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BackgroundWhile therapeutic bronchoscopy has been used to treat malignant central (CAO) airway obstruction for >25 years, there are no studies quantifying the impact of therapeutic bronchoscopy on long-term quality-adjusted survival.MethodsWe conducted a prospective observational study of consecutive patients undergoing therapeutic bronchoscopy for CAO. Patients had follow-up at 1 week and monthly thereafter until death. Outcomes included technical success (ie, relief of anatomic obstruction), dyspnoea, health-related quality of life (HRQOL) and quality-adjusted survival.ResultsTherapeutic bronchoscopy was performed on 102 patients with malignant CAO. Partial or complete technical success was achieved in 90% of patients. At 7 days postbronchoscopy, dyspnoea improved (mean ∆Borg-day-7=−1.8, 95% CI −2.2 to −1.3, pConclusionsTherapeutic bronchoscopy improves HRQOL as compared with baseline, resulting in approximately a 5.8% improvement in HRQOL per day of life. The risk-benefit profile in these carefully selected patients was very favourable.Trial registration numberResults; NCT03326570.

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 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.

Breast cancer treatment recommendations will often require an appraisal of likely benefits in relation to likely side effects on survival and quality of life end points, and possibly also an evaluation of the size of the anticipated net clinical benefit against financial costs. Quality-adjusted survival (QAS) analysis methods provide a formal approach for deriving an estimate of net clinical benefit to facilitate this appraisal process. QAS analysis methods have been applied in trials with breast cancer patients of adjuvant therapies as well as treatments for advanced/metastatic disease. QAS analyses based solely on trial data may fail to capture plausible longer-term benefits; thus, methods to explore the possible outcomes of treatment beyond the limits of trial data have been developed. These modeling approaches can help researchers gain insights and identify future research priorities, but do not replace the need for long-term evidence from randomized trials.

Purpose: To incorporate quality-of-life considerations in assessing high dose therapy (HDT) for patients with Multiple Myeloma (MM). Patients and methods: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to two randomized clinical trials conducted in patients with MM which compared randomized assignment to HDT vs. conventional chemotherapy (CCT) alone (MAG91) or followed by HDT (MAG90). Treatment benefit in terms of mean Q-TWiST was assessed through threshold utility analyses, i.e., sensitivity analyses of the choice of the utility coefficients over all possible values of utility weights. Results: In both trials, results slightly favored the first-line HDT group over the first-line CCT group, with an average gain in TWiST of about 5.5 months over the 58 month-median follow-up period (27.8 vs. 22.3 months, respectively) in the MAG90 trial and 5.8 months over the 56 month-median follow-up period (19.1 vs. 13.3 months, respectively) in the MAG91 trial. The utility threshold analyses revealed that the first-line HDT group had a statistically increased mean quality-of-life adjusted time compared to the other group for a broad range of utility coefficient values. Conclusion: The development of such understandable and intuitive measures of expressing the relative benefit of complex treatment strategies is expected to be used in clinical decision making in the near future.

We develop a method for incorporating covariates as regressors in a quality adjusted survival analysis (Q-TWiST) using Cox's proportional hazards model. The standard Q-TWiST method assumes that patients progress through a series of health states which differ in quality of life. The Kaplan-Meier product limit method is used to estimate the mean duration of each state by estimating the survival curves for the health state transition times. These estimates provide the basis for quality adjusted survival analysis. In this paper, the survival curves are modelled using Cox's proportional hazards regression. Quality adjusted survival is estimated given sets of covariate values, allowing one to profile patients. The results are useful for investigating how prognostic factors affect treatment benefits in terms of quality of life. We give a brief review of the standard Q-TWiST method and illustrate the extended methodology with an example from the International Breast Cancer Study Group Trial V comparing short duration versus long duration chemotherapy in the treatment of node-positive breast cancer.

The benefit of high-dose chemotherapy (HDC) has not been clearly demonstrated. It may offer disease-free survival improvement at the expense of major toxicity and increasing cost. We evaluated the trade-offs between toxicity, relapse, and costs using a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis.The analysis was conducted in the context of a randomized trial (PEGASE 01) evaluating the benefit of HDC for 314 patients with high-risk breast cancer. A Q-TWiST analysis was first performed to compare HDC with standard chemotherapy. We then used the results of this Q-TWiST analysis to inform a cost per quality-adjusted life-year (QALY) comparison between treatments.Q-TWiST durations were in favor of HDC, whatever the weighting coefficients used for the analysis. This benefit was significant when the weighting coefficient related to the time spent after relapse was low (0.38). For quite high values of this coefficient (0.78), HDC offered no benefit. For intermediate values, the results depended on the weighting coefficient attributed to the toxicity period. The incremental cost per QALY ranged from 12,691euro/QALY to 26,439euro/QALY, according to the coefficients used to weight toxicity and relapse.The benefits of HDC outweigh the burdens of treatment for a wide range of utility coefficients. Economic impact is not a barrier to HDC diffusion in this situation. Nevertheless, no significant benefit was demonstrated for a certain range of utility values.

3543 Background: The pivotal phase III PRIME trial demonstrated that, compared with FOLFOX alone, panitumumab plus FOLFOX prolongs overall survival (OS) and progression-free survival (PFS) in patie...

537 Background: The pivotal phase III PRIME trial demonstrated that, compared with FOLFOX alone, panitumumab plus FOLFOX prolongs overall survival and progression-free survival in patients with RASWT mCRC without having a detrimental effect on overall quality of life. The objective of this analysis was to use the quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method to compare quality-adjusted survival between the treatment arms of PRIME. Methods: Patients with RASWT mCRC from each treatment arm of PRIME were included in this analysis, and the area under the survival curve (AUSC) was estimated using the nonparametric Kaplan-Meier method (48 months follow-up). The AUSC was partitioned into three health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST, i.e., PFS minus TOX), and relapse (REL, i.e., OS minus PFS). The durations of the health states were then adjusted using utility weights derived from patient-reported EuroQoL 5 measures. The null hypothesis of no difference between treatment arms was tested based on the normal approximation, with standard errors calculated by the bootstrap method. In the primary analysis, TOX consisted of grade 3 and 4 adverse events. A sensitivity analysis, with grade 2, 3, and 4 adverse events classified as TOX, was performed. Results: Of 1,183 patients with mCRC who were randomized, 512 patients had RAS WT tumors (panitumumab plus FOLFOX, n=259; FOLFOX alone, n=253) and were included in this analysis. Patients receiving panitumumab plus FOLFOX had a significantly longer Q-TWiST (20.5 months) than patients receiving FOLFOX alone (18.2 months) resulting in 2.3 ± 1.0 (SE) additional quality-adjusted months (p

The quality of life of patients is an important component for the evaluation of therapies in clinical trials, especially in cancer. The Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) method evaluates treatment trade-offs in clinical trials using an endpoint based on both quantity and quality of life. The methodology has been most useful for evaluating the trade-off between increased toxic side effects of treatment and improved clinical outcome. This paper provides an overview of the Q-TWiST method, brief descriptions of related statistical tools for regression analysis and meta-analysis, and examples illustrating the techniques using data from cancer clinical trials.

Purpose: To quantify the quality of life of malignant glioma patients treated on a randomized Phase I/II trial of twice-daily radiation therapy (RT) and carmustine, using a modified quality adjusted survival (QAS) model, and to compare the QAS among assigned treatment arms. Materials and Methods: The Radiation Therapy Oncology Group (RTOG) accrued 786 malignant glioma patients to a Phase I/II randomized dose escalation trial of twice-daily RT with carmustine from 1983 to 1989. Patients were randomized to one of four arms of hyperfractionated RT in 1.2 Gy twice daily (BID) fractions (64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.6 Gy) or to either of two accelerated hyperfractionated RT arms in 1.6 Gy BID fractions (48.0 or 54.4 Gy). Although preliminary toxicity and survival data have been published, little information is available regarding the quality of these patients' lives during and following such therapy. QAS is a refinement of the methodology for assessing survival quality among breast cancer patients receiving adjuvant chemotherapy. The QAS method allows for inclusion of both improvement and decline in neurologic functional status. Patients were scored by the presence or absence of 15 neurologic signs and symptoms at on-study and at every follow-up. Within each category were gradations of severity, with the quality survival time (Q-TIME) adjusted according to any changes in these neurologic findings. The summation of all changes in signs and symptoms were weighted by 1/15th and incorporated into the QAS model as QAS=Q-TIME-TOX-RRX. TOX was the time spent with treatment-related toxicities, and RRX was the time spent in recovery from subsequent therapy. Results: Of 747 evaluable patients, the average QAS time was 18.5 months. The average QAS for the hyperfractionated arms of 64.8 Gy, 72.0 Gy, 76.8 Gy, and 81.6 Gy were 15.6, 20.8, 10.0, and 13.7 months, respectively. For the accelerated hyperfractionated RT arms of 48.0 and 54.4 Gy, the average QAS times were 13.1 and 13.4 months. The QAS time of the 72.0 Gy arm was significantly longer than that of all other groups, except the 64.8 Gy arm. As expected, the QAS times were strongly discriminated by both age and Karnofsky Performance Scores (KPS) (p

5049 Background: In a phase 3, randomized, 3-arm study of TEMSR or IFN or the combination of TEMSR + IFN in the first-line treatment of patients with advanced renal cell carcinoma (RCC) and poor-prognostic features, TEMSR improved overall survival (p=0.0069) and progression-free survival (p=0.0001) vs. IFN (Hudes et al. J Clin Oncol. 2006;24:LBA4). Quality-adjusted survival was a pre-defined endpoint and is reported. Methods: Quality-adjusted time without symptoms and toxicity (QTWiST) was estimated by partitioning overall survival into 3 distinct health states: time with serious toxicity, time with progression, and time without symptoms and toxicity (TWiST). Survival was value-weighted when patients completed quality of life questionnaires (EQ-5D) at weeks 12 and 32, when a grade 3 or 4 adverse event (AE) was reported, upon relapse or progression, or upon withdrawal from the study. Treatment group comparisons used restricted means analyses estimated from censored survival data. Restricted means were computed for duration of each health state by truncating data at median follow-up (17.9 months). Variance and covariance were estimated using bootstrap methods. Results: All 626 randomized patients in the study were included in computation of health state durations. EQ-5D questionnaires were obtained from 260/300 (87%) upon progression and 230/570 (40%) after a grade 3/4 AE. Patients receiving TEMSR alone had 38% greater TWiST than those receiving IFN alone (TEMSR=6.5 months vs. IFN=4.7 months, p=0.00048). There was no significant difference in TWiST between the combination arm and IFN alone (IFN+TEMSR=5.4 months vs. IFN=4.7 months, p=0.1288). Patients receiving TEMSR alone had 23% greater Q-TWiST than those receiving IFN alone (TEMSR=7.0 months vs. IFN=5.7 months; p=0.0015). There was no significant difference in Q-TWiST for the combination arm compared with IFN alone (IFN+TEMSR=6.1 months vs. IFN=5.7 months, p=0.3469). Conclusions: Patients with advanced RCC receiving TEMSR alone had significantly greater quality-adjusted survival than those receiving IFN alone. No significant financial relationships to disclose.

3625 Background: QoL is infrequently assessed in RCTs of adjuvant therapy for CRC. This analysis aims to assess QoL and QAS in patients receiving adjuvant 5-FU for stage II and III CRC according to treatment arm, age, gender and primary tumour location. Methods: We performed a multicentre RCT in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (n=404) or 12 weeks of PVI 5-FU (n=397). QoL was assessed by EORTC QoL core 30 questionnaire before randomisation, during treatment and follow-up to a maximum of 5 years. QAS analysis was performed by integrating the product of the grouped QoL and the survival function. P-values