CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: September 13, 2022
Expiration: September 12, 2023
John M. Burke, MD:
CD30 is a surface antigen expressed on Reed-Sternberg cells typically found in cHL.39 BV is an antibody–drug conjugate comprising an anti-CD30 monoclonal antibody and a microtubule-disrupting agent.40
A previous update of ECHELON-1 demonstrated the addition of BV to an AVD chemotherapy backbone improved PFS at 5 years (82.2% vs 75.3%; HR: 0.68; 95% CI: 0.53-0.87; P = .0017) but not OS when compared with ABVD.41 The improved PFS found at 2 years in ECHELON-1 led to the FDA approval of BV in combination with chemotherapy for treatment-naive stage III or IV cHL in 2018.40,42 Despite the FDA approval, BV plus AVD was not universally adopted for these patients. Concerns regarding toxicity, cost, and the lack of an OS advantage led many to restrict its use. An updated 6-year follow-up analysis of OS, efficacy, and safety was presented at ASCO 2022.43,44
John M. Burke, MD:
The international, randomized, open-label phase III ECHELON-1 study compared upfront treatment with BV plus AVD vs ABVD in patients with newly diagnosed stage III or IV cHL. Approximately 1300 patients were randomized to receive either ABVD (control arm; n = 670) for 6 cycles or BV plus AVD (investigational arm; n = 664) for 6 cycles.43,44
The primary endpoint was a modified PFS per independent review. OS was a secondary endpoint that used an alpha-controlled event-driven analysis.43,44
John M. Burke, MD:
The baseline characteristics of the participants were well balanced between the 2 arms. Patients 60 years of age or older accounted for 14% of patients enrolled in the study. Nearly two thirds of patients had stage IV disease at the time of diagnosis. One quarter of patients had a high International Prognostic Score.43,44
John M. Burke, MD:
We now have 6 years of follow-up data from the ECHELON-1 study. An updated OS analysis showed BV plus AVD reduced the risk of death compared with ABVD by 41% (HR: 0.59; 95% CI: 0.40-0.88; P = .009). BV plus AVD also significantly reduced the risk of progression or death by 32% (HR: 0.68; 95% CI: 0.53-0.86; P = .002). The estimated 6-year OS was 93.9% (95% CI: 91.6-95.5) in the BV plus AVD arm and 89.4% (95% CI: 86.6-91.7) in the ABVD arm. The PFS benefit remains consistent with what has been reported in earlier analyses.41-44
The subset analysis showed a few interesting trends. Male patients appeared to benefit more than female patients from the BV plus AVD regimen. Patients younger than 60 years of age benefited more than those 60 years of age or older. Stage IV patients benefited more than stage III patients. However, it’s important to note that ECHELON-1 was not powered to detect differences in these subgroups and, therefore, these subgroup analyses should be considered hypothesis generating.43,44
John M. Burke, MD:
Causes of death were analyzed and were interesting. There were more deaths from Hodgkin lymphoma or its complications in the ABVD group (45 vs 32 in the BV plus AVD arm). There were also more deaths from secondary malignancies in the ABVD group (n = 11) compared with the BV plus AVD group (n = 1). An analysis of the secondary malignancy type indicated similar numbers of solid tumors between the 2 groups (14 in both the ABVD and BV plus AVD arms), but a higher number of hematological malignancies occurred in the ABVD group (n = 17) compared with the BV plus AVD group (n = 9).43,44
John M. Burke, MD:
In total, 292 patients (22%) on the study required subsequent cancer-directed therapy. The number of patients requiring subsequent therapy was lower in the BV plus AVD group compared with the ABVD group (135 20% vs 157 24%).43,44
John M. Burke, MD:
Additional follow-up on the rates of pregnancy and peripheral neuropathy was also reported. Peripheral neuropathy continued to improve over time in patients treated with ABVD or BV plus AVD. Among those who experienced peripheral neuropathy, 87% and 86% reported resolution or continued improvement in symptoms at the 6-year follow-up for the ABVD and BV plus AVD groups, respectively. However, the rate of peripheral neuropathy remains higher in the BV plus AVD group, such that 19% of patients still have some degree of peripheral neuropathy compared with 9% of patients in the ABVD group.
Although there was no formal fertility analysis performed, there were numerically more pregnancies in the BV plus AVD group (n = 113) compared with the ABVD group (n = 78). The reported number of pregnancies includes pregnancies in partners of male patients on the study. Among the female patients who were treated on the study, pregnancies were also more frequent in the BV plus AVD group (49 vs 28). No stillbirths were reported in either group.43,44
John M. Burke, MD:
We can now say that in patients with stage III or IV cHL, BV plus AVD improves OS compared with ABVD (HR: 0.59; 95% CI: 0.40-0.88; P = .009), despite the ability of patients treated with ABVD to receive BV in the salvage setting (24% vs 20% with BV plus AVD). In my opinion, this makes BV plus AVD the new standard of care in patients with newly diagnosed, advanced-stage cHL.
There may still be some room for ABVD in patients with underlying peripheral neuropathy or other comorbidities, but, in my opinion, most patients should be receiving BV plus AVD as the treatment of choice in the frontline setting.
I believe we can reassure our patients that choosing this therapy leads to lower use of second-line therapies, fewer secondary malignancies, fewer disease-related deaths, less progressive disease (PD), and with no adverse impact on pregnancy rates compared with ABVD.
John M. Burke, MD:
Younger patients with MCL are often treated with induction chemoimmunotherapy followed by autologous stem cell transplant and then maintenance rituximab. In contrast, older patients may be treated with less aggressive therapy including bendamustine and rituximab (BR) without autologous stem cell transplantation and either with or without maintenance rituximab. Compared with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), BR prolongs PFS and has a more favorable side effect profile in older patients.45,46
Ibrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor.47 BTK is a critical signaling molecule in the receptor signaling cascade of B-cells.47,48 By binding to BTK, ibrutinib inhibits BTK’s enzymatic activity.47 Ibrutinib has been shown to have strong activity in patients with R/R MCL and is approved by the FDA for patients with MCL who have received at least 1 previous therapy.47,48 It remains unknown whether the addition of ibrutinib to chemoimmunotherapy in the frontline setting and to rituximab in the maintenance setting improves outcomes. The SHINE study was designed to address this question.49,50
John M. Burke, MD:
SHINE is a randomized, double-blind, placebo-controlled phase III trial. Eligible patients were required to be 65 years of age or older with newly diagnosed stage II-IV MCL without plans for autologous stem cell transplant.49,50
In total, 523 patients were enrolled in the study. The control arm (n = 262) received 6 induction cycles of BR followed by 2 years of maintenance rituximab. Ibrutinib placebo was administered during BR induction and rituximab maintenance. The investigational arm (n = 261) received 6 induction cycles with BR plus ibrutinib followed by 2 years of maintenance R plus ibrutinib. Ibrutinib or placebo was administered continuously until PD or unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Key secondary endpoints included ORR, time to next treatment, OS, and safety.49,50
John M. Burke, MD:
Baseline characteristics were well balanced between the 2 study arms. The median age of patients was 71 years in both arms. In this study, 7.3% and 9.9% of patients had unfavorable blastoid/pleomorphic histologies in the ibrutinib plus BR arm and the placebo plus BR arm, respectively. TP53 mutations were present in 9.2% of patients in the placebo plus BR arm and 10% of patients in the ibrutinib plus BR arm, but the TP53 mutation status was not known in approximately 50% of patients.49,50
John M. Burke, MD:
The primary endpoint of SHINE was PFS. The median follow-up was 84.7 months. The median PFS in the ibrutinib plus BR group was 80.6 months vs 52.9 months in the control arm (HR: 0.75; 95% CI: 0.59-0.96; P = .011). A 2.3-year statistically significant difference was noted in PFS improvement with the addition of ibrutinib (6.7 vs 4.4 years in the placebo group). A clear benefit in the median PFS was not noted for patients with blastoid/pleomorphic histologies or tumors with TP53 mutations, but the study was not powered to detect these subgroup differences.49,50
John M. Burke, MD:
A subgroup analysis of PFS suggested that the addition of ibrutinib to BR appeared to benefit some subgroups. Patients younger than 70 years of age had more benefit with the ibrutinib regimen (HR: 0.67; 95% CI: 0.45-0.99).49,50
John M. Burke, MD:
ORRs were similar among the 2 groups (89.7% for ibrutinib plus BR and 85.5% for placebo plus BR). The CR rate was numerically higher in the ibrutinib plus BR group at 65.5% vs 57.6% (P = .057).49,50 Undetectable MRD in blood or bone marrow was noted in over one half of participants in each group.50
John M. Burke, MD:
There was no difference in OS between the groups. The median OS was not yet reached in either group (HR: 1.07; 95% CI: 0.81-1.40). At 84.7 months, the OS was 55% with ibrutinib plus BR compared with 57% with placebo plus BR.49,50
John M. Burke, MD:
The median time to next treatment was longer in the ibrutinib plus BR group (not reached vs 92 months; HR: 0.48; 95% CI: 0.34-0.66). Fewer patients who received ibrutinib plus BR received subsequent second-line therapy (19.9% vs 40.5%).49,50
John M. Burke, MD:
The overall toxicity rate between the groups was quite similar (51.4% in ibrutinib plus BR vs 52.3% in placebo plus BR). Patients treated with ibrutinib had more grade 3 or 4 diarrhea (6.9% vs 3.8%), rashes (12% vs 1.9%), and anemia (15.4% vs 8.8%) compared with those who received a placebo.49,50
John M. Burke, MD:
Treatment-emergent AEs of interest included bleeding, major bleeding, atrial fibrillation, hypertension, and arthralgia. Patients in the ibrutinib plus BR group experienced more bleeding (42.9% vs 21.5%), the majority of which was classified as minor bleeding. In the ibrutinib plus BR group, 5.8% of patients experienced a major bleed compared with 4.2% in the placebo plus BR group. Patients in the ibrutinib plus BR group also had a higher rate of atrial fibrillation (13.9% vs 6.5%).49,50 The rate of atrial fibrillation seen in the ibrutinib plus BR arm of SHINE was similar to that seen in other studies of ibrutinib.47 Rates of second primary malignancies were similar between the groups (21% with ibrutinib plus BR vs 19% with placebo plus BR).49,50
John M. Burke, MD:
In conclusion, the addition of ibrutinib to a BR backbone clearly prolonged PFS with only modest additional toxicities. However, the addition of ibrutinib to BR provided no additional OS benefit after 7 years of follow-up. The investigators have argued that this is a new benchmark for elderly MCL patients or patients ineligible for an autologous stem cell transplant.
I certainly think that statement is true in that this study achieved an unprecedented median PFS that was superior to the PFS without ibrutinib. The question for practitioners remains whether we should use this regimen. On one hand, prolonging PFS is certainly a valuable endpoint, especially when the added toxicities are modest. Many patients may value the ability to stay in remission for an extra couple years with ibrutinib added to the regimen.
On the other hand, no OS benefit was seen with the addition of ibrutinib to BR. BTK inhibitors are readily available for use in the second-line setting. Delaying BTK inhibitor therapy until relapse would reduce toxicities, reduce exposure to BTK inhibitors for many years, and reduce the costs to society of a drug that is administered continuously until progression.
The answer to the question of whether we should start using this in practice is difficult. It will generate considerable debate. I can certainly see both sides of the argument. I believe this will likely be a decision we make on an individual basis with our patients.
John M. Burke, MD:
Glofitamab is a bispecific antibody with a unique structure consisting of 2 binding sites to CD20 on B-cells and 1 for CD3 on T-cells.51 The 2:1 configuration allows for potentially more potent antitumor activity.51,52 Results from a phase I study of glofitamab in heavily pre-treated patients with various R/R B-cell malignancies demonstrated good response rates (ORR: 65.7% with the recommended phase II glofitamab dose of 30 mg) but yielded relatively high rates of cytokine-release syndrome (CRS) at 50.3%.51 T-cell activation and CRS can be mitigated by pretreatment with the CD20-targeted monoclonal antibody obinutuzumab and a step-up dosing schedule of glofitamab.52 This initial B-cell depletion can reduce the risk of developing CRS when treated with glofitamab.51,52
John M. Burke, MD:
This is a pivotal single-arm, phase II expansion trial of glofitamab in 155 patients with R/R DLBCL who received at least 2 previous therapies (including CD20-directed therapy and anthracyclines). Eligible study patients were required to have a diagnosis of DLBCL, high-grade B-cell lymphoma, transformed FL, or primary mediastinal B-cell lymphoma.
Glofitamab was administered in step-up doses up to the 30 mg target dose. A single dose of obinutuzumab 1000 mg IV was administered 7 days before glofitamab as a pretreatment for the prevention of CRS. The primary endpoint was the CR rate determined by an independent review committee. Key secondary endpoints included ORR, DoR, duration of complete response (DoCR), PFS, and OS.53
John M. Burke, MD:
The median age of enrolled patients was 66 years. Most patients had a diagnosis of DLBCL (71.4%). Patients received a median of 3 previous lines of therapy (range 2-7), with 85.7% of patients reported to be refractory to their last therapy. More than one half (58.4%) of patients had primary refractory disease. In total, 33.1% received CAR T-cell therapy and 29.9% were refractory to their previous CAR T-cell therapy. Of the enrolled patients, 83.1% were refractory to any previous CD20-directed antibody.53
In summary, these were very high-risk patients with limited treatment options.
John M. Burke, MD:
The ORR was 51.6% and the CR rate was 39.4%. In the primary efficacy population of 108 patients, the CR rate was 35.2%, which is superior to the chosen historical control arm where the CR rate was 20% (P <.0001).
Subgroup analyses showed that the CR rate was similar in patients who were post–CAR T-cell therapy compared with those who had not received CAR T-cell therapy (35% vs 42%, respectively). CR rates were higher in those with relapsed disease at 70% compared with a CR rate of 34% in patients who were refractory to their last previous therapy.53
John M. Burke, MD:
This table summarizes the DoR with a median follow-up of 10.6 months. If patients were noted to have any response to glofitamab (n = 80), the median DoR was 18.4 months (13.7 months to not reached). If patients were noted to have a CR (n = 61), the median DoR was not yet reached (16.8 months to not reached). An analysis of 35 patients who had achieved a CR from an earlier cohort indicated that with a median follow-up of 24.8 months, the median DoCR is 34.2 months, indicating that many of those who achieve a CR can have a prolonged CR.53
John M. Burke, MD:
At a median follow-up of 12.6 months (0-22 months), the median PFS was 4.9 months (95% CI: 37.2-53.8) and the median OS was 11.5 months (95% CI: 7.9-15.7).53
John M. Burke, MD:
In total, 154 patients were included in the safety analysis. The most common AE was CRS at 63%. The second most common was neutropenia, with an occurrence rate of 37.7%. Grade 3 or 4 AEs occurred in 56.5% of patients. Although 5.2% of patients died during the study period, no deaths were thought to be related to glofitamab. Five of the 8 deaths occurred from COVID-19 and the remaining 3 deaths resulted from other events (sepsis and delirium). In total, 9.1% of patients discontinued glofitamab but only 3.2% were thought to have discontinued therapy due to glofitamab toxicity.53
John M. Burke, MD:
Of all patients, 63% experienced any grade of CRS; however, the majority were reported as grade 1 (47.4%) or grade 2 (11.7%). Only 3.9% of patients experienced grade 3 or 4 CRS. The median time to onset of CRS from the first dose of glofitamab was 13.6 hours (range: 6.2-51.8 hours). In total, 27.8% of patients required corticosteroids for treatment of CRS and 32% required tocilizumab therapy. CRS events primarily occurred during cycle 1.
In total, 3.2% of patients had more serious neurological toxicities, classified as grade ≥ 3. Data about true immune effector cell–associated neurotoxicity syndrome (ICANS) were not collected prospectively. Retrospectively, investigators deemed that 7.8% of patients developed ICANS.53
John M. Burke, MD:
In conclusion, glofitamab appears to be a highly active, T-cell–engaging bispecific antibody treatment for patients with heavily pretreated, relapsed, or refractory DLBCL and other aggressive B-cell malignancies. CR rates for glofitamab were consistent among those who received CAR T-cell therapy in a previous line of therapy and those who had not had CAR T-cell therapy exposure.
This was a fixed duration of therapy, given for approximately 9 months. The most common toxicity patients experienced was CRS, which occurred in 63% of patients, but it was largely grade 1 and took place during the first cycle of therapy.
If glofitamab were to become available, a major question that will arise is how to sequence it in relation to CAR T-cell therapy and other available options like tafasitamab plus lenalidomide and loncastuximab tesirine. If glofitamab is granted approval, most physicians would probably use it after CAR T-cell therapy. Theoretically, CAR T-cell therapy would be administered before bispecifics based on second-line approval, strong efficacy results, and longer follow-up of studies indicating probable cures of some patients. However, most patients eligible for CAR T-cell therapy do not receive it due to access issues. Glofitamab will likely be more readily available than CAR T-cell therapies and could be delivered quickly for patients in relatively urgent need. It would seem reasonable to use this as an option in the third-line setting before CAR T-cell therapy exposure for patients who do not have immediate access to CAR T-cell therapy.
John M. Burke, MD:
To date, BTK inhibitors have not achieved regulatory approval for FL. One of the original reports of ibrutinib in patients with R/R FL who received ≥2 previous therapies demonstrated an ORR of 21%, which led to relatively subdued enthusiasm for BTK inhibition in FL.54 Another trial with BTK inhibition in early lines of therapy has suggested clinical benefit.55
Zanubrutinib is an oral second-generation BTK inhibitor that has greater selectivity for BTK and fewer off-target effects compared with the first-generation BTK inhibitor ibrutinib.55 A previous phase 1B trial of zanubrutinib in combination with obinutuzumab demonstrated an ORR of 72% and a CR rate of 39% in 36 patients with R/R FL.55 These promising results led to the development of the phase II ROSEWOOD study.
John M. Burke, MD:
The ROSEWOOD trial was designed to determine whether adding zanubrutinib to obinutuzumab conferred clinical benefit in patients with grade 1-3a R/R FL who had received ≥2 previous therapies (including a CD20-targeted antibody and an alkylating agent) with no previous exposure to a BTK inhibitor.56
ROSEWOOD is an international, randomized open-label phase II study. Patients were randomized in a 2:1 fashion to receive either zanubrutinib plus obinutuzumab (ZO, n = 145) or obinutuzumab monotherapy (n = 72). Zanubrutinib was dosed orally at 160 mg twice daily and continued until PD. Obinutuzumab 1000 mg IV was administered on Days 1, 8, and 15 of cycle 1 and on Day 1 only of cycles 2-6. Obinutuzumab cycles were 28 days in length. After 6 cycles, obinutuzumab could be continued every 8 weeks for a maximum of 20 doses.
The primary endpoint was the ORR as assessed by an independent review committee. Key secondary endpoints included investigator-assessed ORR, CR, DoR, PFS, OS, and safety.56
John M. Burke, MD:
The study arms were well balanced with some minor differences. Patients in the ZO arm were slightly younger with a median age of 63 years (31-84 years) compared with the obinutuzumab arm, which had a median age of 65.5 years (32-88 years). Only 40.7% of patients who received ZO had an ECOG performance status of ≥1 compared with 56.9% of patients who received obinutuzumab. Patients in both groups had received a median of 3 previous lines of therapy, with 32.4% of ZO patients and 40.3% of obinutuzumab patients noted to be refractory to their most recent line of therapy. In total, 53.8% of patients who received ZO were refractory to rituximab compared with 50% of obinutuzumab patients. In total, 34.5% of patients randomized to ZO and 41.7% of patients randomized to obinutuzumab were noted to have PD within 24 months of completing frontline therapy, which is known to be an adverse prognostic factor.56
John M. Burke, MD:
The median follow-up was 12.5 months. The ORR in the ZO group was 68.3% and 45.8% in the single-agent obinutuzumab group. The CR rates were 37.2% and 19.4% for ZO and obinutuzumab monotherapy, respectively. In a subgroup analysis, the ORR was improved in most subgroups with ZO, except in patients with bulky disease. In total, 29 patients in the single-agent arm crossed over to the ZO arm and 7 patients (24.1%) achieved an objective response, including 2 patients who achieved a CR.56
John M. Burke, MD:
The median PFS for the ZO and obinutuzumab groups was 27.4 and 11.2 months, respectively (HR: 0.51; 95% CI: 0.32-0.81; P = .004). The median OS was not reached in either group (HR: 0.44; 95% CI: 0.22-0.88; P = .0177). This study was not powered to show an OS difference. The median time to next treatment was not reached in the ZO group compared with 12.1 months in the obinutuzumab group (HR: 0.37; 95% CI: 0.23-0.60; P <.0001).56
John M. Burke, MD:
The rate of AEs was only slightly higher in the ZO arm (92.3% vs 88.7%). Zanubrutinib increased the rates of grade 3 or 4 toxicity to a minor extent (53.8% vs 47.9%). In terms of special-interest AEs, the rate of atrial fibrillation/flutter was 2.1% with ZO,56 which was consistent with the zanubrutinib incidence in a trial comparing ibrutinib and zanubrutinib in Waldenström macroglobulinemia patients.57 Rates of hypertension were relatively low at 3.5% and 4.2% of ZO and obinutuzumab patients, respectively. Hemorrhage was noted in 26.6% of ZO patients compared with 8.5% of patients who received obinutuzumab, but major hemorrhage was only noted in 1.4% of patients in both groups.
Infection rates were slightly higher in the ZO arm at 47.6% vs 36.6% of patients in the single-agent arm. Second primary malignancies were also slightly more prevalent in the ZO arm at 6.3% vs 2.8% in the monotherapy obinutuzumab arm.56
John M. Burke, MD:
In the ZO arm, patients received obinutuzumab for a longer period of time with a median duration of exposure of 8.31 months (0.3-35.35 months) compared with 6.41 months (0.1-28.3 months) in the obinutuzumab arm, presumably due to fewer progression events. The median relative dose intensity of zanubrutinib was high at 99.47% (30.7%-100%).56
John M. Burke, MD:
In conclusion, the ZO combination appears to be more effective than single-agent obinutuzumab in patients with R/R FL. Zanubrutinib added a meaningful improvement to ORR (68.3% ZO vs 45.8% obinutuzumab; P = .0017) and demonstrated improved PFS and OS without unacceptable or unexpected toxicities.
A noted limitation of this study is that single-agent obinutuzumab is not approved by the FDA in relapsed FL, so whether that would be considered an appropriate control arm for regulatory approval is uncertain. However, I will point out that the AUGMENT trial, which compared lenalidomide plus rituximab with rituximab alone, had a similar design and led to the FDA approval of lenalidomide for relapsed/refractory FL.58 ROSEWOOD was a randomized phase II but not a phase III trial. I find the efficacy results to be impressive, with an ORR of 68.3%, a CR rate of 37.2%, and a median PFS of 27.4 months in a population of third-line and higher patients, one half of whom were refractory to rituximab.
A big question is whether ZO will require further study in a phase III trial to become approved and available for use in R/R FL. We hope and expect that bispecific antibody therapies may gain accelerated approval based on single-arm, phase II studies. Whether that same type of approval could be extended to ZO based on this study is not clear, but it does appear to be an active regimen in this disease.
John M. Burke, MD:
Acalabrutinib is a potent, oral, next-generation BTK inhibitor that is approved by the FDA for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL), or previously treated patients with MCL who have received ≥1 previous therapy.59
The phase III ELEVATE-TN trial was an international, randomized, open-label study that compared acalabrutinib with or without obinutuzumab vs obinutuzumab plus chlorambucil in 535 treatment-naive CLL patients. After approximately 2 years of follow-up, the primary endpoint of PFS favored acalabrutinib plus obinutuzumab over obinutuzumab plus chlorambucil (median PFS not reached vs 22.6 months; HR: 0.1; 95% CI: 0.06-0.17; P <.0001) with an estimated 24-month PFS of 93% (95% CI: 87%-96%) with acalabrutinib plus obinutuzumab and 47% (95% CI: 39%-55%) with obinutuzumab monotherapy.60 We now have results from the 5-year follow-up for ELEVATE-TN.61
John M. Burke, MD:
In the 5-year update, the acalabrutinib arms continued to achieve better PFS than obinutuzumab and chlorambucil. The 5-year PFS for acalabrutinib plus obinutuzumab was reported to be 84% compared with 21% for obinutuzumab plus chlorambucil (HR: 0.11; 95% CI: 0.07-0.16; P <.0001).
The 5-year PFS with acalabrutinib plus obinutuzumab was also better than the PFS with acalabrutinib alone at 84% and 72%, respectively (HR: 0.51; 95% CI: 0.32-0.81; P = .0259), which represents an absolute difference of 12%.61 At the 4-year publication of these results, those numbers were 87% and 78%, with an absolute difference of 9%. The 2-year results showed a PFS of 93% and 87% for an absolute difference of 6%.60,62
The PFS curves between the acalabrutinib plus obinutuzumab and acalabrutinib monotherapy groups are widening over time, indicating that the addition of obinutuzumab to acalabrutinib is providing long-term additional benefit in terms of PFS. This was one of the key findings of interest in this update.61
John M. Burke, MD:
A second interesting takeaway was that the median OS of acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil is now statistically significant (HR: 0.55; P = .0474).This survival benefit was observed despite 41% of the patients in the obinutuzumab plus chlorambucil arm crossing over to receive acalabrutinib monotherapy later on during the study.61
John M. Burke, MD:
The most common AEs observed in the 5-year follow-up were consistent with those from previously reported findings of this study. Headache (40.4% vs 11.8%), diarrhea (43.4% vs 21.3%), and arthralgia (33.7% vs. 5.9%) occurred more frequently in the acalabrutinib plus obinutuzumab arm compared with those who received obinutuzumab.61
John M. Burke, MD:
Not only does the combination of acalabrutinib and obinutuzumab improve OS compared with obinutuzumab and chlorambucil, it appears to be trending in that direction compared with acalabrutinib alone.61 This makes me rethink my practice of giving single-agent BTK inhibitors without a CD20 antibody in the frontline setting.
John M. Burke, MD:
CAPTIVATE is an international, randomized phase II study of ibrutinib plus venetoclax in the first-line setting for treatment of CLL/SLL in patients 70 years of age or older who require treatment per the International Workshop on Chronic Lymphocytic Leukemia criteria.63 Ibrutinib is an oral BTK inhibitor that is approved by the FDA for CLL/SLL in adult patients with or without a 17p deletion.47 Venetoclax is an oral BCL2 inhibitor that is approved by the FDA for CLL/SLL as a treatment for adult patients as a single agent or with anti-CD20 monoclonal antibodies (obinutuzumab or rituximab).64 At the end of treatment, individuals with PD were eligible for retreatment with fixed-duration (FD) ibrutinib and venetoclax if they had a durable response. The primary endpoint of the CAPTIVATE study was the CR/CRi (CRi defined as CR with incomplete bone marrow recovery) rate per an investigator assessment in patients without a 17p deletion. Findings from the FD cohort primary analysis demonstrated a CR/CRi rate of 56% (95% CI: 48%-64%; P <.0001) at approximately 2 years of follow-up.65
John M. Burke, MD:
The results of this 3-year follow-up demonstrated similar CR rates to the previously reported findings. The 3-year PFS rate was 88% in all treated patients (95% CI: 82%-92%) and 80% (95% CI: 58%-91%) in those with TP53 mutations or a 17p deletion. No additional serious AEs or second primary malignancies were reported with the additional follow-up.63
In total, 12 patients who developed PD after the 1-year FD of therapy were retreated with single-agent ibrutinib; 11 of those were evaluable for response. Of those 11 retreated patients, 10 responded to retreatment with monotherapy ibrutinib, with 9 patients achieving a PR and 1 patient achieving a PR with lymphocytosis.63
John M. Burke, MD
The 3-year update of CAPTIVATE continues to show durable as well as deep responses to upfront therapy with ibrutinib plus venetoclax, with no increase in AEs. Early data also suggest that if patients develop PD on this combination therapy, successful retreatment with ibrutinib monotherapy can be considered.63
If this doublet is approved by the FDA, how often physicians use this combination will remain to be seen. The option of FD with an all-oral doublet therapy may be attractive for many patients.
John M. Burke, MD:
The ASCEND study was an international, multicenter, randomized, open-label phase III trial of acalabrutinib vs rituximab plus idelalisib or rituximab plus bendamustine in 310 adult R/R CLL patients who had received ≥2 lines of therapy, but no previous exposure to BCL2 or B-cell receptor inhibitor therapies. The primary endpoint was PFS.
At a median 16.1-month follow-up, acalabrutinib significantly improved PFS compared with rituximab plus idelalisib/BR (PFS not reached in monotherapy arm vs 16.5 months; 95% CI: 14-17.1 months; HR: 0.31; 95% CI: 0.20-0.49; P <.0001). The estimated 1-year PFS was 88% (95% CI: 81%-92%) for acalabrutinib monotherapy compared with 68% (95% CI: 59%-75%) for investigator’s choice.66
John M. Burke, MD:
At the ASCEND 4-year update, acalabrutinib continued to significantly prolong the PFS (median not reached vs 16.8 months; HR: 0.28; 95% CI: 0.20-0.38; P <.0001). The PFS at 42 months was 62% in the acalabrutinib arm vs only 19% in the rituximab plus idelalisib/BR arm. The median OS has not yet been reached in either group (HR: 0.69; 95% CI: 0.46-1.04; P = .0783). The 4-year OS rates were 78% and 65% for acalabrutinib and rituximab plus idelalisib/BR, respectively.67
John M. Burke, MD:
Acalabrutinib was consistent with its tolerability profile in the 4-year update of ASCEND. No new safety signals were noted. Fewer patients discontinued treatment due to AEs in the acalabrutinib arm compared with the investigator’s choice arm (23% vs 84%).67
John M. Burke, MD:
In patients with R/R CLL, acalabrutinib continues to significantly prolong PFS compared with rituximab plus idelalisib/BR while maintaining a tolerable safety profile. The median OS has not yet been reached in either arm.67 These updated data continue to support long-term use of acalabrutinib in patients with R/R CLL.
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