CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 17, 2023
Expiration: April 16, 2024
ALPINE: Final Analysis of Zanubrutinib vs Ibrutinib for R/R Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
John M. Burke, MD:
We will now discuss 3 important trials in CLL.
As background, BTK is an important component of the B-cell antigen receptor signaling pathway, and this pathway is necessary for the proliferation of CLL/SLL cells.47 Ibrutinib, a first-generation BTK inhibitor, is approved by the FDA for use in CLL/SLL. However, approximately 20% of patients discontinue treatment with ibrutinib because of AEs, and the levels of the drug in plasma drop below half-maximal inhibitory levels between dosing intervals. Compared with ibrutinib, zanubrutinib is a second-generation BTK inhibitor with a higher specificity for BTK and better exposure coverage. In the phase III SEQUOIA trial, zanubrutinib demonstrated superior PFS compared with CIT in treatment-naive patients with CLL/SLL and those without del(17p).48
ALPINE is a randomized, open-label phase III trial comparing single-agent zanubrutinib vs ibrutinib in 652 patients with R/R CLL/SLL who have received ≥1 previous systemic therapy. At ASH 2022, the final analysis of the efficacy and safety data from ALPINE was reported after a median follow-up of 29.6 months.49,50
ALPINE: Baseline Characteristics
John M. Burke, MD:
Of the 652 patients enrolled on the trial, 327 and 325 were randomly assigned to receive zanubrutinib and ibrutinib, respectively. In general, the baseline characteristics were well balanced between arms.
On the zanubrutinib arm, the median age was 67 years (range: 35-90), and on the ibrutinib arm, the median age was 68 years (range: 35-89). On both treatment arms, patients had received a median of 1 previous line of therapy; 7.3% of patients on the zanubrutinib arm had received >3 prior lines of therapy compared with 9.2% of patients on the ibrutinib arm. On both treatment arms, approximately 23% of patients harbored del(17p) and/or TP53 mutations, and approximately 73% had unmutated IGHV.
ALPINE: Investigator-Assessed PFS in ITT Population
John M. Burke, MD:
In ALPINE, the investigator-assessed PFS in the intention-to-treat (ITT) population was tested hierarchically, because the primary endpoint of noninferiority and superiority of investigator-assessed ORR was met and previously reported in the first interim analysis of the study.51
In the final analysis reported at ASH 2022, the investigator-assessed 2 year PFS rate in the ITT population favored zanubrutinib at 78.4% compared with 65.9% for ibrutinib (HR: 0.65; 95% CI: 0.49-0.86; P = .002). The 2-year PFS rates by an independent review committee (IRC) were similar at 79.5% and 67.3% for zanubrutinib and ibrutinib, respectively (HR: 0.65; 95% CI: 0.49-0.86; P = .0024). In addition, zanubrutinib demonstrated superior PFS benefit compared with ibrutinib across all major subgroups, including patients with CLL/SLL harboring unmutated IGHV (HR: 0.64; 95% CI: 0.47-0.87).
ALPINE: Investigator-Assessed PFS in ITT Population (cont'd)
ALPINE: Investigator‑Assessed PFS in Patients With del(17p) and/or TP53 Mutation
John M. Burke, MD:
The 2-year PFS rates by investigator assessment in the subgroup of patients with del(17p) and/or TP53 mutations were significantly improved with zanubrutinib vs ibrutinib: 72.6% vs 54.6% (HR: 0.53; 95% CI: 0.31-0.88). When assessed by IRC, the 2-year PFS rates in this patient population were similar at 77.6% for zanubrutinib vs 55.7% for ibrutinib (HR: 0.52; 95% CI: 0.30-0.88).
ALPINE: Response
John M. Burke, MD:
The ORR was significantly higher with zanubrutinib compared with ibrutinib: 86.2% vs 75.7% (P = .007). More patients on the ibrutinib arm achieved PR with lymphocytosis (7.4%) compared with those on the zanubrutinib arm (5.5%).
ALPINE: Investigator-Assessed OS
John M. Burke, MD:
After a median follow-up of 29.6 months, there was no significant difference in OS. However, there were more deaths in the ibrutinib arm vs the zanubrutinib arm: 48% vs 60% (HR: 0.76; 95% CI: 0.51-1.11). The median OS had not been reached in either arm at the time of data cutoff.
ALPINE: Safety
John M. Burke, MD:
There were fewer serious AEs, dose reductions, dose interruptions, and treatment discontinuations among patients on the zanubrutinib arm compared with the ibrutinib arm. Neutropenia was more common on the zanubrutinib arm, whereas diarrhea was more common on the ibrutinib arm. The incidence of hypertension was relatively similar between the treatment arms.
ALPINE: Cardiac Events
John M. Burke, MD:
Overall, there were fewer cardiac AEs with zanubrutinib (21.3%) compared with ibrutinib (29.6%). The incidence of serious cardiac AEs was 1.9% with zanubrutinib vs 7.7% with ibrutinib. Furthermore, there were no fatal cardiac events with zanubrutinib compared with 6 (1.7%) deaths on the ibrutinib arm. Of note, the incidence of atrial fibrillation or flutter of any grade with zanubrutinib was 5.2% vs 13.3% with ibrutinib.
ALPINE: Cardiac Events (cont'd)
ALPINE: Clinical Implications
John M. Burke, MD:
In conclusion, zanubrutinib yielded a higher ORR, better PFS, and a more favorable safety profile compared with ibrutinib in patients with R/R CLL/SLL. In my clinical practice, I no longer start patients with R/R CLL/SLL on ibrutinib. Between ibrutinib and zanubrutinib, zanubrutinib is my preferred option. Although the ALPINE trial did not investigate acalabrutinib, it is important to point out that acalabrutinib remains a reasonable choice in the setting of R/R CLL/SLL.
Peter Martin, MD:
Those are great conclusions and, like you, I no longer treat my patients with R/R CLL/SLL with ibrutinib. The ALPINE results are interesting on many levels. A particularly interesting question that arises from the ALPINE trial is: Why would one BTK inhibitor be better than another? If that question can be answered, we may have some clues as to how to better target the BTK pathway in the future. In the past, I thought there was no big need to further develop BTK inhibitors. Apparently, I was wrong—and now I am further convinced that there is still some mystery around targeting BTK, and the ALPINE trial somewhat suggests to me that there may be opportunities to better target BTK.
John M. Burke, MD:
Do you think there is more to the differences in the results than just the differences in the selectivity of these 2 agents for BTK?
Peter Martin, MD:
Yes, I do. I think some of these BTK inhibitors may actually elicit superior activity beyond selectivity and tolerability, although there is no proof of this. Nonetheless, with the emerging data from clinical trials of noncovalent BTK inhibitors and BTK degraders, I think all of these approaches may reveal different results. In summary, the field of BTK inhibitors is turning out to be much more interesting than we may have previously thought.
CAPTIVATE: 5-Year Follow-up of Continued Ibrutinib vs Placebo in Patients With CLL/SLL and uMRD After 1L Ibrutinib + Venetoclax
John M. Burke, MD:
CAPTIVATE is a phase II trial assessing the safety and efficacy of first-line ibrutinib and venetoclax in patients with CLL/SLL (NCT02910583). At ASH 2022, Allen and colleagues52 presented an update of the MRD cohort of CAPTIVATE, where patients who achieved confirmed uMRD in the peripheral blood and bone marrow after receiving 3 cycles of ibrutinib during the lead-in phase followed by 12 cycles of ibrutinib and venetoclax were randomly assigned to receive either placebo or ibrutinib. Patients without confirmed uMRD were randomly assigned to receive either ibrutinib or ibrutinib in combination with venetoclax.
Primary analysis of results from the confirmed uMRD cohort showed a 1-year disease-free survival (DFS) rate (the primary endpoint) of 95% with continued placebo compared with 100% with continued ibrutinib after a median follow-up of 31.3 months (P = .15).53 A subsequent analysis with a median follow-up of 38.2 months continued to show no significant difference between the 2 arms, with a 2-year DFS rate of 95% with continued placebo vs 100% with continued ibrutinib (P = .1573).54 At ASH 2022, long-term efficacy and safety results after 5 years of follow-up in this cohort of patients were presented.52
CAPTIVATE MRD Cohort Update: Baseline Characteristics
John M. Burke, MD:
Of the 164 patients on the CAPTIVATE trial who received first-line ibrutinib followed by ibrutinib and venetoclax, 86 achieved confirmed uMRD, of whom 43 were randomly assigned to receive either continued ibrutinib or placebo. The median age was 56 years (range: 34-69) on the ibrutinib arm and 61 years (range: 43-69) on the placebo arm. By chance, there were significantly more patients on the ibrutinib arm with del(17p) and/or TP53 mutations compared with the placebo arm (30% vs 5%). There also were more patients with a complex karyotype on the ibrutinib arm compared with the placebo arm (30% vs 9%). On the other hand, a larger number of patients on the placebo arm had Rai stage III/IV disease compared with the ibrutinib arm (35% vs 19%).
CAPTIVATE MRD Cohort Update: 3-Year DFS (Primary Endpoint)
John M. Burke, MD:
Post randomization, the 3-year DFS rate was 93% with ibrutinib vs 85% with placebo (HR: 0.435; 95% CI: 0.131-1.446; P = .1621). With respect to the previously reported 1-year DFS (the primary endpoint) and 2-year DFS rates in patients with confirmed uMRD, there continues to be no significant difference between the 2 arms at 3 years post randomization.53,54 In patients with del(17p), TP53 mutations, or complex karyotype, 3-year DFS rates were similar to the overall population.52
CAPTIVATE MRD Cohort Update: PFS and OS (Secondary Endpoints)
John M. Burke, MD:
At 4 years post randomization, there was no significant difference in PFS or OS rates between the 2 arms. The 4-year PFS rates were 95% with ibrutinib and 88% with placebo, whereas the 4-year OS rates were 98% with ibrutinib and 100% with placebo.
The 4-year PFS rate in patients with unmutated IGHV was similar to that reported in the overall patient population. Likewise, the 4-year PFS and OS rates among patients with del(17p), TP53 mutations, or complex karyotype were similar to that reported in the overall population.
CAPTIVATE MRD Cohort Update: CR Rate (Secondary Endpoint)
John M. Burke, MD:
Of interest, some patients on the placebo arm converted from PRs to CRs despite not receiving any treatment, which resulted in a 12% improvement in the CR rate from pre randomization to 3 years post randomization. Approximately the same number of patients on the ibrutinib arm (14%) also converted from PRs to CRs over time. In my opinion, this may be because of measurement variations on the scans. For example, a 1.6-cm node may have been remeasured as 1.5 cm, which then allowed the patient to be reclassified. Of note, however, this is purely speculation on my part.
CAPTIVATE MRD Cohort Update: CR and MRD Status (Secondary Endpoints)
John M. Burke, MD:
On both treatment arms, the rate of MRD negativity dropped from 100% at the time of randomization to 75% on the ibrutinib arm and 74% on the placebo arm at 3 years post randomization. Overall, there was no difference in the rate of MRD negativity between the arms.
CAPTIVATE MRD Cohort Update: Safety
John M. Burke, MD:
In general, there was a little more arthralgia and hypertension in the ibrutinib group compared with the placebo group. However, post randomization, there does not appear to be any significant difference in the incidence of neutropenia, diarrhea, or atrial fibrillation between the treatment arms.
CAPTIVATE MRD Cohort Update: Clinical Implications
John M. Burke, MD:
I think these data will guide the use of the doublet combination of ibrutinib/venetoclax, if the combination receives approval in CLL/SLL. It appears that patients who discontinue ibrutinib after 1 year of receiving the ibrutinib/venetoclax combination and achieving confirmed uMRD do well over time. At this point, it is unclear whether patients who discontinue ibrutinib will relapse any sooner than those who continue to receive ibrutinib, but a longer follow-up of the CAPTIVATE trial should answer this question.
For healthcare professionals today, I would say that if the ibrutinib/venetoclax combination receives approval as initial therapy for patients with CLL/SLL, discontinuing treatment with ibrutinib after 1 year is reasonable. However, it is uncertain whether patients will need to achieve confirmed uMRD to prove that they can discontinue treatment or whether stopping treatment without MRD testing, as was done in the phase III GLOW trial of fixed-duration ibrutinib/venetoclax, will be sufficient.55
Phase II Trial: Updated Results of Frontline Acalabrutinib/Venetoclax/Obinutuzumab in Patients With Untreated High-Risk CLL
John M. Burke, MD:
To set the stage for the last study we will discuss, I would like to note that management of patients with high-risk CLL/SLL, including those with TP53-altered disease, remains a challenge. The phase III ELEVATE-TN trial demonstrated that the combination of acalabrutinib/obinutuzumab as frontline therapy for patients with CLL significantly prolonged PFS and resulted in lower rates of AEs compared with chlorambucil/obinutuzumab.56 Benefit with acalabrutinib/obinutuzumab was demonstrated in patients with high-risk disease, including those with TP53 mutations. Furthermore, several phase II studies of triplet regimens including a BTK inhibitor, venetoclax, and obinutuzumab have demonstrated encouraging results in patients with previously untreated and R/R CLL/SLL with and without TP53 alterations.57-59
This single-arm phase II trial evaluated frontline triplet therapy with AVO for patients with CLL/SLL with and without high-risk genetic features (NCT03580928). In this trial, patients with uMRD in the bone marrow after fixed-duration treatment could elect to discontinue treatment. Patients whose bone marrow showed MRD positivity and thus continued with 9 cycles of doublet acalabrutinib/venetoclax were divided into 2 cohorts. Patients on cohort 1 (initial cohort) were unrestricted by genetic risk, whereas cohort 2 (expansion cohort) was enriched for patients with disease harboring TP53 alterations. In addition, patients on this trial were required to receive prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex virus/varicella zoster virus, which, to my knowledge, has not been a standard requirement in most frontline CLL/SLL studies of novel agents.
Data from the initial cohort (cohort 1) of patients with CLL/SLL with and without high-risk genetic features were reported previously.61 At ASH 2022, updated results from the initial cohort (cohort 1) with a longer follow-up, as well as data from the expansion cohort (cohort 2), were reported.60
Frontline AVO in High-Risk CLL: Baseline Characteristics
John M. Burke, MD:
In both cohorts, 68 patients were enrolled and treated on the trial, with a median age of 63 years (range: 36-80). The baseline characteristics are indicative of the high-risk features harbored by this patient population. Overall, the majority of the patients on the trial had a TP53 mutation: 60.3% had del(17p) and/or TP53 mutations, 41.2% had both del(17p) and TP53 mutations, 14.7% had TP53 mutations only, 4.4% had del(17p) only, 73.5% had unmutated IGHV, and 16.7% had a complex karyotype.
Frontline AVO in High-Risk CLL: Efficacy at Cycle 16
John M. Burke, MD:
The primary endpoint of the study was CR rate with uMRD in the bone marrow (BM-uMRD-CR rate) after 15 cycles (cycle 16, Day 1). Among 56 evaluable patients who had reached cycle 16 of treatment at the time of the analysis, the BM-uMRD-CR rate was 43%, and in the 29 evaluable patients with TP53 alterations, the BM-uMRD-CR rate was 45%.
The CR and PR rates in all 56 evaluable patients were 48% and 50%, respectively, whereas the CR and PR rates in the 29 evaluable patients with TP53 alterations were 52% and 48%, respectively.
Frontline AVO in High-Risk CLL: MRD Status at Cycle 16
John M. Burke, MD:
Among all evaluable patients, the rate of uMRD at cycle 16 was 86% in the peripheral blood, and this was equivalent to that achieved in the bone marrow. This provides more evidence that in CLL/SLL, uMRD results in the peripheral blood usually are similar to that in the bone marrow after approximately 1 year of therapy. In addition, the rates of uMRD were in the 80% to 90% range regardless of TP53 mutation status at cycle 16. In all evaluable patients, given that the uMRD rate was twice the BM-uMRD-CR rate, it could be concluded that at cycle 16, approximately one half of these patients had achieved PR by iwCLL criteria.62
Frontline AVO in High-Risk CLL: Response at Cycle 25 (Exploratory Endpoint)
John M. Burke, MD:
Exploratory analysis of clinical response rates at cycle 25 in 45 evaluable patients demonstrated a CR rate of 44%, a PR rate of 51%, and uMRD rates of 89% in the peripheral blood and 84% in the bone marrow. These results are relatively similar to those achieved at cycle 16.
Frontline AVO in High-Risk CLL: Safety
John M. Burke, MD:
The most common AE with the AVO triplet combination was headache, which was reported in 78% of patients. It is highly likely that the headaches were caused by acalabrutinib. It is not surprising that infections and COVID-19 infections occurred in 31% and 9% of patients, respectively. Of note, the rate of atrial fibrillation was low at 3%, and there were no ventricular arrhythmias. Of interest, none of the patients experienced febrile neutropenia.
Frontline AVO in High-Risk CLL: Survival
John M. Burke, MD:
Four patients experienced disease progression; for 3 patients, this was because of Richter transformation to HL (n = 2) and DLBCL (n = 1). There was 1 death on study from COVID-19 pneumonia.
At a median follow-up of 35 months, 67 patients (98.5%) were alive, 63 (92.6%) of whom were progression free and alive.
Frontline AVO in High-Risk CLL: Clinical Implications
John M. Burke, MD:
Based on these results, I would conclude that the AVO triplet appears to be effective and reasonably well tolerated by patients with newly diagnosed CLL. Previous studies of triplet therapy containing a BTK inhibitor, a BCL2 inhibitor, and an anti CD20 antibody all have shown that these triplet regimens are safe and effective. As yet, it is not clear whether patients clinically benefit from receiving a triplet combination vs a doublet combination or perhaps even a single agent BTK inhibitor. A remaining question pertains to how best to sequence all these agents and combinations. Ongoing randomized studies are attempting to answer these questions, but so far, none has provided conclusive answers to guide us on how to incorporate triplet regimens into clinical practice. I think the triplet combinations remain interesting and should be investigated in clinical trials, but I am not using them routinely in clinical practice until the results of ongoing randomized trials become available.
Peter Martin, MD:
I agree. In my clinical practice, I still use single agent BTK inhibitors for most of my patients with previously untreated CLL/SLL, although I recognize that the combination of venetoclax/obinutuzumab is effective. However, I will be happy to change my practice to using doublets or even triplets when the ongoing trials are completed and results are available. At present, however, I am keeping the treatment of my patients simple.
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