A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Abstract

Background: Acalabrutinib (Acala) is a next-generation, highly selective, covalent BTK inhibitor (BTKi) approved for the treatment of CLL. The phase 3 ASCEND study demonstrated significant progression-free survival (PFS) benefit with Acala vs investigator's choice of chemoimmunotherapy (bendamustine + rituximab [BR]) or pi3K inhibitor (idelalisib) + rituximab (IR) in R/R CLL patients (pts) (Ghia et al. J Clin Oncol. 2020). In ELEVATE-RR, Acala demonstrated non-inferior PFS vs a first-generation BTKi (ibrutinib [Ibr]) in R/R CLL pts with high-risk genomics (Byrd et al. J Clin Oncol. 2021). Acala was well tolerated in both trials. Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis balances risks (toxicity) and benefits (prolonged survival without symptoms of disease progression or adverse events [AEs]) of oncology treatments. We conducted a Q-TWiST analysis using data from these trials to assess risk-benefit of Acala vs comparators among R/R CLL pts. Methods: Patient survival time with 16 months (ASCEND) and 41 months (ELEVATE-RR) of median follow-up data were partitioned into 3 states: time with toxicity before disease progression (TOX); time without progression or toxicity (TWiST); and time from disease progression until death or end of follow-up (relapse [REL]). Toxicity was defined as grade 3/4 AEs and, for the comparison vs Ibr, an additional definition of toxicity included AEs of any grade with frequency ≥10% (AE ≥10%). Sensitivity analyses with toxicity defined as grade 2-4 AEs will be presented. Kaplan-Meier survival curves were constructed for TOX, PFS, and overall survival (OS). For the TOX curve, event time for each pt was calculated by summing days with AEs (per toxicity definition) before disease progression, with no pt censored. Restricted means were calculated for the longest PFS time among treatment arms. Restricted mean TWiST duration was estimated using the difference between restricted means of PFS and TOX. Restricted mean REL duration was estimated using the difference between restricted means of OS and PFS. Q-TWiST was calculated by summing weighted restricted mean durations of TOX, TWiST, and REL. Utility of 1.0 for TWiST and 0.5 for TOX and REL (Gelber et al. Am Statistician. 1995) were applied. Sensitivity analysis was conducted using utility measures from trial data. Two-sided p<0.05 indicated statistical significance. Results: Among Acala vs IR/BR-treated pts, significantly longer duration of TWiST (mean diff, 3.58 months [95% CI, 2.42, 4.74]) and shorter duration of REL (mean diff, −2.51 months [95% CI, −3.50, −1.60]) and TOX (mean diff, −0.73 months [95% CI, −1.24, −0.24]) were found, indicating Acala vs IR/BR-treated pts had longer time without disease progression and toxicity and shorter time with toxicity. Q-TWiST was significantly different (1.96 months [95% CI, 1.13, 2.81]) between Acala (17.48 months) and IR/BR (15.52 months). In the Acala and Ibr comparison, differences in durations of TWiST and TOX varied based on the toxicity definition while the difference in REL durations remained consistent (mean diff, 0.37 months [95% CI, −1.82, 2.60]; p=0.33]). With the toxicity definition of AE ≥10%, Q-TWiST was significantly different (2.56 months [95% CI, 0.19, 4.83]) for Acala (33.02 months) vs Ibr (30.46 months). When toxicity was defined as grade 3/4 AEs, Q-TWiST had higher estimates for Acala but the difference was not statistically significant (1.28 months [95% CI, −1.34, 3.80]). In the sensitivity analysis, Q-TWiST gains were not statistically significant, most likely because the study was not designed to collect EQ-5D data post-treatment discontinuation. Conclusions: Q-TWiST analyses integrate efficacy, safety, and quality of life into a more appropriate measure useful for detailed benefit-risk assessment of cancer treatment. This analysis demonstrated that Acala treatment is significantly superior to IR/BR treatment. Quality-adjusted survival gains of Acala over Ibr varied by toxicity definition, but was numerically higher for Acala. Overall, Acala demonstrated a favorable benefit-risk profile vs different comparators in R/R CLL. Figure 1 Figure 1. Disclosures Seymour: Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaitonde: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Cai: Celgene Corporation: Ended employment in the past 24 months; Google: Current equity holder in publicly-traded company; AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Mato: Johnson and Johnson: Consultancy, Research Funding; MSKCC: Current Employment; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genmab: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AstraZeneca: Consultancy.

Health Utility Adjusted Survival: a Composite Endpoint for Clinical Trial Designs

“…Some methods that can combine survival and utility have been proposed and used to analyze clinical trial data, and the most commonly used method is called Q-TWiST (Quality-adjusted Time Without Symptoms of disease or Toxicity). [5][6][7][8][9][10][11][12] Though Q-TWiST has not been commonly seen as a primary endpoint for designing new studies, researchers have derived its statistical properties as well as formulas for sample size calculations. 8 That being said, one major issue about Q-TWiST is that it divides each patient's status into three states (toxicity, time without symptoms and toxicity, and relapse) and uses pre-selected weights for different states.…”