https://orcid.org/0000-0003-2040-4961
Abstract
Objective
The purpose of this analysis was to assess health-related quality of life (HRQoL) in patients treated with zanubrutinib and ibrutinib in the ALPINE trial (NCT03734016).
Methods
HRQoL was measured by the EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every third cycle until the end of treatment. Key patient-reported outcome (PRO) endpoints included global health status (GHS), physical and role functioning, as well as symptoms of fatigue, pain, diarrhea, and nausea/vomiting. A mixed model repeated-measure analysis using key PRO endpoints at key clinical cycles (cycles 7 and 13) was performed.
Results
652 patients were randomized to receive zanubrutinib (n = 327) or ibrutinib (n = 325). By cycle 7, GHS scores improved with zanubrutinib versus ibrutinib, and in cycle 13, GHS scores remained higher in the zanubrutinib arm. The zanubrutinib arm experienced clinically meaningful improvements in physical and role functioning, as well as pain and fatigue symptoms at both cycles. Patients in the zanubrutinib arm reported lower diarrhea scores. Nausea/vomiting scores maintained in both arms. EQ-VAS scores showed greater improvement from baseline at both cycle 7 (7.92 versus 3.44) and cycle 13 (7.75 versus 3.92) of treatment with zanubrutinib compared to ibrutinib, respectively.
Conclusions
Patients with R/R CLL/SLL treated with zanubrutinib demonstrated improvement versus ibrutinib in the GHS scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanubrutinib positively affected HRQoL over time. Given the generally good HRQoL at baseline in both arms, the differences between the arms were not significant.
Introduction
Patients with chronic lymphocytic leukemia (CLL), including small lymphocytic lymphoma (SLL), the most common form of leukemia in western countries, can experience a range of symptoms including fatigue, pain, nausea, vomiting, and diarrheaCitation1–4. These symptoms affect patients’ physical functioning and overall health state, resulting in a profoundly negative impact on health-related quality of life (HRQoL)Citation2. Low HRQoL in patients with CLL is associated with the manifestation of disease and worsens with increased disease severityCitation2,Citation3. Low HRQoL can also be associated with treatment-related adverse events (AEs)Citation4, which worsen with multiple lines of therapyCitation2,Citation3. Patient-reported outcomes (PROs) have long been recognized as important tools in evaluating drugs in clinical trials, particularly the positive effects of treatment and the negative effects of treatment-related AEs on HRQoLCitation5.
Bruton’s tyrosine kinase (BTK) inhibitors have changed the therapeutic landscape for patients with relapsed or refractory (R/R) CLL/SLL in the last decadeCitation6,Citation7. Specifically, there is growing evidence that treatment of patients with CLL/SLL using BTK inhibitors results in improvements in HRQoL, likely due to increased treatment efficacy and/or reduced treatment-related AEs, compared with chemoimmunotherapyCitation8,Citation9. Ibrutinib, a first-in-class irreversible BTK inhibitor, was approved in 2013Citation10; however, off-target and on-target binding has been associated with discontinuation-inducing AEs such as bleeding and atrial fibrillationCitation7. Zanubrutinib, a next-generation irreversible BTK inhibitor, was formulated with improved selectivity to BTK and to reduce the off-target effects associated with earlier-generation BTK inhibitorsCitation11. Zanubrutinib is currently approved in 55 countries for a number of different indications including treatment-naive, R/R CLL/SLL, R/R mantle cell lymphoma, Waldenström macroglobulinemia, and R/R marginal zone lymphomaCitation12–15. Zanubrutinib has shown promising results in improving HRQoL outcomes in patients with Waldenström macroglobulinemiaCitation16, as well as in patients with treatment-naive CLL/SLL compared with chemoimmunotherapyCitation17.
The ALPINE trial (BGB-3111-305; NCT03734016) is a multinational, open-label, randomized, phase 3 study of adult patients with R/R CLL/SLL to compare the efficacy, safety, and HRQoL outcomes following treatment with zanubrutinib versus ibrutinib monotherapyCitation18. At a median follow-up of 29.6 months, zanubrutinib demonstrated superiority to ibrutinib in investigator-assessed progression-free survival (hazard ratio [HR] for disease progression or death: 0.65; 95% confidence interval [CI]: 0.49, 0.86; p = .002). The percentage of patients with an overall response, as assessed by the investigators, was higher in the zanubrutinib arm than in the ibrutinib arm (83.5% versus 74.2%). There were fewer deaths with zanubrutinib compared with ibrutinib (HR for overall survival: 0.76; 95% CI: 0.51, 1.11)Citation19. Furthermore, the incidence of AEs leading to treatment discontinuation (15.4% versus 22.2%) and incidence of overall cardiac disorders (21.3% versus 29.6%) were lower with zanubrutinib compared with ibrutinib. No fatal cardiac events occurred in patients treated with zanubrutinib, while six occurred in the ibrutinib armCitation19. The purpose of the current analyses was to assess HRQoL, as a secondary objective, in patients treated with zanubrutinib or ibrutinib in the ALPINE trial.
Methods
Detailed methodology for the ALPINE trial (NCT03734016) has previously been publishedCitation18; relevant details are summarized below.
Study design
Patients were randomized 1:1 to receive zanubrutinib 160 mg oral twice daily or ibrutinib 420 mg oral once daily until disease progression, unacceptable treatment-related toxicity, or patient withdrawal. Randomization was stratified by age (<65 years versus ≥65 years), geographic region (China versus non-China), refractory status (yes or no), and del(17p)/TP53 mutation status (present or absent). To be eligible, patients were at least 18 years of age, had a confirmed diagnosis of CLL/SLL that met International Workshop on CLL criteria, were R/R to ≥1 prior systemic therapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Exclusion criteria included prior treatment with a BTK inhibitor and known prolymphocytic leukemia or possible Richter’s transformation. Written informed consent was obtained from patients before participation in the study. The study was carried out in accordance with the International Conference for Harmonisation Good Clinical Practice Guideline, the principles of the Declaration of Helsinki, and local laws and regulations. All patients provided written informed consent before participating.
PRO endpoints
HRQoL was assessed using two validated PRO instruments: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30)Citation20 and the EuroQoL EQ-5D 5-level questionnaireCitation21. The EORTC QLQ-C30 was used to assess the overall HRQoL of cancer patients during the past week20. Key endpoints from the EORTC QLQ-C30 included the 2-item global health status (GHS) scale, two functional scales (physical functioning [5-item] and role functioning [2-item]), and four symptom scales (fatigue [3-item], pain [2-item], nausea/vomiting [2-item], and diarrhea [single item]), as these constructs measure the most relevant disease symptoms and treatment effectsCitation2,Citation20–23. The GHS scale items are rated using a numeric rating scale from 1 to 7 (anchored at very poor and excellent), whereas the remaining items are rated using a verbal-descriptive scale from 1 to 4 (not at all, a little, quite a bit, and very much). Higher scores on the GHS and functioning scales indicate better HRQoL, whereas higher scores on the symptom scales suggest worsening HRQoL. The EQ-5D is a generic evaluation of overall health status, which incorporates a visual analog scale (EQ-VAS) for patients to rate their general health “today” on a scale from 0 (the worst health you can imagine) to 100 (the best health you can imagine)Citation20.
Both PRO measures were assessed at baseline, cycle 1, and then every third cycle; each cycle constituted 28 d. Key clinical cycles were selected at cycles 7 and 13, representing approximately 6 months and 12 months from the first treatment, respectively. The questionnaires were completed before the study drug was administered and before performing any other procedures or having health-related discussions with patients.
Statistical analyses
The population evaluated for HRQoL was the intent-to-treat population including all randomized patients. Adjusted completion rates were defined as the number of patients who completed the questionnaires at each cycle divided by the number still on treatment. Raw scores were calculated as the average of the item(s) that contribute to each scale; a linear transformation to standardize the raw scores was then utilized so that the scores for each scale ranged from 0 to 100. Scores and score changes from baseline for each of the key EORTC QLQ-C30 scales and the EQ-VAS were analyzed descriptively using means and standard deviations (SD). A mixed model for repeated measures (MMRM) was also used to evaluate and compare the EORTC QLQ-C30 scores by treatment arms at cycles 7 and 13. The model used an unstructured covariance matrix with the baseline score and a treatment arm by assessment timepoint interaction as covariates; changes from baseline in each of the EORTC QLQ-C30 scores by treatment arm, as well as treatment differences, were estimated. 95% CIs were calculated; p-values were two-sided and nominal, without multiplicity adjustment. The clinically meaningful change was defined as a ≥ 5% (i.e. 5-point) mean difference from baselineCitation24–26. All HRQoL analyses were conducted using a data cutoff date of August 8, 2022.
Results
The intent-to-treat population consisted of a total of 652 patients (327 patients randomized to receive zanubrutinib and 325 patients randomized to receive ibrutinib). Patient demographics and baseline characteristics () were generally comparable in the zanubrutinib and ibrutinib treatment arms, although the zanubrutinib arm had fewer males than the ibrutinib arm (65.1% versus 71.4%). Median patient age was 67 years for zanubrutinib versus 68 years for ibrutinib, and most patients were White (79.8% versus 81.5%), resided in Europe (60.6% versus 58.8%), and had an ECOG performance status of ≥1 (60.6% versus 62.5%). Furthermore, most patients had previously received chemoimmunotherapy (79.5% for zanubrutinib and 76.0% for ibrutinib) and the frequency of genetic mutations was similar in both treatment arms (del[17p]: 13.8% versus 15.4%; del[11q]: 27.8% versus 27.1%). Full demographic and clinical characteristics of the intent-to-treat population at baseline have been published within the primary manuscriptCitation19.
Table 1. Patient demographics and disease characteristics.
Adjusted completion rates
The adjusted completion rates were high (>87%) in both treatment arms at each assessment timepoint ().
Table 2. Adjusted completion rates for HRQoL assessments.
Descriptive analysis
The observed means and mean change from baseline for the QLQ-C30 are provided in Supplemental Table 1. At baseline, mean scores on the QLQ-C30 GHS, functional, and symptom scales were similar between treatment arms. Mean change (estimated mean [SD] from baseline at cycle 7 was as follows: GHS 8.45 (18.90) versus 4.62 (20.28), physical functioning 6.65 (16.03) versus 4.56 (16.65), role functioning 7.33 (25.90) versus 4.86 (22.12), with reduction in fatigue −12.63 (21.30) versus −10.24 (22.357), pain −4.61 (22.22) versus −4.13 (23.94), diarrhea −3.15 (17.73) versus 0.78 (16.87), and nausea/vomiting −0.91 (7.81) versus −0.85 (9.92) in the zanubrutinib arm versus ibrutinib arm, respectively. At cycle 13, mean change from baseline was as follows: GHS 8.18 (20.73) versus 5.05 (18.90), physical functioning 6.19 (17.38) versus 3.75 (14.87), role functioning 7.92 (26.32) versus 3.85 (21.82), with reduction in fatigue −11.59 (23.34) versus −9.65 (21.85), pain −5.36 (21.79) versus −3.19 (24.38), diarrhea −4.40 (18.08) versus 0.00 (17.13), and nausea/vomiting −0.83 (8.31) versus −0.27 (10.22) in the zanubrutinib arm versus ibrutinib arm, respectively.
MMRM analysis
At cycle 7, the mean change from baseline in GHS (estimated mean [95% CI]: 8.18 [6.25, 10.12] versus 5.18 [3.20, 7.17]), physical functioning (6.55 [4.96, 8.15] versus 4.73 [3.08, 6.38]), and role functioning (6.95 [4.85, 9.06] versus 6.32 [4.14, 8.50]) showed improvements in both the zanubrutinib and ibrutinib arms. All improvements were clinically meaningful for the zanubrutinib arm. Although the numerical values of the mean changes were higher in the zanubrutinib arm, the differences between the arms were significant only for GHS (3.00 [0.23, 5.77; p = .034]) ().
Figure 1. EORTC QLQ-C30 Mean change from baseline in GHS and functioning scales at cycle 7 (6 months) by treatment. Abbreviations. CI, confidence interval; EMTD, estimated mean treatment difference; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; GHS, global health status.
Clinically meaningful improvements continued into cycle 13 for the zanubrutinib arm for GHS (7.28 [5.41, 9.15] versus 5.93 [3.97, 7.89]), physical functioning (5.46 [3.87, 7.04] versus 4.31 [2.65, 5.97]), and role functioning (6.81 [4.61, 9.02] versus 5.01 [2.69, 7.33]) (). The estimated mean treatment difference (95% CI) was 1.34 (−1.37, 4.06; p = .330) for GHS, 1.15 (−1.15, 3.44; p = .327) for physical functioning, and 1.80 (−1.40, 5.00; p = .270) for role functioning.
Figure 2. EORTC QLQ-C30 Mean change from baseline in GHS and functioning scales at cycle 13 (12 months) by treatment. Abbreviations. CI, confidence interval; EMTD, estimated mean treatment difference; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; GHS, global health status.
For the symptom-specific scales at cycle 7, the zanubrutinib arm experienced clinically meaningful improvements in fatigue (−12.54 [−14.47, −10.60] versus −10.63 [−12.63, −8.62]) and pain (−5.06 [−7.21, −2.91] versus −3.63 [−5.85, −1.42]). Although an improvement was observed for diarrhea in the zanubrutinib arm (estimated mean [95% CI]: −2.11 [−3.80, −0.42] versus −0.52 [−2.27, 1.22]), it did not reach the clinically meaningful threshold. Nausea/vomiting remained relatively stable in both arms (−1.21 [−2.03, −0.38] versus −0.92 [−1.77, −0.07]) (). The estimated mean treatment difference (95% CI) was −1.59 (−4.01, 0.84; p = .200) for diarrhea, −1.91 (−4.70, 0.87; p = .178) for fatigue, −0.29 (−1.48, 0.89; p = .629) for nausea/vomiting, and −1.43 (−4.51, 1.66; p = .364) for pain.
Figure 3. EORTC QLQ-C30 Mean change from baseline in symptom scales at cycle 7 (6 months) by treatment. Abbreviations. CI, confidence interval; EMTD, estimated mean treatment difference; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30.
The zanubrutinib arm continued to experience clinically meaningful improvements from baseline at cycle 13 for fatigue (−11.13 [−13.19, −9.08] versus −10.78 [−12.93, −8.63]) and pain (−5.18 [−7.38, −2.97] versus −2.76 [−5.06, −0.44]). The zanubrutinib arm again experienced an improvement in diarrhea (estimated mean [95% CI]: −3.23 [−4.79, −1.66] versus −1.38 [−3.03, 0.27]) but it was not clinically meaningful. As in cycle 7, nausea/vomiting remained stable in both arms (−0.92 [−1.94, 0.10] versus −0.40 [−1.47, 0.66]) (). The estimated mean treatment difference (95% CI) was −1.85 (−4.12, 0.43; p = .112) for diarrhea, −0.35 (−3.32, 2.62; p = .817) for fatigue, −0.51 (−1.99, 0.96; p = .493) for nausea/vomiting, and −2.43 (−5.62, 0.77; p = .136) for pain.
Figure 4. EORTC QLQ-C30 Mean change from baseline in symptom scales at cycle 13 (12 months) by treatment. Abbreviations. CI, confidence interval; EMTD, estimated mean treatment difference; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30.
EQ-VAS
At baseline, the EQ-VAS scores were similar between treatment arms (mean [SD]: 70.79 [19.40] for zanubrutinib and 72.59 [17.38] for ibrutinib). The mean change from baseline in the EQ-VAS also demonstrated a similar pattern of improvement with zanubrutinib and ibrutinib therapy up to cycle 13. At cycle 7, the mean change (SD) from baseline was 7.92 (18.25) and 3.44 (16.97) for zanubrutinib and ibrutinib, respectively. At cycle 13, the mean change (SD) from baseline was 7.75 (18.81) for zanubrutinib compared to 3.92 (16.78) for ibrutinib.
Discussion
In these PRO analyses of the ALPINE trial, patients with R/R CLL/SLL who received zanubrutinib monotherapy reported improvements in HRQoL. Descriptive analysis showed improvements (increase in GHS and functioning scales) and decrease or maintenance in the CLL/SLL-related symptoms and improved general health status measured via the EQ-VAS scores through cycle 13. Examination of the clinical meaningfulness of the key PRO endpoints in the key clinical cycles showed that patients treated with zanubrutinib experienced clinically meaningful improvements in GHS, physical functioning, role functioning, fatigue, and pain. Moreover, the improvements in GHS/QoL at cycle 7 experienced by the zanubrutinib arm were significantly greater than improvements in the ibrutinib arm; however, there were no significant differences between the arms for the remaining outcomes.
Compared with baseline, the positive improvements in some facets of HRQoL, as assessed by disease-related symptoms and treatment-related effects and functioning, were more pronounced at 6 months with zanubrutinib than ibrutinib. This suggests that treatment with zanubrutinib could potentially improve HRQoL earlier than ibrutinib in this patient population. Alternatively, it could suggest that patients with side effects on ibrutinib are still included early in the study, but drop out between 6 and 13 months, leaving patients who are doing better on ibrutinib. Additionally, improvements in certain domains may take longer to manifest than changes in disease progressionCitation25, which could explain why there were numerical but not significant improvements in some EORTC QLQ-C30 endpoints from baseline to 12 months, indicating that the HRQoL results could be even more pronounced after a longer follow-up duration.
These HRQoL findings appear consistent with previously published safety results from the ALPINE trialCitation19. Specifically, the rates of AEs such as cardiac disorders and serious AEs leading to discontinuation were lower in patients treated with zanubrutinib versus ibrutinib, which aligns with greater HRQoL improvements in patients treated with zanubrutinib. Although this is encouraging, further analyses are needed to examine the relationships between the HRQoL results and AEs. Additional analysis into other clinical endpoints, including efficacy, are warranted; however, it may be challenging to untangle the effects of improved efficacy versus lower rates of AEs on HRQoL following treatment with zanubrutinib.
The ALPINE trial adds to the growing evidence that treatment with BTK inhibitors can further improve the HRQoL of patients with CLL/SLL. The RESONATE-2 study was a phase 3 study investigating the use of ibrutinib versus chlorambucil to treat patients with treatment-naive CLL/SLLCitation8. PROs assessed, including the EQ-VAS, resulted in significantly greater improvements with ibrutinib versus chlorambucil (p <.001). The SEQUOIA study is an ongoing phase 3 trial investigating the use of zanubrutinib versus bendamustine plus rituximab in patients with treatment-naive CLL/SLLCitation27. An interim data analysis found that patients treated with zanubrutinib versus bendamustine plus rituximab had significantly greater improvements in the EORTC QLQ-C30 GHS (least squares mean difference: 4.9; p = .017), physical functioning (3.8; p = .012), diarrhea (–6.2; p = .001), fatigue (–4.5; p = .047), and nausea/vomiting (–4.2; p = .002) at week 24 of treatmentCitation17.
The ALPINE trial is an open-label study that is currently ongoing and it is possible that the unblinded design may have affected patient sentiment about quality of life. Further data are needed to assess whether these results will represent long-term improvement patterns in patients. While the analyses conducted in this study were mostly descriptive, future studies should incorporate statistical modeling to investigate associations among the changes in PRO endpoints. Furthermore, an investigation of differences related to sex and regional/ethnic characteristics in HRQoL outcomes is paramount.
Conclusions
HRQoL is an important factor for patients and physicians to consider when choosing treatment options. The results of this study suggest that zanubrutinib monotherapy improves HRQoL outcomes in patients with R/R CLL/SLL. These results were maintained from 6 months through 12 months, the cutoff point for these analyses. Long-term follow-up as well as additional analyses linking PRO endpoints to clinical outcomes will further determine the full extent to which zanubrutinib improves patient HRQoL.
Transparency
Disclosure of financial/other relationships
PH received honoraria from Janssen, AbbVie, and Roche and received travel funds from Janssen and AbbVie. JB has served as a consultant for AbbVie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, MorphoSys AG, Nextcea, Novartis, Pfizer, and Rigel. NL received research funding from Loxo Oncology, Juno, Oncternal, Verastem, TG Therapeutics, MingSight, and Octapharma and has been in a consulting role for AbbVie, AstraZeneca, BeiGene, Genentech, Celgene, Gilead, Janssen, and Pharmacyclics. SO has served as a consultant for AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb, Celgene, DynaMed, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma, Inc., Merck, NOVA Research, Pfizer, Pharmacyclics, TG Therapeutics, Vaniam, Verastem, and Vida Ventures and received research funding from Acerta, Alliance, BeiGene, Ltd, Caribou Biosciences, Inc., Gilead, Kite, Loxo Oncology, Inc., Mustang, Nurix Therapeutics, Inc., Pfizer, Pharmacyclics, Regeneron Pharmaceuticals, and TG Therapeutics. CST received research funding from Janssen and AbbVie and received honoraria from Janssen, AbbVie, BeiGene, Novartis, and Roche. KY, GB, and KW are employees of BeiGene and may own company stock/stock options. BE has served as a consultant for Janssen, Roche, Novartis, AbbVie, Gilead, Celgene, ArQule, AstraZeneca, Oxford Biomedica (UK), and BeiGene; has served on the speaker’s bureaus for Janssen, Gilead, Roche, AbbVie, Novartis, Celgene, Adaptive Biotechnologies, BioGene, and AstraZeneca; received research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; and received travel funds from Janssen, Roche, Novartis, AbbVie, Gilead, and Celgene. The other authors declare no competing interests.
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
JB, CT, NL, SO, LQ, BE, GB were responsible for study design and data collection. All authors were responsible for data interpretation and reviewing and approving drafts of the manuscript. KW and GB were responsible for data analysis. KY, GB, TS, KW were responsible for data interpretation.
Ethics statement
This protocol was approved by the ethics committees of the participating sites. The study was performed according to the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and the requirements of the public registration of clinical trials.
Written informed consent was obtained prior to participation in the study.
Supplemental Material
Download MS Word (22.5 KB)Acknowledgements
Editorial assistance was provided by Jason C. Allaire, PhD, of Generativity Solutions Group. This assistance was funded by BeiGene, Ltd.
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