Abstract
Acalabrutinib monotherapy (A) and acalabrutinib plus obinutuzumab (A + O) demonstrated improved efficacy and safety versus chlorambucil plus obinutuzumab (C + O) among treatment-naive patients with chronic lymphocytic leukaemia (CLL) in the ELEVATE-TN trial. The relative risk-benefit at a median follow-up of 47 months was assessed using Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) methodology. Patient data were partitioned into 3 states: time with toxicity (TOX); time without symptoms or toxicity (TWiST); and time after relapse (REL). Mean Q-TWiST was estimated by summing the mean time in each state, multiplied by its respective utility weight. Patients receiving A or A + O experienced significantly longer Q-TWiST versus C + O when toxicity was defined as grade 3–4 adverse events (AEs) (41.79 vs 34.56 months; 42.07 vs 34.56 months) and grade 2–4 AEs (35.07 vs 30.64 months; 34.21 vs 30.64 months). Overall, patients with treatment-naive CLL treated with A or A + O experienced significant gains in Q-TWiST compared with C + O.
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
Introduction
Acalabrutinib is a next-generation, selective Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and previously treated mantle cell lymphoma [Citation1]. In the ELEVATE-TN study, patients with untreated CLL received acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or chlorambucil plus obinutuzumab [Citation2]. At a median follow-up of 47 months, median progression-free survival (PFS) was significantly longer with acalabrutinib monotherapy (median not reached) and acalabrutinib plus obinutuzumab (median not reached) than with chlorambucil plus obinutuzumab (median 27.8 months; hazard ratio: 0.10 [acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab] and 0.19 [acalabrutinib monotherapy vs chlorambucil plus obinutuzumab]; p < 0.0001) [Citation2]. The median overall survival (OS) was not reached in any treatment arm; estimated 48-month OS rates were 93% for acalabrutinib plus obinutuzumab, 88% for acalabrutinib monotherapy, and 88% for obinutuzumab plus chlorambucil [Citation3]. Adverse events (AEs) of any grade reported in ≥30% of patients were diarrhea and headache with acalabrutinib monotherapy; diarrhea, headache, and neutropenia with acalabrutinib plus obinutuzumab; and neutropenia, infusion-related reaction, and nausea with chlorambucil plus obinutuzumab [Citation3]. The frequent occurrences of low-grade AEs, such as headache and diarrhea, across treatment arms may have negatively impacted patients’ daily activities.
Although treatment duration was longer with either acalabrutinib alone or combined with obinutuzumab than with chlorambucil plus obinutuzumab, treatment discontinuations due to AEs were not higher (9%, 11%, and 14%, respectively) [Citation2]. Assessment of patient-reported outcomes was an exploratory endpoint of ELEVATE-TN and was not collected in patients after they progressed, so there was a high percentage of missing data. The Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis is used to assess the balance of risk and benefit of oncology treatments [Citation4, Citation5]. The Q-TWiST analysis is an alternative quality-adjusted life-year (QALY) method that captures toxicity and mortality effects of treatment observed over the follow-up duration of a clinical trial. Q-TWiST has been assessed in patients with hematologic cancers [Citation5, Citation6]. Thus, the objective was to conduct a comprehensive Q-TWiST analysis to assess patients’ experiences when treated with acalabrutinib monotherapy or acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. We implemented the Q-TWiST approach by considering toxicity data and disease progression data, as a proxy for symptoms, from ELEVATE-TN. As a scenario analysis, an alternative definition of toxicity (i.e. grade 2–4 AEs) was used as compared to a typical Q-TWiST analysis (i.e. grade 3–5 AEs) to account for patients’ experiences associated with some lower-grade AEs that occur with BTK inhibitors.
Methods
Data source
This was an analysis of patient-level data from the randomized, open-label, phase 3 ELEVATE-TN study that enrolled patients with treatment-naive CLL [Citation2]. Patients who participated in ELEVATE-TN were either aged ≥65 years or were aged 18–64 years with comorbidities (creatinine clearance of 30–69 mL/min or Cumulative Illness Rating Scale for Geriatrics score >6). Patients were required to have an Eastern Cooperative Oncology Group performance status score of ≤2 and adequate hematologic, hepatic, and renal function. Patients were randomly assigned (1:1:1) to receive acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or chlorambucil plus obinutuzumab, administered in 28-day cycles. Oral acalabrutinib 100 mg was administered twice daily until progressive disease or unacceptable toxicity. Intravenous obinutuzumab was administered on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 (with chlorambucil) or cycle 2 (with acalabrutinib) and on day 1 (1000 mg) of cycles 2–6 (with chlorambucil) or 3–7 (with acalabrutinib). In the chlorambucil plus obinutuzumab arm, oral chlorambucil was given (0.5 mg/kg) on days 1 and 15 of each cycle, for 6 cycles. Investigator-assessed PFS was captured. Crossover to acalabrutinib monotherapy was allowed in patients who had disease progression with chlorambucil plus obinutuzumab. Safety was assessed in all patients who received at least 1 dose of treatment.
Statistical analyses
To conduct the Q-TWiST analysis, patient survival time was first partitioned into 3 health states: time with toxicity (TOX), time without symptoms (i.e. progression) or toxicities (TWiST), and time from progression until death, end of follow-up, or data cutoff (relapse [REL]) ( ).
Figure 1. Q-TWiST components. aToxicity was defined as either grade 3–4 AEs or grade 2–4 AEs. PFS, progression-free survival; REL, relapse; TOX, toxicity; TWiST, Time Without Symptoms or Toxicity.
The TOX state is the cumulative time spent with toxicity during the period from the date of randomization to either the day before the relapse date for patients with a relapse event or the relapse censor date for patients without a relapse event, where the relapse event is either disease progression or death. The relapse date was the earliest of progressive disease per investigator assessment and death. Toxicity was defined as grade 3–4 AEs for the primary analysis and grade 2–4 AEs for the scenario analysis. The TOX state was calculated at the patient level by summing up the time spent with toxicity for each patient. The number of days spent with toxicity was calculated from the “AE start date” to “AE end date.” For example, grade 2 infusion toxicity that resolved following infusion would count as 1 day of toxicity for that patient. AEs that occurred before randomization or after disease progression were not included in the summation. If a patient had multiple AEs in a day, the day was only counted once. If a patient had a toxicity that was not resolved before the relapse date, time spent in the TOX state for the patient was truncated at the relapse date. If a patient did not experience toxicity before the relapse date or relapse censor date, time spent in the TOX state for the patient was assigned 0 days.
The TWiST state is time spent without symptoms (i.e. without progression) or toxicity starting from the randomization date to 1 day before the relapse date or relapse censor date. The REL state is time spent in relapse starting from the relapse date or 1 day after the relapse censor date to the death date. If a patient had a relapse event date equal to their death date (i.e. died without disease progression), the REL state was recorded as 1 day.
Kaplan-Meier (K-M) survival curves were constructed for TOX, PFS, and OS. For the TOX curve, the event time for each patient was calculated by summing the days with toxicity before progression, with no patient censored. The restricted mean duration for each health state was derived from the area under or between the K-M survival curves using a cutoff of τ = 46.42 months, which is the minimum of the longest PFS event time among all 3 treatment arms.
Restricted mean TWiST duration equals restricted mean PFS minus restricted mean TOX, and restricted mean REL duration equals restricted mean OS minus restricted mean PFS. Q-TWiST was estimated by summing the utility-weighted restricted mean (RM) durations of TOX, TWiST, and REL: Q-TWiST = (UTOX x RM_TOX) + (UTWiST x RM_TWiST) + (UREL x RM_REL), where UTOX, UTWiST, and UREL are equal to the utility weight for each health state, respectively, and RM_TOX, RM_TWiST, and RM_REL represent RM durations of health states. The standard utility weights associated with each health state are fixed utility values traditionally used when utility values are not available from the clinical trial: 0.5 was used for TOX and REL, and 1.0 was used for TWiST, which represents a state of best health [Citation4].
Two sets of sensitivity analyses were conducted to assess the effect of varying utility weights on Q-TWiST. One sensitivity analysis used mean utility values estimated from the EuroQoL 5-Dimension 3-Level (EQ-5D-3L) data from ELEVATE-TN, while in the other, utility weights were varied from 0 to 1 for TOX and 0 to 1 for REL.
The EQ-5D-3L self-reported questionnaire is a health-related quality-of-life (QoL) measure that includes 5 dimensions (mobility, self-care, usual activities, pain and discomfort, anxiety and depression), each with 3 levels. Information from the EQ-5D-3L questionnaire was collected at baseline, every 4 weeks from cycles 1–7, then every 24 weeks until death, disease progression EQ-5D-3L single-index utility weights are mean EQ-5D-3L utility values [Citation7] estimated from a mixed model for repeated measures (MMRM) (Supplementary Table S1).
The second sensitivity analysis was conducted to explore the robustness of the treatment benefit with respect to uncertainty in utility values. The analysis was a 2-dimensional (2D, i.e. 2 utility weights out of the 3 included in the Q-TWiST calculation were varied) threshold analysis. In the 2D threshold analysis, the utility values for TOX and REL varied from 0 to 1 while assuming 1 for TWiST. However, it should be noted that utilities >0.70 for TOX and REL can be considered clinically implausible for patients with CLL based on health-related QoL data from patients with CLL [Citation8]. Threshold analysis was used to assess utility weights at which Q-TWiST difference favors an acalabrutinib-containing regimen or chlorambucil plus obinutuzumab. The results of the threshold (sensitivity) analysis are presented graphically indicating scenarios in which the differences are statistically significant (Supplementary Fig. S1 and S2). The magnitude of the Q-TWiST difference (in months) is given by the numbered lines within the plot, with positive numbers favoring acalabrutinib monotherapy or acalabrutinib plus obinutuzumab over chlorambucil plus obinutuzumab.
Relative Q-TWiST gains were calculated by dividing the difference in Q-TWiST between treatment arms by the restricted mean survival duration of the comparator (SoC) arm using the formula (Q-TWiST exptal arm – Q-TWiST SoC ) ÷ (TOX SoC + TWiST SoC + REL SoC ), where TOX SoC, TWiST SoC , and REL SoC represent the restricted mean duration of TOX, TWiST, and REL, respectively, for the comparator arm; their sum equals the restricted mean of overall survival of the comparator arm. We then appraised the results based on the clinically important threshold of ≥10% [Citation9].
The 95% confidence intervals (CIs) for the mean differences were read from bootstrapped samples while the P-values were calculated using t-tests based on the normal approximation, in which variances were estimated by bootstrapping. A total of 25,000 replications were done in bootstrapping. p < 0.05 was considered statistically significant.
Results
The Q-TWiST analysis included 179 patients who received acalabrutinib monotherapy, 178 patients who received acalabrutinib plus obinutuzumab, and 177 patients who received chlorambucil plus obinutuzumab. Grade 2–4 AEs and grade 3–4 AEs were reported in 150 (83.8%) and 83 (46.4%) of the patients who received acalabrutinib monotherapy, 159 (89.3%) and 120 (67.4%) of the patients who received acalabrutinib plus obinutuzumab, and 159 (94.0%) and 114 (67.4%) of the patients who received chlorambucil plus obinutuzumab, respectively.
Q-TWiST analysis for toxicity definition of grade 3–4 adverse events
When toxicity was defined as grade 3–4 AEs, patients in either acalabrutinib, containing arm had a significantly longer duration of TWiST (mean difference for acalabrutinib monotherapy, 13.42 months [95% CI, 10.49, 16.34], p < 0.0001; the mean difference for acalabrutinib plus obinutuzumab, 13.63 months [95% CI, 10.81, 16.40], p < 0.0001) and a significantly shorter duration of REL (mean difference for acalabrutinib monotherapy, −12.22 months [95% CI, −14.68, −9.74], p < 0.0001; mean difference for acalabrutinib plus obinutuzumab, −13.49 months [95% CI, −15.79, −11.21], p < 0.0001), with a numerically shorter duration of TOX for acalabrutinib monotherapy (mean difference, −0.15 months [95% CI, −1.48, 1.15], p = 0.8245), compared with patients receiving chlorambucil plus obinutuzumab (,). A slightly longer duration of TOX was observed with acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab; however, the difference was not statistically significant (mean difference, 1.23 months [95% CI, −0.22, 2.68], p = 0.0940).
Figure 2. Partitioned survival plots with (A) acalabrutinib monotherapy and chlorambucil plus obinutuzumab and (B) acalabrutinib plus obinutuzumab and chlorambucil plus obinutuzumab based on toxicity definitions of grade 3–4 AEsa. The area of the yellow shading corresponds to the mean duration for TOX. The area of the blue shading between the TOX and PFS curves corresponds to the mean duration for TWiST. The area of the red shading between the PFS and OS curves corresponds to the mean duration for REL. aBased on PFS per INV as a relapse event. bNumber of patients in TOX state. Numbers at risk for TOX, PFS, and OS correspond to the Kaplan–Meier curves in the upper borders of the TOX, TWiST, and REL areas, respectively. A: acalabrutinib; AEs: adverse events; C: chlorambucil; INV: local investigator; O: obinutuzumab; OS: overall survival; PFS: progression-free survival; REL: relapse; TOX: toxicity; TWiST: Time Without Symptoms or Toxicity.
Table 1. Mean duration of health states and Q-TWiST with acalabrutinib monotherapy versus chlorambucil plus obinutuzumab and acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab based on grade 3–4 AEs.
When utility values for TOX, TWiST, and REL were fixed, Q-TWiST duration was significantly longer with acalabrutinib-containing arms than with chlorambucil plus obinutuzumab (mean difference for acalabrutinib monotherapy, 7.23 months [95% CI, 5.14, 9.29], p < 0.0001; mean difference for acalabrutinib plus obinutuzumab, 7.51 months [95% CI, 5.45, 9.52], p < 0.0001). In the sensitivity analysis, when weights were mean EQ-5D-3L utilities estimated from MMRM, Q-TWiST duration for acalabrutinib monotherapy was not different from that of chlorambucil plus obinutuzumab (mean difference, 1.31 months [95% CI, −0.23, 2.86], p = 0.0979), but was statistically significantly longer for acalabrutinib plus obinutuzumab (mean difference, 1.60 months [95% CI, 0.05, 3.18], p = 0.0452). In the 2D threshold analysis, the relative Q-TWiST gains favored acalabrutinib, containing arms over chlorambucil plus obinutuzumab across variations of the utility weights (0–1) for REL and TOX, while holding the utility weight constant at 1 for TWiST (Supplementary Fig. S1). The relative Q-TWiST gains were not sensitive to the TOX utility value, primarily because the TOX duration difference between the 2 treatments was small.
Q-TWiST analysis for toxicity definition of grade 2–4 adverse events
For the scenario analysis, where the definition of toxicity was changed to include grade 2 AEs (and therefore based on grade 2– 4 AEs), compared with chlorambucil plus obinutuzumab, patients in acalabrutinib, containing arms had significantly longer durations of TOX (mean difference for acalabrutinib monotherapy, 5.45 months [95% CI, 2.35, 8.50], p = 0.0006; mean difference for acalabrutinib plus obinutauzumab, 9.10 months [95% CI, 5.93, 12.21], p < 0.0001) and TWiST (mean difference for acalabrutinib monotherapy, 7.82 months [95% CI, 4.45, 11.21], p < 0.0001; mean difference for acalabrutinib plus obinutuzumab, 5.76 months [95% CI, 2.51, 9.00], p = 0.0005), and a significantly shorter duration of REL (mean difference for acalabrutinib monotherapy, −12.22 months [95% CI, −14.68, −9.74], p < 0.0001; mean difference for acalabrutinib plus obinutuzumab, −13.49 months [95% CI, −15.79, −11.21], p < 0. 0001) (,).
Figure 3. Partitioned survival plots with (A) acalabrutinib monotherapy and chlorambucil plus obinutuzumab and (B) acalabrutinib plus obinutuzumab and chlorambucil plus obinutuzumab based on toxicity definitions of grade 2–4 AEsa. The area of the yellow shading corresponds to the mean duration for TOX. The area of the blue shading between the TOX and PFS curves corresponds to the mean duration for TWiST. The area of the red shading between the PFS and OS curves corresponds to the mean duration for REL. aBased on PFS per INV as relapse event. bNumber of patients in TOX state. Numbers at risk for TOX, PFS, and OS correspond to the Kaplan–Meier curves in the upper borders of the TOX, TWiST, and REL areas, respectively. A: acalabrutinib; AEs: adverse events; C: chlorambucil; INV: local investigator; O: obinutuzumab; OS: overall survival; PFS: progression-free survival; REL: relapse; TOX: toxicity; TWiST: Time without symptoms or toxicity.
Table 2. Mean duration of health states and Q-TWiST with acalabrutinib monotherapy versus chlorambucil plus obinutuzumab and acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab based on grade 2–4 AEs.
The duration of Q-TWiST using fixed utility values for all health states remained significantly longer for patients who received acalabrutinib-based therapy compared with patients who received chlorambucil plus obinutuzumab (mean difference for acalabrutinib monotherapy, 4.43 months [95% CI, 2.27, 6.59], p < 0.0001; the mean difference for acalabrutinib plus obinutuzumab, 3.57 months [95% CI, 1.45, 5.66], p = 0.0009). Results of the sensitivity analysis showed that the duration of Q-TWiST with acalabrutinib-containing arms was not different than the duration for chlorambucil plus obinutuzumab when weights were mean EQ-5D-3L utilities estimated from MMRM (mean difference for acalabrutinib monotherapy, 0.02 months [95% CI, −1.55, 1.61], p = 0.9835); mean difference for acalabrutinib plus obinutuzumab, 0.12 months [95% CI, −1.45, 1.72], p = 0.8848). Results of the 2D threshold analysis showed that Q-TWiST difference was sensitive to the utility values, favored acalabrutinib, containing arms over chlorambucil plus obinutuzumab, and was statistically significant in clinically plausible regions (Supplementary Fig. S2).
Relative Q-TWiST gains
Compared with chlorambucil plus obinutuzumab, the relative gains in Q-TWiST for acalabrutinib monotherapy were 16.8% when toxicity was defined as grade 3–4 AEs and 10.3% when toxicity was defined as grade 2–4 AEs. Relative gains in Q-TWiST for acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab were 17.4% when toxicity was defined as grade 3–4 AEs and 8.3% when toxicity was defined as grade 2–4 AEs.
Discussion
When assessing the benefits versus the risks of therapy, the Q-TWiST analysis is a useful tool to assist patients and physicians in making treatment decisions. Available evidence about treatment preferences in CLL demonstrates that, although patients and physicians similarly value PFS as the most important treatment attribute and agree on the relative importance of high-grade adverse events, they differ regarding the relative importance of associated bothersome toxicities [Citation10,Citation11]. The Q-TWiST analysis offers valuable context to patients by evaluating time with and without toxicity while on a given therapy before relapse and time spent in relapse and integrates these factors into a single measure that can aid physicians in guiding patients through treatment options [Citation6,Citation9]. The current analysis was conducted using 47 months median follow-up data from the ELEVATE-TN study that demonstrated significant PFS benefit, low incidences of cardiovascular toxicities, and low rates of discontinuation for acalabrutinib-containing arms compared with the chlorambucil–obinutuzumab arm [Citation3]. This Q-TWiST analysis took into account the findings from ELEVATE-TN to assess patients’ experiences and estimated statistically significantly longer Q-TWiST for acalabrutinib monotherapy or acalabrutinib plus obinutuzumab than chlorambucil plus obinutuzumab. The relative gain in Q-TWiST, depending on the definition of toxicity, was equivalent to 16.8% (grade 3–4 AEs) and 10.3% (grade 2–4 AEs) of the restricted mean of OS (of chlorambucil plus obinutuzumab) for acalabrutinib monotherapy and 17.4% (grade 3–4 AEs) for acalabrutinib plus obinutuzumab, all of which were considered clinically important because they met the criterion of ≥10% used to determine clinically important Q-TWiST improvement [Citation9]. Although the relative Q-TWiST gain reported in this analysis was 8.3% for acalabrutinib plus obinutuzumab (grade 2–4 AEs), it exceeds the relative mean/median Q-TWiST gain of 7.8%/7.2% reported from a systematic review of 81 Q-TWiST comparisons across various cancer types [Citation6].
In the current Q-TWiST analysis, the definition of toxicity included grade 3–4 AEs, as a primary analysis, or grade 2–4 AEs, as a scenario analysis. Grade 2 AEs occurred more frequently with BTK inhibitor treatment; therefore, changing the definition accounted for the patients’ experiences typically associated with low-grade AEs, which could be comparable in terms of duration with the patients’ experiences associated with grade 3–4 AEs. Based on the definition of toxicity as grade 3–4 AEs, time in the TWiST state was significantly longer for both acalabrutinib monotherapy and acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab, while time in the TOX state was not significantly different. When the definition of toxicity was grade 2–4 AEs, time spent in the TOX state increased for all treatments. In addition, time in the TOX state was significantly longer with acalabrutinib monotherapy and acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. This could be due to the significantly longer time on treatment for acalabrutinib, which was given until progression, compared with chlorambucil plus obinutuzumab, which was given for a fixed duration of 6 months. However, time in the TWiST state remained significantly longer with both acalabrutinib monotherapy and acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab, demonstrating that patients experience longer times without symptoms or toxicity while on acalabrutinib therapy. Time spent in REL did not vary by toxicity definition and was significantly shorter with acalabrutinib monotherapy and acalabrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. ELEVATE-TN was designed to assess superiority of acalabrutinib with or without obinutuzumab versus chlorambucil plus obinutuzumab and the study was powered to detect a difference (hazard ratio: 0.60) in PFS. Although it was not powered to detect a difference in PFS between the acalabrutinib-containing arms [Citation2,Citation12], Q-TWiST results were similar for the acalabrutinib arms despite longer time with TOX for acalabrutinib plus obinutuzumab and longer time in REL for acalabrutinib monotherapy.
Given the indolent nature of CLL and that acalabrutinib is a chronic treatment, long-term assessment of health-related QoL is important. This analysis used longer-term clinical trial data with a median follow-up of 47 months, representing an update from previously presented results [Citation13]. The use of EQ-5D-3L utility weights in the sensitivity analysis was a potential limitation because the ELEVATE-TN study was not designed to collect EQ-5D-3L data after disease progression, which likely resulted in an unreliable estimate of the utility of the relapse state. This element of the ELEVATE-TN study design also made it necessary to use fixed utility weights (0.5 for TOX and REL and 1 for TWiST) as a base case instead of trial-based utilities. We conducted the 2D threshold analysis to demonstrate the robustness of the findings of the Q-TWiST analysis. The results of the 2D threshold analysis showed that the Q-TWiST gains were more sensitive to the utility weights when TOX was defined as grade 2–4 AEs compared with when TOX was defined as grade 3–4 AEs. Overall, however, the results of the 2D threshold analysis, regardless of the TOX definition, favored acalabrutinib monotherapy or acalabrutinib plus obinutuzumab in clinically plausible regions (utility value <0.70 for TOX and REL). The relative Q-TWiST gain indicated a clinically important difference in favor of acalabrutinib alone or with obinutuzumab versus chlorambucil plus obinutuzumab for both toxicity definitions except for acalabrutinib plus obinutuzumab, in which it was 8.3% when toxicity was defined as grade 2–4 AEs. This result could have been caused by the additional burden associated with lower-grade AEs that occurred during acalabrutinib combination therapy.
In conclusion, treatment with acalabrutinib, as monotherapy or in combination with obinutuzumab, resulted in a statistically significant and clinically important improvement in quality-adjusted time without symptoms of disease progression and toxicity compared with chlorambucil plus obinutuzumab (except when toxicity was defined as grade 2–4 AEs for the combination). The findings from this analysis showed that patients in ELEVATE-TN who received either acalabrutinib monotherapy or acalabrutinib plus obinutuzumab had prolonged survival without progression or toxicity and a shorter time in relapse compared with patients who received chlorambucil plus obinutuzumab. Even when the definition of toxicity was expanded to include grade 2 AEs, and despite the chronic nature of administration of acalabrutinib, use of this BTK inhibitor demonstrated longer time spent in the TWiST state and continues to represent better treatment potential than chlorambucil plus obinutuzumab.
Supplemental Material
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Medical writing and editorial support were provided by Cathy R. Winter, PhD, and Maria Ali, PhD of Peloton Advantage, LLC (Parsippany, NJ, USA), an OPEN Health company, and funded by AstraZeneca. The authors directed the development of the manuscript and are fully responsible for all content and editorial decisions.
Data availability statement
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.
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