CME
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: October 18, 2023
Expiration: October 17, 2024
Introduction
In this module, Catherine C. Coombs, MD, MS, of UCI Health and Toby Eyre, MBChB, MD, of the University of Oxford review key data from the Society of Hematologic Oncology (SOHO) 2023 Annual Meeting on the use of BTK inhibitors in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. A question will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Poll
Presurvey
Matching-Adjusted Indirect Comparison of 3 Randomized Phase III Trials of Ibrutinib for R/R CLL
Toby Eyre, MBChB, MD:
The first study from SOHO 2023 that we will discuss is a matching adjusted indirect comparison (MAIC) of 3 randomized phase III trials in relapsed/refractory (R/R) CLL that all included ibrutinib.1 The RESONATE trial compared ibrutinib with ofatumumab and supported the FDA approval of ibrutinib for patients with previously treated CLL.2 In addition, we have seen more recent important trials—the ALPINE trial3 of ibrutinib vs zanubrutinib and the ELEVATE RR trial4 of ibrutinib vs acalabrutinib—with some slightly different results in the performance of ibrutinib.
Catherine C. Coombs, MD, MS:
This study asks an interesting question: How has ibrutinib performed over time in all of the randomized studies that that have been completed in the relapsed CLL setting? As mentioned, an MAIC was done of 3 different randomized phase III trials where ibrutinib was used in 1 of the 2 arms: RESONATE, ALPINE, and ELEVATE RR.1 As we know, the dogma in medicine is that you should not do cross trial comparisons, yet they are being done—and perhaps more commonly so in recent years. Although these analyses are thought-provoking, certainly the gold standard is always a prospective randomized, controlled trial where the groups are truly balanced. When these MAICs are done, the groups are inherently different, so they make a statistical attempt to match the baseline characteristics. Although this is a way to equalize the playing field, it is an imperfect exercise.
MAIC of Ibrutinib: Selected Baseline Characteristics
Catherine C. Coombs, MD, MS:
Patients were matched based on several important clinical features—including age, presence of bulky disease, number of prior treatments, and cytogenetics—resulting in a RESONATE adjusted population to compare with the phase III trials using ibrutinib as the control arm: ALPINE (ibrutinib vs zanubrutinib) and ELEVATE RR (ibrutinib vs acalabrutinib).1
MAIC of Ibrutinib: ORR
Catherine C. Coombs, MD, MS:
The ORR was numerically higher for the RESONATE adjusted population compared with both ALPINE and ELEVATE RR. This difference did reach statistical significance in both comparisons, although to a greater effect when comparing the RESONATE-adjusted population with ALPINE.1
MAIC of Ibrutinib: PFS
Catherine C. Coombs, MD, MS:
Next, progression free survival (PFS) was evaluated, and I think this is particularly interesting. After ALPINE was reported, there was discussion about whether ibrutinib underperformed in this trial. So, in this MAIC of ibrutinib, it did show that when the RESONATE adjusted population was compared with ALPINE, the median PFS was higher (40.7 months vs 34.2 months). However, when comparing the RESONATE adjusted population with ELEVATE RR, there was no statistically significant difference in PFS, which suggests that perhaps ALPINE did have an underperformance of ibrutinib in the control population.1
MAIC of Ibrutinib: Impact on Practice
Catherine C. Coombs, MD, MS:
Now, what am I going to take from this study as far as my clinical practice? This analysis is not going to outweigh the findings from ALPINE, which in my view is a positive study—zanubrutinib did outperform ibrutinib. However, I think what it does reflect is how control arms can perform over time and how I will think about ibrutinib control arms in the future. With subsequent years in our history of CLL, I think it is not unexpected to see a change in PFS with ibrutinib, because the eras are very different.
RESONATE, being the oldest study, reflects a population of patients with CLL who had few, if any, good treatment options, so I think their motivation to stay on therapy is absolutely the highest. Now, as time goes on, our options for alternative therapies for our patients continue to evolve, and I think when a patient has many options, perhaps their motivation to stay on a therapy in the setting of toxicity becomes slightly lower because they have more therapies available in that setting. I think it is an interesting study—not practice changing but certainly thought provoking and data that I will consider with future studies using ibrutinib as a control arm with respect to its performance.
Toby Eyre, MBChB, MD:
Yes, absolutely. I very much concur with the change over time, HCP and patient preferences, and the way studies may be managed now. Of course, we very rarely get to see the postprotocol care data in significant granularity, so certainly that will be something I will be watching for when we hopefully see longer follow-up from ALPINE. How many of these patients did ultimately stop and switch to a second-generation BTK inhibitor outside of clinical studies, and were there any global disparities? That would be very interesting to see, and we will need to continue to monitor this space.
Meta-Analysis of Cardiovascular Adverse Events With Second-Generation BTK Inhibitors in CLL
Toby Eyre, MBChB, MD:
The second selected abstract is a systematic review and meta analysis of cardiovascular adverse events with second-generation BTK inhibitors.5 Now that we have multiple BTK inhibitor options, we scrutinize small differences in the rates of toxicities—and certainly cardiovascular adverse events such as atrial fibrillation—between therapies. Dr Coombs, could you talk through some of the key findings in this analysis?
Catherine C. Coombs, MD, MS:
The investigators in this study evaluated randomized phase II/III studies of acalabrutinib and zanubrutinib in CLL and subsequently included 5 trials that met eligibility for the meta analysis. The goal was to understand how these newer-generation BTK inhibitors are performing with respect to some of the key toxicities that we consider when using these medications, including cardiovascular adverse events and bleeding risk. The eligible studies were combined to assess toxicity among the second-generation BTK inhibitors vs the control arms, which differed across the trials.5
Meta-Analysis: CVAEs Leading to Death
Catherine C. Coombs, MD, MS:
They found a significant reduction in cardiovascular mortality, with an odds ratio of 0.16, favoring the safety profile of the second-generation BTK inhibitors vs their comparators.5
Meta-Analysis: Any Bleeding Events
Catherine C. Coombs, MD, MS:
We also know that these drugs can lead to significant bleeding events. The meta analysis found a significantly higher risk of any bleeding event in patients enrolled on studies in treatment-naive CLL, with an odds ratio of 6.18.5
Meta-Analysis: Major Bleeding Events
Catherine C. Coombs, MD, MS:
Similarly, they identified a higher risk of major bleeding, once again, in the population with treatment naive CLL, with an odds ratio of 2.84.5
Meta-Analysis of CVAEs With Second-Generation BTK Inhibitors in CLL: Impact on Practice
Catherine C. Coombs, MD, MS:
This is an interesting study combining the data that we have from our second-generation BTK inhibitors—acalabrutinib and zanubrutinib—demonstrating that they are better tolerated and certainly pose an advantage vs the predecessor comparator arms from these pooled studies. However, it is important to consider the bleeding risk, which I have found in practice to be similar among all available covalent BTK inhibitors. This is certainly a class effect, in my opinion, that one needs to watch out for when using these drugs.
Toby Eyre, MBChB, MD:
It is certainly an interesting observational study—although, as you stated, unlikely to change clinical practice. I do wonder whether there may be an effect of cumulative events occurring in patients receiving a BTK inhibitor in the frontline setting compared with R/R disease, where we know patients will be receiving a BTK inhibitor for a shorter period of time. So, I wonder if an adjustment needs to be made for the time receiving therapy, because to me that is an important part of an analysis such as this—but certainly intriguing and thought provoking data.
Catherine C. Coombs, MD, MS:
That is a good point, and with any study evaluating BTK inhibitors, it is important to understand if the reporting periods are equal and if they are being compared with a time-limited therapy such as bendamustine/rituximab. That type of granularity was not clear to me in this study.
BRUIN: Updated Results and Subgroup Analysis With Pirtobrutinib for Previously Treated MCL
Catherine C. Coombs, MD, MS:
Pivoting to MCL, the first study that we will discuss is the BRUIN trial.6 We have seen updated results from this study of pirtobrutinib in MCL.
Toby Eyre, MBChB, MD:
Pirtobrutinib is a noncovalent reversible BTK inhibitor that is highly selective with a very favorable pharmacokinetic profile. It is being evaluated across a range of B-cell malignancies in the phase I/II BRUIN trial. The primary analysis set of 90 patients with MCL has been presented6 and was published in the Journal of Clinical Oncology earlier this year.7 In the study, 200 mg once daily was determined to be the recommended phase II dose, and most patients have received that dose.7
BRUIN MCL: Baseline Characteristics
Toby Eyre, MBChB, MD:
When reviewing the baseline characteristics, these are heavily pretreated patients, nearly all of whom have been exposed to chemotherapy, an anti-CD20 monoclonal antibody, and a prior covalent BTK inhibitor. Among patients who received a prior covalent BTK inhibitor, the majority (82.2%) discontinued the BTK inhibitor because of progressive disease.6
BRUIN MCL: Response
Toby Eyre, MBChB, MD:
There was a small BTK naive cohort (n = 14), which provides some insight on how active this agent is in covalent BTK naive relapsed MCL, and the ORR in that subgroup was high at 85.7%. Now, with longer follow-up, the ORR was 56.7% in the group of patients previously treated with a covalent BTK inhibitor, with a complete response (CR) rate of 18.9%.6
BRUIN: DoR, PFS, and OS in Pretreated Patients With MCL per IRC Assessment
Toby Eyre, MBChB, MD:
Among patients pretreated with a covalent BTK inhibitor, the median duration of response was 17.6 months, and the median PFS was 7.4 months. So, if patients did respond, quite durable responses were observed, which is important given the clinical context. The median overall survival was approximately 2 years (23.5 months), which is certainly a positive finding, especially compared with how patients historically have done following failure of a covalent BTK inhibitor.6
BRUIN: DoR, PFS, and OS in High-Risk MCL Subgroups per IRC Assessment
Toby Eyre, MBChB, MD:
An interesting subanalysis that was presented was duration of response by high risk features: high Ki 67 and TP53 status. Now, an issue with this study was the small numbers being assessed here, and clearly more data need to be collated from these patients, and hopefully they will be in time. But in these small subgroups, there was no real difference in terms of duration of response according to risk,6 which suggests that pirtobrutinib may be as active in patients with higher-risk features. However, I think we certainly need more data before that is confirmed.
Assessment
BRUIN: Safety in MCL
Toby Eyre, MBChB, MD:
The safety data with pirtobrutinib look excellent to date. Although it is still a relatively short follow-up overall, the rates of discontinuation due to adverse events are very low (3% in the MCL cohort), and the rates of grade 3 toxicities are very minimal.6
BRUIN in MCL: Impact on Practice
Catherine C. Coombs, MD, MS:
I am interested to see what results from the phase III BRUIN-MCL-321 study (NCT04662255), where pirtobrutinib will be compared with investigator’s choice of covalent BTK inhibitor—acalabrutinib, ibrutinib, or zanubrutinib—in patients with MCL who are pretreated and BTK inhibitor naive. What are your thoughts on this study, and what would you expect given the promising responses in the small subset of patients with MCL who are BTK inhibitor naive in the BRUIN trial?
Toby Eyre, MBChB, MD:
This is a phase III superiority study of 500 patients with relapsed MCL—so innately a fairly brave study—and also will compare pirtobrutinib with the de facto standard of care. In Europe, ibrutinib is most commonly used, as it is approved by the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency. By contrast, in the United States, the second-generation BTK inhibitors acalabrutinib and zanubrutinib are very much at the forefront, especially with the recent FDA withdrawal of ibrutinib labeling for MCL. I suppose it is anticipated here that rates of discontinuation due to toxicity will be very low with pirtobrutinib. The reversible nature of pirtobrutinib and the pharmacokinetic profile, with the IC90 being exceeded across the entire 24 hour period,7 should lend itself well to being particularly active in more proliferative diseases. We have seen data in MCL and Richter transformation,8 and it appears very active as a monotherapy.
We need to continue to watch this space. The study is recruiting well, and we will not only have head to head data from an efficacy standpoint, but also very intriguing head to head data from a toxicity standpoint, which may have broader ramifications beyond MCL. So, this is an important study for numerous reasons.
ViPOR: Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide for R/R and TN MCL
Catherine C. Coombs, MD, MS:
The final study is the ViPOR trial combining venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide for 6 cycles in patients with R/R and treatment naive MCL.9 Dr Eyre, can you please touch on the findings that we have seen thus far from this study?
Toby Eyre, MBChB, MD:
Yes, this is an intriguing study designed in the National Cancer Institute. The ViPOR combination has been tested in a range of malignancies, including diffuse large B-cell lymphoma,10 and now we are seeing early data in MCL. This is an ongoing phase I/II study with a 3+3 design evaluating dose-escalation cohorts of venetoclax with fixed doses of ibrutinib, prednisone, obinutuzumab, and lenalidomide and then dose-expansion cohorts in R/R and treatment naive MCL.9
When you evaluate the existing literature, certainly venetoclax, ibrutinib, and lenalidomide are all active drugs in MCL. Historically, there have been challenges combining immunomodulatory drugs and BTK inhibitors in terms of toxicity, so one must be wary about this. Furthermore, an additional consideration with a multidrug regimen such as this is that there may be substantial financial toxicity.
Data were reported for 26 patients: 12 in the R/R setting and 14 in the frontline setting.9
ViPOR: Hematologic Adverse Events, Cycles (%)
Toby Eyre, MBChB, MD:
As expected, the main toxicities were hematologic, but rates of grade ≥3 cytopenias were relatively low.9
ViPOR: Grade ≥3 Nonhematologic Adverse Events, n (%)
Toby Eyre, MBChB, MD:
In terms of nonhematologic toxicities, the rates of grade ≥3 atrial fibrillation and rash were 8% and 12%, respectively, with low rates of infections and other toxicities observed. Dose reductions were required in 27% of patients, most of which were with lenalidomide (87%) and related to cytopenias, as would be expected. The majority (86%) of patients completed 6 cycles.9 So, this appears to be a manageable regimen to deliver in trial fit patients, and it does have the advantage of being fixed-duration therapy.
ViPOR: Change in Tumor Burden
Toby Eyre, MBChB, MD:
The CR rate in those who were evaluable for efficacy was 100%, which is impressive, and this included patients with high-risk features such as blastoid disease and TP53 mutations.9
ViPOR: Outcomes
Toby Eyre, MBChB, MD:
The outcomes appear durable to date, although longer follow-up certainly is needed.9
ViPOR: Interim MRD
Toby Eyre, MBChB, MD:
Minimal residual disease (MRD) also was assessed, and this was impressive, with a high rate of MRD negativity (95%) demonstrated.
Overall, the conclusions were that the fixed-duration ViPOR regimen resulted in high levels of undetectable MRD and CRs, including in high risk patients, in both the frontline and R/R settings. The combination does appear to be safe. No dose-limiting toxicities were observed, and there were no reports of tumor lysis syndrome.9 Some patients had to dose attenuate, but overall it appeared to be a manageable regimen.
ViPOR: Impact on Practice
Toby Eyre, MBChB, MD:
Whether this regimen gains any momentum moving forward in terms of a genuine development pathway beyond an academic study I think is up for debate, but clearly if you carefully manage a protocol, you can combine numerous active drugs together in a regimen such as this.
Catherine C. Coombs, MD, MS:
Yes, given the number of novel agents evaluated in combination here, I do have concerns about cost, but the tolerability is definitely better than I would have anticipated.
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