to about 75% to 80% [PFS rate with venetoclax/obinutuzumab].⁷ This wasn’t updated at the American Society of Hematology [ASH] meeting in December 2020. The key question here is re-treatment. Can we re-treat the patient with venetoclax and get them back in remission? The early data from ASH was you can’t, not very effectively, but that was on short duration of treatment. The patients relapse early. I don’t think we know the answer to that question.

In terms of TP53 mutations, it was about 60% PFS rate [with venetoclax/obinutuzumab], which is far inferior to the BTK inhibitors.

The MRD data [show]...in the peripheral blood it’s 76% [undetectable]; in the bone marrow, 57% [undetectable] with venetoclax/ obinutuzumab. That’s probably important because the obinutuzumab affects the blood more effectively than the marrow. In the chlorambucil arm, it was 35% versus 17% [respectively].

The [combination] was well tolerated. We see some neutropenia, 53% with venetoclax/obinutuzumab. Both drugs cause that. Febrile neutropenia was only 5% with venetoclax/obinutuzumab.

<sub><sup>REFERENCES:
1. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23-33. doi:10.1016/j.annonc.2020.09.019
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutu- zumab versus chlorambucil and obinutuzumab for treatment-naive chronic lympho- cytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
3.Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388
4. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibru- tinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x 5. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/ NEJMoa1817073
6. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial. Presented at: American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 127.
7. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225‐2236. doi:10.1056/ NEJMoa1815281</sup></sub>