CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: May 10, 2022
Expiration: May 09, 2023
Peter Martin, MD:
BTK inhibitors are a preferred first-line treatment for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Zanubrutinib is a selective second-generation BTK inhibitor that demonstrated promising activity in R/R CLL/SLL in the phase III ALPINE trial, with improved PFS and a lower rate of atrial fibrillation compared with ibrutinib.20 The SEQUOIA trial is an open‑label, part randomized phase III trial that evaluated zanubrutinib vs bendamustine in combination with rituximab for patients aged 65 years or older with previously untreated CLL/SLL.21 All patients were unsuitable for treatment with fludarabine in combination with cyclophosphamide and rituximab. The SEQUOIA trial included 3 patient cohorts. Cohort 1 included 450 patients without del(17p) by fluorescence in situ hybridization, who were randomized to receive either zanubrutinib or bendamustine/rituximab for up to 6 cycles. Cohort 2 included 100 patients with del(17p) who received zanubrutinib monotherapy. Cohort 3 included patients with del(17p) who received zanubrutinib in combination with the BCL2 inhibitor venetoclax. The focus of the presentation at ASH 2021 was primarily on cohort 1, but it also touched briefly on cohort 2. The primary endpoint for cohort 1 was PFS by independent review.
Peter Martin, MD:
The patient characteristics for cohort 1 reflect the study as designed and were balanced across both treatment arms. Of note, even though patients with del(17p) were excluded from this cohort, approximately 6% of the patients harbored TP53 mutations and approximately half of the patients had an unmutated IGHV gene.
Peter Martin, MD:
The study met its primary endpoint, which was to demonstrate a significant difference in PFS between the treatment arms. The 2-year PFS was 85.5% in the zanubrutinib arm vs 69.5% in the bendamustine/rituximab arm (HR: 0.42; 95% CI: 0.27-0.63; P <.0001). Of note, the curves continue to diverge even after 2 years.
Peter Martin, MD:
The PFS benefit with zanubrutinib was seen across all patient subgroups analyzed—regardless of age, disease stage, performance status, and tumor bulk. The PFS difference between treatments may be less significant in patients with mutated IGHV status, although the number of patients with that prognostic marker who experienced an event was quite low.
Peter Martin, MD:
Of interest, at a median follow-up of 26.2 months, there was no difference observed in OS between the treatment arms. Based on the curves, it does not look like there will be a difference in OS between the treatment groups even with extended follow-up.
Peter Martin, MD:
As expected, the safety of zanubrutinib was generally better than that observed with bendamustine/rituximab. Patients treated with zanubrutinib had fewer grade ≥3 adverse events, fewer serious adverse events, and fewer adverse events leading to dose interruptions or delays, dose reductions, or treatment discontinuation.
Peter Martin, MD:
Atrial fibrillation is a particular adverse event of interest with BTK inhibitors. There was a slightly higher number of any grade atrial fibrillation in the zanubrutinib arm (3.3%) vs bendamustine/rituximab (2.6%), but it does not appear that this difference will be statistically significant. It is important to remember that patients received zanubrutinib until disease progression or unacceptable toxicity, whereas bendamustine/rituximab was administered for only 6 x 28-day cycles. An adverse event that was clearly more frequent in the zanubrutinib arm was bleeding. All-grade bleeding occurred in 45% of patients in the zanubrutinib arm vs 11% of patients in the bendamustine/rituximab arm, and there was a slightly higher incidence of major bleeding in 5% of patients who received zanubrutinib vs 1.8% in the bendamustine/rituximab arm. These observations are, however, consistent with the mechanism of action of BTK inhibitors.
Peter Martin, MD:
Cohort 2 of this trial is probably the largest single study cohort of patients with de novo CLL harboring del(17p) who were treated with a single-agent BTK inhibitor. The PFS outcomes are excellent, and this is consistent with the results from other studies of a BTK inhibitor in this patient population.
Peter Martin, MD:
In summary, SEQUOIA is an important registrational trial that clearly demonstrated the superiority of zanubrutinib over bendamustine/rituximab in previously untreated CLL/SLL without del(17p) (cohort 1). The lack of a difference in OS between arms is similar to outcomes seen in clinical trials of other single-agent BTK inhibitors, such as the Alliance A041202 trial of ibrutinib in untreated patients aged 65 years or older with CLL.22 It appears that it will be increasingly difficult to demonstrate differences in OS in an era when patients can ultimately receive BTK or BCL2 inhibitors after experiencing disease progression following chemoimmunotherapy. It is particularly notable that in patients with IGHV unmutated disease, there was a very large difference in PFS outcomes between treatment arms (HR: 0.24; 95% CI: 0.13-0.43). The era of chemotherapy in IGHV unmutated CLL is clearly over. In addition, the PFS results in patients with del(17p) (cohort 2) who received zanubrutinib monotherapy are clearly supportive of the role of BTK inhibitors in that population.
John M. Burke, MD:
I agree that the SEQUOIA trial results are important for physicians to know about. The hope is that the SEQUOIA trial results will lead to FDA approval of zanubrutinib in the frontline setting, joining ibrutinib and acalabrutinib to give 3 BTK inhibitor options for frontline use in CLL/SLL. Zanubrutinib has a slightly different toxicity profile than the other BTK inhibitors, with less atrial fibrillation compared with ibrutinib, less headache compared with acalabrutinib, and no restriction on concurrent use with proton pump inhibitors as acalabrutinib currently has, which may make it an appropriate treatment choice for many patients with CLL/SLL in the frontline setting.
John M. Burke, MD:
In addition to BTK inhibitors, the use of the BCL2 inhibitor venetoclax is standard of care for CLL requiring treatment. Early evidence suggests that combining a BTK inhibitor with a BCL2 inhibitor may elicit synergistic activity. The randomized phase II CAPTIVATE study is one of several trials exploring the combination of ibrutinib with venetoclax in patients with treatment‑naive CLL. In this trial, 164 patients younger than 70 years were initially treated for 3 months with ibrutinib, after which venetoclax was added for 1 year. Patients who achieved a confirmed undetectable MRD at 1 year were randomized to receive either ibrutinib monotherapy (n = 43) or placebo (n = 43). Those patients who did not achieve a confirmed undetectable MRD at 1 year were randomly assigned to receive ibrutinib monotherapy (n = 31) or to continue to receive the combination of ibrutinib with venetoclax (n = 32). Undetectable MRD was defined as having <10-4 CLL cells on 3 consecutive flow cytometry tests in both peripheral blood and bone marrow. The primary endpoint of the study was 1-year DFS rate in patients with confirmed undetectable MRD.
The primary analysis of the CAPTIVATE trial, presented at ASH 2020 and recently published, demonstrated a 1-year DFS rate of 95% to 100% in patients with confirmed undetectable MRD, regardless of whether they received ibrutinib or placebo.23,24 At ASH 2021, Ghia and colleagues25 presented results from the cohort of patients with confirmed undetectable MRD and those without a confirmed undetectable MRD after 1 year of additional follow-up
John M. Burke, MD:
It is worth noting that within the group of patients with confirmed undetectable MRD, patients harboring TP53 mutations of del(17p) or those with a complex karyotype were more common on the ibrutinib‑treated arm compared with those on the placebo arm.
John M. Burke, MD:
Similar to the previously reported 1-year DFS rates in patients with confirmed undetectable MRD who were randomized to receive ibrutinib or placebo, the 2-year DFS rates remained the same in this patient population with a 2-year DFS rate of 95.3% in the placebo group and 100% in the ibrutinib group. There were no additional relapses or deaths during the second year after randomization.
John M. Burke, MD:
The PFS curves look similar to the DFS curves. In patients with confirmed undetectable MRD, the 3-year PFS rate was 95.3% in the placebo group and 100% in the ibrutinib group. Among patients without confirmed undetectable MRD, there was no difference in the 3-year PFS rate. Regardless of whether ibrutinib was administered alone or in combination with venetoclax, the 3-year PFS was 96.7%.
John M. Burke, MD:
In patients with confirmed undetectable MRD, continuing ibrutinib led to a slightly higher CR rate compared with stopping all therapy. At 2 years after randomization, the CR rates were 72% among patients who received ibrutinib and 60% among those who received placebo.
In patients without confirmed undetectable MRD after 1 year of doublet therapy, continuing the doublet resulted in greater improvements in CR rates compared with dropping venetoclax and continuing ibrutinib alone.
John M. Burke, MD:
Similarly, in patients who did not achieve undetectable MRD in the peripheral blood and in the bone marrow after 1 year of the ibrutinib/venetoclax doublet, continuing the doublet improved the rate of undetectable MRD compared with discontinuing venetoclax and continuing with single-agent ibrutinib.
John M. Burke, MD:
During the overall conduct of the study, the most common grade 3/4 toxicities were neutropenia (36%), hypertension (10%), thrombocytopenia (5%) and diarrhea (5%). In the overall population, atrial fibrillation occurred in 10% of patients, and major hemorrhage was reported in 2% of the patients. There were modest differences in toxicities between the groups after randomization. For instance, by 13-24 months post randomization, the rates any-grade neutropenia in patients treated with the ibrutinib–venetoclax doublet and with ibrutinib monotherapy were 15% and 3%, respectively.
John M. Burke, MD:
A total of 12 patients experienced disease progression after receiving fixed-duration treatment with the ibrutinib–venetoclax doublet and were retreated with ibrutinib. The median follow-up after restarting ibrutinib was 4.9 months. Out of the 12 retreated patients, all 9 patients who were evaluable for response assessments achieved a partial response. Of note, 6 of the responders had high-risk disease with 2 harboring del(17p) and 4 harboring complex karyotypes.
John M. Burke, MD:
The updated results from the CAPTIVATE trial provide additional information on the efficacy and safety of the combination of ibrutinib with venetoclax. Patients with confirmed undetectable MRD have the same 2-year DFS and PFS whether they stop all therapy (receive placebo) or continue ibrutinib. In patients without confirmed undetectable MRD, the 3-year PFS rate is high and equivalent irrespective of whether patients continue doublet therapy or drop venetoclax and continue ibrutinib.
How should these results be applied to practice? First, we await the FDA approval of the ibrutinib–venetoclax doublet. My guess is that such an approval will be forthcoming based on the results of the GLOW study. Then, we need to decide how long patients should take the doublet beyond 1 year. Options include stopping all therapy at 1 year in all patients or using MRD to guide treatment decisions. Based on CAPTIVATE, it would seem justified to stop all therapy in patients with undetectable MRD. In my opinion, it is less clear whether patients who do not achieve undetectable MRD at 1 year should stop therapy, continue the doublet (which achieves better rates of undetectable MRD), or switch to single-agent ibrutinib (which still leads to excellent PFS).
The CAPTIVATE trial results confirm that the combination of ibrutinib and venetoclax is safe with a manageable safety profile, and the trial results shed more light on what toxicities to expect with this combination.
Peter Martin, MD:
An interesting observation about the CAPTIVATE study is that some of the patients without confirmed undetectable MRD after the initial 15 months of treatment who were subsequently randomized to receive either ibrutinib alone or in combination with venetoclax later achieved undetectable MRD after 1 year of follow-up. In fact, the increase in the achievement of undetectable MRD in this population of patients was more pronounced in the ibrutinib plus venetoclax arm with an improvement from 31% prerandomization to 66% after 1 year of receiving treatment post randomization. Beyond 1-year post randomization, however, there was no additional treatment benefit regarding the percentage of patients who achieved undetectable MRD. This suggests that there may not be a role for longer duration dual therapy with ibrutinib and venetoclax and that some patients may subsequently achieve MRD‑negative status.
Peter Martin, MD:
The randomized phase III GLOW trial also evaluated survival and MRD outcomes after fixed-duration ibrutinib and venetoclax. In the GLOW trial, however, the combination was compared with chlorambucil plus obinutuzumab in patients with previously untreated CLL/SLL without del(17p) or known TP53 mutations. In total, 211 patients older than 65 or younger than age 65 with a high cumulative illness rating scale (CIRS) score (>6) or renal dysfunction were enrolled on the study.26
A primary analysis of the results from the GLOW trial at a median follow-up of 27.7 months previously showed superior PFS as assessed by an independent review committee with ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab.27 In the primary analysis, the median PFS was not reached in the ibrutinib plus venetoclax arm compared with 21 months in the chemotherapy arm (HR: 0.216; 95% CI: 0.131-0.357; P <.0001). At ASH 2021, MRD outcomes of the GLOW trial were reported after a median follow-up of 34.1 months.26
Peter Martin, MD:
With longer follow-up, ibrutinib/venetoclax continued to show superior PFS compared with chlorambucil/obinutuzumab. The 30-month PFS rate was 80.5% with ibrutinib/venetoclax vs 35.8% with chlorambucil/obinutuzumab (HR: 0.212; 95% CI: 0.129-0.349; P <.0001). The PFS benefit with ibrutinib/venetoclax was seen across multiple response categories with a 30-month PFS rate that was greater than 85% in patients who achieved a CR or CR with incomplete bone marrow recovery with the ibrutinib/venetoclax combination. On the other hand, most of the patients on the chlorambucil/obinutuzumab arm who achieved a partial response had experienced disease progression at the median follow-up of 34.1 months. At the median follow-up of 34.1 months, there were 11 deaths in the ibrutinib/venetoclax arm vs 16 deaths in the chlorambucil/obinutuzumab arm (HR: 0.76; 95% CI: 0.35-1.64).
Peter Martin, MD:
MRD was measured using next-generation sequencing with cutoffs of <10-4 and 10-5 in the peripheral blood and bone marrow at the end of treatment plus 3 months (EOT+3). At EOT+3, the rates of undetectable MRD were significantly higher in the ibrutinib/venetoclax arm than in the chlorambucil/obinutuzumab arm in both peripheral blood and bone marrow at both cutoffs. There was a small drop in the number of patients with undetectable MRD at EOT+3 between the 10-4 and the 10-5 sensitivity cutoffs in both treatment arms.
Peter Martin, MD:
The rates of patients who achieved undetectable MRD were consistently higher with ibrutinib/venetoclax compared with chlorambucil/obinutuzumab across all prespecified subgroups. Independent of age, performance score, presence or absence of bulky disease, CIRS status, cytogenetic profile, or disease stage, treatment with ibrutinib/venetoclax yielded a higher rate of MRD-negative disease compared with treatment with chlorambucil/obinutuzumab.
Peter Martin, MD:
As expected, patients who achieved MRD‑negative status were more likely to sustain that MRD‑negative status over time if they were treated with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab. Between EOT+3 and end of treatment plus 12 months, undetectable MRD <10-4 diminished by only 6% in the ibrutinib plus venetoclax arm compared with 27% in the chlorambucil plus obinutuzumab arm.
Peter Martin, MD:
The GLOW study results are notable because the study was one of the first to show that ibrutinib plus venetoclax is tolerable in an older patient population and that this combination is clearly better at inducing deeper responses across all patient subgroups, especially when looking at the more sensitive 10‑5 next-generation sequencing threshold. An interesting observation in the GLOW study is that patients who were treated with ibrutinib plus venetoclax who had MRD-positive disease (MRD ≥10-4) were also less likely to experience disease progression or have worsening MRD detectable levels compared with patients who were treated with chlorambucil plus obinutuzumab. There is something biologically beneficial from the use of this combination of ibrutinib and venetoclax in patients with untreated CLL/SLL that causes an improvement in prognosis even for patients who are MRD positive 12 months after treatment is discontinued.
John M. Burke, MD:
Based on the results from the GLOW and CAPTIVATE trials, I suspect that the combination of ibrutinib and venetoclax will receive FDA approval for the treatment of patients with previously untreated CLL/SLL.
The GLOW trial report included several particularly interesting results. Of note, patients with unmutated IGHV achieved undetectable MRD (<10-5) at higher rates in the bone marrow (45.5%) and in the peripheral blood (49.1%) compared with patients with mutated IGHV, which was reported as 29.6% in the bone marrow and 37.0% in the peripheral blood. This is counterintuitive because patients with mutated IGHV have a more favorable prognosis than patients with unmutated IGHV, and it would have been expected that deeper remissions would have been reported in those with mutated IGHV; however, in fact, the opposite occurred with the ibrutinib/venetoclax combination.
Another really interesting finding is that at 1-year post treatment with ibrutinib/venetoclax, patients who did not achieve undetectable MRD still had a PFS greater than 90%. In fact, the PFS rate of patients on the ibrutinib/venetoclax arm was better than the PFS of the chlorambucil/obinutuzumab patients with undetectable MRD. To my knowledge, this is the first time that MRD status with time‑limited therapy was not the most important prognostic factor in terms of predicting PFS. In other words, the treatment received was more important at predicting PFS than the MRD status at the end of therapy. As concluded by the investigators, it is highly likely that the broader clearance of multiple disease compartments beyond the peripheral blood and bone marrow resulting from the complementary mechanisms of action of ibrutinib and venetoclax led to the PFS improvements observed with the combination, which occurred regardless of the presence or absence of detectable MRD. Patients treated with ibrutinib/venetoclax may have had better clearance in their lymph nodes and that led to improved PFS results even with MRD-positive disease at the end of therapy.
John M. Burke, MD:
Nemtabrutinib (MK-1026; formerly known as ARQ 531) is a novel BTK inhibitor. It is a noncovalent or reversible inhibitor of both wild‑type and C481S‑mutated BTK. Nemtabrutinib was investigated in a single‑arm, dose expansion phase II trial in patients with symptomatic R/R CLL/SLL, R/R B‑cell NHL and Waldenström macroglobulinemia (WM).28 Patients received nemtabrutinib at the recommended phase II dose of 65 mg daily until disease progression, unacceptable toxicity, or withdrawal from the study. For the cohort of patients with CLL/SLL, the primary endpoint was overall response rate according to the International Workshop on CLL. At ASH 2021, the efficacy results for the patients with CLL/SLL and the safety results from the entire patient population were presented.
John M. Burke, MD:
In total, 118 patients with CLL/SLL, B-cell NHL, and WM were enrolled on the trial. The study included 68 patients (54.6%) with CLL/SLL, 44 patients (37.3%) with B‑cell NHL, and 4 patients with WM (3.4%). Of these, 94 patients (79.6%) were treated with nemtabrutinib at the recommended phase II dose of 65 mg daily, including 51 (54.3%) with R/R CLL/SLL. Among the 51 patients with CLL/SLL treated with nemtabrutinib at 65 mg daily, the median number of prior lines of therapy was 4, and 84.3% had previously received a BTK inhibitor. There were 12 patients (23.5%) with del(17p), and 32 (62.7%) of the patients harbored a C481S BTK mutation. Of importance, the C481S mutation in BTK renders CLL cells resistant to covalent or irreversible BTK inhibitors like ibrutinib and acalabrutinib.
John M. Burke, MD:
After a median follow-up of 4.56 months, there were 38 evaluable patients with CLL/SLL. The overall response rate in patients with CLL/SLL was 57.9% (95% CI: 40.8-73.6) and the CR rate was 2.6% (95% CI: 0.0-13.8). The median duration of response was not reached.
John M. Burke, MD:
The safety data for all enrolled patients included patients with CLL/SLL, B-cell NHL, and WM. Grade ≥3 treatment-emergent adverse events occurred in 68% of patients. Adverse events leading to treatment discontinuation occurred in 7.6% of patients. The most frequently occurring grade ≥3 adverse event was hypertension, which occurred in 9.3% of patients.
John M. Burke, MD:
I see this study as both good and bad news. The good news is that nemtabrutinib has promising activity in CLL/SLL, and evaluations at this dose and higher doses are ongoing. The bad news is that nemtabrutinib has the misfortune of being developed in the same era as another reversible BTK inhibitor, pirtobrutinib, which has undergone more rapid development with larger trials. Efficacy of pirtobrutinib appears to be at least as high as with nemtabrutinib, and the toxicity profile may be even more favorable. In the phase I/II BRUIN trial, pirtobrutinib achieved an overall response rate of 62% in a patient population with R/R CLL/SLL who had received a median of 4 prior lines of therapy.29 Also, multiple phase III trials of pirtobrutinib are now underway in patients with previously treated CLL/SLL (NCT04666038, NCT04965493, NCT05023980). It is not clear how and when nemtabrutinib might become available for use. We will have to wait and see how things play out.
Peter Martin, MD:
I agree that this trial raises the question of whether there is room for another BTK inhibitor in this space. Of note, nemtabrutinib is a noncovalent BTK inhibitor, so in that sense it does not necessarily compete with ibrutinib, acalabrutinib, and zanubrutinib. Pirtobrutinib, however, also appears to be more selective and may be even better tolerated than nemtabrutinib. A comparison of the efficacy and safety of nemtabrutinib vs pirtobrutinib in a clinical setting will be helpful. However, it remains to be seen how nemtabrutinib will be developed in such a complicated treatment landscape.
Peter Martin, MD:
As we have already noted, there are multiple BTK inhibitors available for CLL/SLL, and the next-generation BTK inhibitors are attempting to reduce off-target effects and toxicity. The randomized phase III ELEVATE‑RR trial compared a second-generation BTK inhibitor acalabrutinib vs ibrutinib, which was the first irreversible BTK inhibitor that was approved in CLL/SLL. ELEVATE-RR was performed in patients with previously treated CLL who required treatment, according to the International Workshop on CLL 2008 criteria.30 To be eligible for enrollment, patients must have disease with a del(17p) and/or del(11q) without any prior exposure to a BTK inhibitor, PI3K inhibitor, Syk inhibitor, or BCL2 inhibitor. In total, 533 patients were randomized to receive acalabrutinib at 100 mg twice daily or ibrutinib at 420 mg once daily. The primary endpoint was noninferiority of PFS as assessed by an independent review committee. Key secondary endpoints were primarily related to safety, and included the rates of atrial fibrillation, grade ≥3 infections, and Richter’s transformation as well as OS.
Initial results from the ELEVATE-RR trial were reported at ASCO 2021, and acalabrutinib demonstrated noninferior PFS with fewer cardiotoxic events and discontinuations due to adverse events compared with ibrutinib.31 At ASH 2021, additional safety comparisons between these 2 BTK inhibitors were reported.
Peter Martin, MD:
The baseline characteristics were well balanced between the treatment arms. In each of the arms, 45% of patients had del(17p) and 62% to 66% had del(11q). More than 80% of patients in each arm had unmutated IGHV.
Peter Martin, MD:
The incidence of diarrhea, arthralgia, back pain, muscle spasm, and dyspepsia was statistically higher with ibrutinib compared with acalabrutinib (P <.05). The incidence of headache and cough were higher with acalabrutinib vs ibrutinib (P <.05). The adverse events with acalabrutinib or ibrutinib were almost entirely grade 1/2, with very few grade 3/4 adverse events.
Peter Martin, MD:
In this trial, atrial fibrillation was a key secondary endpoint. The incidence of atrial fibrillation or flutter was significantly higher with ibrutinib vs acalabrutinib (16% vs 9%; P <.05). Hypertension (23% vs 9%) and bleeding (51% vs 38%) were also more frequently observed in the ibrutinib arm compared with the acalabrutinib arm. These events were more common with ibrutinib vs acalabrutinib even after correction for exposure time.
Peter Martin, MD:
In conclusion, acalabrutinib and ibrutinib are similarly effective in previously treated CLL, and the study met its primary endpoint for noninferiority of PFS. Also, patients treated with acalabrutinib were less likely to experience certain grade 1/2 toxicities such as atrial fibrillation and some grade 3/4 toxicities, primarily hypertension.
It is also worth noting that acalabrutinib, which historically has not been recommended in patients treated with proton pump inhibitors, is undergoing a change in its formulation such that in the future it could be used in that patient population. We are still awaiting the rollout of this new formulation, but that ultimately may affect treatment selection as well.
John M. Burke, MD:
As we are moving away from PI3K inhibitors and bendamustine toward BTK inhibitors as the preferred next line of therapy for patients with CLL/SLL who relapse after chemoimmunotherapy, the longer follow-up of the ELEVATE‑RR trial confirmed what many have suspected for some time now – namely, that acalabrutinib has a more favorable safety profile than ibrutinib.
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