Quality-adjusted Time Without Symptoms Or Toxicity Research Articles

Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma

BackgroundThe phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity.MethodsUsing data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important.ResultsIn all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up.ConclusionsNIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.

Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of patients in CheckMate 649: Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC).

273 Background: In CheckMate 649 (CM 649), a randomized phase 3 trial of first-line treatment of advanced GC/GEJC/EAC, patients receiving nivolumab combined with chemotherapy (NIVO plus chemo) experienced superior overall survival (OS), progression-free survival (PFS), and maintained their HRQOL for longer duration versus chemo alone. In this analysis, we combined efficacy and HRQOL data from CM-649 into a single metric, quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST), to compare the net benefits of NIVO plus chemo versus chemo alone. Methods: In this analysis, OS was partitioned into three health states: time with grade 3/4 toxicity after randomization and before progression (TOX), time without symptoms of disease progression or toxicity (TWiST), and time from relapse or progression until death (ie, relapse, REL). Mean Q-TWiST was determined by multiplying each state’s duration with its utility (U) (U[TWiST], 1.0; U[TOX], 0.5; U[REL], 0.5). Relative Q-TWiST gains (calculated as Q-TWiST difference divided by chemo only OS) of ≥ 10% and ≥ 15% were defined as clinically important and clearly clinically important, respectively, based on established thresholds for clinical importance in prior Q-TWiST literature. Q-TWiST differences between treatments were calculated separately for patients whose tumors expressed PD-L1 CPS ≥ 5 and for all randomized. A threshold utility analysis assessed Q-TWiST differences by varying the TOX and REL utility between 0 and 1. Results: Compared with chemo alone, treatment with NIVO plus chemo was associated with Q-TWiST improvement of 2.8 months (95% CI 1.0-3.7; relative gain 20.6% [clearly clinically important]) in patients with PD-L1 CPS ≥ 5, and 1.8 months (95% CI 0.9-2.7; relative gain 12.7% [clinically important]) in all randomized patients, respectively. Threshold analyses showed that compared with chemo alone, treatment with NIVO plus chemo was associated with statistically significant Q-TWiST improvements exceeding minimum clinically important differences across the full range of TOX and REL utility values. Conclusions: Among previously untreated patients with GC/GEJC/EAC in CM-649, NIVO plus chemo significantly improved quality-adjusted survival compared with chemo alone. Q-TWiST gains with NIVO plus chemo were driven mostly by longer time patients experienced without symptoms of disease progression or toxicity (TWiST), and were associated with statistically significant and clinically meaningful gains. These Q-TWiST results provide further understanding of both a survival and quality of life benefit of NIVO plus chemo versus chemo alone, and may aid clinicians and patients in management decisions for this patient population.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial

BackgroundMONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. MethodsKaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. ResultsMean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022). ConclusionR+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of trastuzumab deruxtecan (T-DXd) versus chemotherapy in patients with advanced gastric cancer from the DESTINY-Gastric01 trial.

4057 Background: DESTINY-Gastric01 (NCT03329690) is a randomized, phase 2 study evaluating trastuzumab deruxtecan (T-DXd) in patients with HER2-positive advanced gastric cancer who progressed after ≥2 regimens. T-DXd significantly improved objective response rate (51% vs. 14%; P &lt; 0.001) and overall survival (median OS; 12.5 vs. 8.4 months; P = 0.01) relative to chemotherapy (irinotecan or paclitaxel), leading to regulatory approval in USA and Japan. This post hoc analysis evaluated the overall effect of treatment differences on the quality of survival after discounting for time spent with toxicities or disease progression by comparing the Q-TWiST for patients who received T-DXd versus those who received chemotherapy. Methods: Patients were randomized 2:1 to receive T-DXd or chemotherapy. For each treatment arm, OS, truncated at 10.1 months (the median OS for the entire analysis population, following Q-TWiST convention), was partitioned into three health states: time with grade ≥3 toxicities before disease progression (TOX), time before disease progression without symptoms of disease progression or toxicity (TWiST), and time following disease progression prior to death or censoring (PROG). Mean duration in each state was weighted by a utility score, determined first in a threshold analysis, using a range of hypothetical utility values to generate quality-adjusted states, and then based on observed EQ-5D-5L scores, for that state; the sum of the utility-weighted durations yielded the Q-TWiST value for the time until the end of 10.1 months’ follow-up. In both threshold and observed utility analyses, 95% confidence intervals (CIs) and two-sided P values were calculated using the bootstrap method. Results: Relative to patients receiving chemotherapy (n = 62), patients receiving T-DXd (n = 125) had significantly longer unweighted durations of TOX (3.0 vs. 1.6 months; P &lt; 0.01) and TWiST (3.1 vs. 2.1 months; P &lt; 0.05) and a shorter unweighted duration of PROG (2.4 vs. 3.7 months; P &lt; 0.01). Using a matrix of 25 hypothetical utility-weight combinations, with a TWiST utility of 1 and TOX and PROG utilities ranging from 0 to 1, Q-TWiST differences between treatment arms ranged from −0.5 to 2.3 months, favoring T-DXd in 22 combinations, of which 15 were statistically significant. Using observed EQ-5D-5L utility values, Q-TWiST was 0.9 months (95% CI, 0.2-1.5) longer for T-DXd than for chemotherapy (6.6 vs. 5.7 months), significantly favoring T-DXd ( P &lt; 0.05). Conclusions: Over a 10-month follow-up period, treatment with T-DXd was associated with a statistically significant gain in quality-adjusted OS versus chemotherapy among previously treated patients with gastric cancer. An analysis using observed EQ-5D-5L utility scores found a statistically significant advantage in Q-TWiST for T-DXd. Clinical trial information: NCT03329690.

Quality-adjusted survival in patients with metastatic colorectal cancer treated with fruquintinib in theFRESCO trial.

Aim: To assess whether the survival benefit of fruquintinib is quality-adjusted. Materials &methods: Data of 416 metastatic colorectal cancerpatients from the Phase III FRESCO trial were used. The Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis assessed the quality-adjusted survival benefit of fruquintinib versus placebo, accounting for freedom from symptomatic disease and from severe side effects of treatment. Results: Fruquintinib significantly improved patients' Q-TWiST (difference: 2.23 [1.41, 3.04] months) versus placebo. The Q-TWiST gain was 28.3% in the base case and ranged from 16.7 to 39.9% in the threshold analysis, favoring fruquintinib. The Q-TWiST benefit was observed in fruquintinib-treated patients regardless of prior targeted therapy. Conclusion: Fruquintinib provides a clinically meaningful quality-adjusted survival benefit versus placebo as a third-line treatment for metastatic colorectal cancer patients.

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma.

PURPOSETo investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.PATIENTS AND METHODSPatients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.RESULTSThe visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.CONCLUSIONThe significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell carcinoma (RCC).

5067 Background: In the primary analysis of Study 205 phase II trial (NCT01136733), lenvatinib+everolimus (vs everolimus) significantly prolonged progression-free survival (median PFS; 14.6 vs 5.5 months, HR = 0.40, 95% CI [0.24, 0.68]) in advanced RCC patients who received one prior anti-angiogenic therapy. Overall treatment differences were evaluated in a post hoc analysis using a quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) methodology. Methods: Patients’ survival time was partitioned into three mutually exclusive health states: time spent with grade 3/4 toxicity (TOX), time prior to disease progression and without grade 3/4 toxicity (TWiST) and time post disease progression (REL). Mean time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. Non-parametric bootstrapping method was used to generate 95% CI, which evaluates the between-treatment differences. At base case, utility for TWiST, TOX and REL were assigned as 1.0, 0.5 and 0.5, respectively. A sensitivity analysis was used, applying utilities across the range of 0 (similar to death) to 1.0 (perfect health). A relative gain in Q-TWiST of ≥10% and ≥15% has been established in previous literature as clinically important and clearly clinically important, respectively. Results: Patients receiving lenvatinib+everolimus (n = 51) vs everolimus (n = 50) had significantly longer mean time in TWiST (10.9 vs 6.4 months; difference 4.5 [95% CI: 1.4, 7.8]) and numerically longer in TOX (1.9 vs 0.7 months; difference 1.2 [95% CI: -0.3, 3.1]) but shorter in REL (5.8 vs 8.5 months; difference -2.8 [95% CI: -6.2, 0.6]). At base case, lenvatinib+everolimus patients had a significant mean Q-TWiST gain of 3.7 months (14.7 vs 11.0; 95% CI of difference [1.3, 6.3]), with a relative gain of 24% vs everolimus. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 - 0.9) with utility of TOX and REL both set as 0.5, absolute mean Q-TWiST gain ranged from 1.7 to 3.3 months, with a relative gain ranging from 11.0% to 21.2% (all significant). With TWiST utility set as 1.0 and utility of TOX and REL varying from 0 to 1.0, Q-TWiST gain ranged from 1.7 to 5.8 months (mostly significant and became non-significant as the REL utility gets closer to 1.0 and TOX utility gets closer to 0). Conclusions: Within Study 205, lenvatinib+everolimus resulted in a statistically significant and clinically important gain in Q-TWiST vs everolimus alone. Clinical trial information: NCT01136733 .

Gefitinb along with methotrexate as palliative therapy in PS 3 and above in metastatic esophagus squamous cell carcinoma with focus on Q-TWIST.

355 Background: Metronomic therapy is proven method for treatment of terminally ill patients with malignancy, who are not fit for chemotherapy. The median PFS was significantly superior in responders in previous Indian experiences. However most of them were done in head and neck cancers.The prognosis of patients with metastatic esophageal cancer remains poor with only option being symptomatic care. As the previous experiences show metronomic therapy is safe among various options and there is no study focusing on Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) in southern Indian population,we thought of evaluating the same. Methods: Details of 42 subjects with refractory or progressive metastatic squamous cell carcinoma esophagus having PS &gt; 2 were evaluated. Case records between 2017 September and 2018 September were analyzed for TWIST and QOL. Patients received Gefitinib (250 mg/day), Methotrexate 15 mg IM weekly or in combination. Patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy based on physician/ patient preference. Metronomic therapy could be continued beyond disease progression- if there is TWIST/QOL improvement. Results: Out of 42 subjects, 29 had improvement in the PS and were continued later. 9 had stable PS and disease. 4 had worsening of PS. 34 subjects have clinically meaningful response (stable disease + complete + partial responses) and had symptomatic improvement. The median number of cycles was 6 (4–11). The median PFS was 198 days (95% CI, 174 to 214), and the median improvement in QOL was 6 points on a scale of 25. Grade II/IV toxicities were observed in 21 (50%) cases predominantly skin rash, stomatitis and diarrhea. Conclusions: Metronomic therapy is well tolerated and may have a role in the treatment of advanced cancers with poor performance status. 67% of the patients who are otherwise not eligible for any active therapy became eligible and had better QOL and longer PFS, which re-emphasizes role of metronomic therapy in advanced squamous cell carcinoma of esophagus.

Quality-Adjusted Time without Symptoms or Toxicity (Q-TWiST) Analysis of Quizartinib Vs Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Quality-Adjusted Time without Symptoms or Toxicity (Q-TWiST) Analysis of Quizartinib Vs Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

PCN295 PATIENT-CENTERED OUTCOMES IN ARIEL3, A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF RUCAPARIB MAINTENANCE TREATMENT IN PATIENTS WITH RECURRENT OVARIAN CARCINOMA

In ARIEL3, rucaparib (600 mg BID) maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined cohorts. This post hoc exploratory analysis investigated quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST). QA-PFS was calculated as PFS function × EQ-5D index score function. Q-TWiST was calculated as (μTOX × TOX) + TWiST. TOX represents the mean duration with grade ≥3 adverse events (AEs) or grade ≥2 AEs of nausea, vomiting, fatigue, and asthenia only. TWiST represents the mean duration without AEs or symptoms of progression. μTOX represents the standardized mean EQ-5D index score. This analysis utilized the primary efficacy data after unblinding (April 15, 2017, visit cutoff). In the intent-to-treat population, for rucaparib (n=375) vs placebo (n=189): mean (95% confidence interval [CI]) QA-PFS was 12.02 (10.96–13.03) months vs 5.74 (4.98–6.42) months (difference, 6.28 [4.85–7.47] months); mean (95% CI) Q-TWiST adjusting for grade ≥3 AEs was 13.32 (12.11–14.46) months vs 6.44 (5.78–7.18) months (difference, 6.88 [5.71–8.23] months); and mean (95% CI) Q-TWiST adjusting for common grade ≥2 AEs was 13.16 (12.01–14.33) months vs 6.40 (5.75–7.15) months (difference, 6.77 [5.64–8.14] months). In patients with a BRCA mutation (germline, somatic, or origin unknown), for rucaparib (n=130) vs placebo (n=66): mean (95% CI) QA-PFS was 15.28 (13.22–17.45) months vs 5.92 (4.71–7.23) months (difference, 9.37 [6.65–11.85] months); mean (95% CI) Q-TWiST adjusting for grade ≥3 AEs was 16.42 (14.29–18.18) months vs 6.70 (5.49–8.02) months (difference, 9.73 [7.10–11.94] months); and mean (95% CI) Q-TWiST adjusting for common grade ≥2 AEs was 16.24 (14.11–17.95) months vs 6.68 (5.45–8.00) months (difference, 9.56 [6.99–11.81] months). The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib vs placebo in all predefined cohorts.

Quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of a Phase III randomized trial to compare the benefit of gefitinib versus pemetrexed/carboplatin for epidermal growth factor receptor-mutated non-small cell lung cancer

Background:> In an open-label, Phase III randomized study, gefitinib was found to be superior to pemetrexed-platinum in terms of progression-free survival in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. In this analysis, we have assessed the efficacy of gefitinib over pemetrexed-platinum using quality-adjusted time without symptoms or toxicity (Q-TWiST) of treatment analysis method. Methods: The overall survival in each arm was partitioned into the following three health states: time spent in Grade 2 or above toxicity after randomization and before progression (TOX state), time spent after randomization and before progression without Grade 2 or above toxicity (TWiST state), and time spent after progression (REL state). The mean Q-TWiST was calculated for each arm using utility coefficients of 0.65 for TOX, 0.71 for TWiST, and 0.67 for REL states. The difference in Q-TWiST and the 95% confidence interval (CI) of the difference were calculated using a nonparametric bootstrap.P= 0.05 was considered statistically significant. Results: The mean TOX duration (37.6 vs. 16.2 days,P Conclusion: The mean Q-TWiST of patients in the gefitinib arm was similar to that of patients in the pemetrexed-carboplatin arm. These results challenge the superiority of sequencing gefitinib followed by chemotherapy over pemetrexed-carboplatin followed by gefitinib in terms of Q-TWiST.

Utilization of Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) Method In Oncology: A Systematic Review of Clinical Trials

Background: Common endpoints of many cancer clinical trials are overall survival, progression-free survival or relapse. Despite their given importance, these measures do not account for quality of life (QOL). The Q-TWiST (Quality adjusted Time Without Symptoms and Toxicity) method has been proposed by Gelber in the 1990s to enable a statistical comparison between two treatment groups by incorporating both benefit (survival) and risk (toxicity, QOL). Q-TWiST partitions lifespan of patients from beginning of treatment until death into three time segments corresponding to three distinct health states: toxicity (TOX), TWiST (Time Without Symptoms of Treatment or Diseases) and relapse (REP). Aim: The purpose of this systematic review was to evaluate the utilizations of Q-TWiST method in cancer clinical trials and how these results were translated to clinical practice in oncology field. Methods: We searched PubMed, Embase, Cochrane library and the bibliographies of relevant articles to locate additional publications in Jan 2018. Two evaluators independently reviewed and selected eligible studies based on keyword “Q-TWiST” and predetermined selection criteria. Clinical trials in oncology field quantifying Q-TWiST in the analysis were included. We focused how health states were defined and utility coefficients were determined. Other relevant contents were collected and summarized. Results: Out of 79 studies, 36 oncology clinical trials utilizing Q-TWiST method were identified. We included 20 studies published within last decade (2008-2018) in final review. Trials ranged from 182 to 1110 subjects. Breast cancer was most common cancer type. All studies were post hoc analysis which used data from previous publications and applied Q-TWiST in analysis. Methods in determining QOL, also called utility coefficients, varied among included trials. Among 20 studies, six directly measured QOL in their trials and used it for Q-TWiST method, two obtained QOL data from other studies with similar study participants. Most commonly used questionnaires were EORTC QLQ-C30 and EuroQOL EQ-5D. Utility coefficients were arbitrarily set in 12 studies. Most common values were 0.5, 1 and 0.5 for TOX, TWiST and REP respectively. Definition of these health states, especially toxicity, were consistent among included studies. Few studies discussed both statistical and clinical significance of their findings. Conclusion: Q-TWiST method has been increasingly used as a post hoc analysis in many oncology clinical trials within last decade. However, some current limitations should be compromised to make Q-TWiST become a clinically useful method for physicians and patients. We suggest that definition of health states must be standardized, methods to determine utility coefficients must be validated and universal in the future analysis.

Quality-adjusted survival of nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma: a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis.

To compare the quality-adjusted survival of nivolumab plus ipilimumab combination and nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma based on a minimum 36-month follow-up from the CheckMate 067 trial. Overall survival was partitioned into time without symptoms of progression or toxicity (TWiST), time with treatment-related grade ≥ 3 adverse events after randomization but before progression (TOX), and time from progression until end of follow-up or death (REL). Mean quality-adjusted TWiST (Q-TWiST) was calculated by multiplying the mean time spent in each health state by a utility of 1.0 for TWiST and 0.5 for TOX and REL. Sensitivity analyses included varying utilities of TOX and REL; Q-TWiST gains at different follow-up times were calculated using EQ-5D-3L utilities from the trial. Relative Q-TWiST gain of ≥ 10% was considered clinically important. Compared with ipilimumab-treated patients, those who received nivolumab + ipilimumab combination had significantly longer TWiST and TOX but shorter REL; nivolumab-treated patients had significantly longer TWiST, shorter REL, and shorter but statistically nonsignificant TOX. Mean Q-TWiST was highest for nivolumab + ipilimumab (23.5months; 95% CI 21.9-25.2), followed by nivolumab (21.8months; 95% CI 20.2-23.4) and ipilimumab (15.3months; 95% CI 13.9-16.6). Relative Q-TWiST gains were favorable and clinically important for nivolumab + ipilimumab combination (+ 36.81%) and nivolumab alone (+ 29.18%) versus ipilimumab alone. Relative gains increased with follow-up from 3 to 40months for all comparisons. These gains remained consistent in magnitude and direction in the different sensitivity analyses. Nivolumab + ipilimumab combination and nivolumab alone resulted in a statistically significant and clinically important improvement in quality-adjusted survival compared with ipilimumab alone.

Quality-adjusted time without symptoms or toxicity (Q-TWiST): Analysis of cabozantinib (Cabo) vs sunitinib (Sun) in patients with advanced renal cell carcinoma (aRCC) of intermediate or poor risk (Alliance A031203).

4556Background: CABOSUN (NCT01835158), a randomized, open-label phase II trial, demonstrated significant improvement in progression-free survival with Cabo (8.6 months) versus Sun (5.3) months) in ...

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer (mCRC) treated with fruquintinib in the randomized phase III FRESCO trial.

3544Background: The FRESCO Study is a randomized, double-blind, phase III trial comparing fruquintinib + best supportive care (BSC), to placebo + BSC in the treatment of metastatic colorectal cance...

Quality-adjusted Outcomes Stratified by Response in Patients With Advanced Non–Small-cell Lung Cancer Receiving First-line nab-Paclitaxel/Carboplatin or Paclitaxel/Carboplatin

BackgroundFirst-line nab-paclitaxel/carboplatin was associated with a significantly improved overall response rate (primary endpoint) versus paclitaxel/carboplatin in a phase III trial of advanced non–small-cell lung cancer (NSCLC). We report the results of an analysis evaluating the correlation of response and the time to response with survival and quality-adjusted outcomes. Patients and MethodsUsing a landmark approach, progression-free survival (PFS), overall survival (OS), and quality-adjusted time without symptoms or toxicity (Q-TWiST) were compared between patients with a confirmed partial or complete response at or before 6 weeks (≤ 6-week responders) and those without (≤ 6-week nonresponders). The outcomes were also analyzed in two 12-week landmark analyses: ≤ 12-week responders versus ≤ 12-week nonresponders and early responders (≤ 6 weeks) versus late responders (6-12 weeks) versus ≤ 12-week nonresponders. ResultsThe median OS and PFS for the ≤ 6-week responders versus ≤ 6-week nonresponders were 14.5 versus 10.3 months (P < .001) and 5.5 versus 4.5 months (P = .002), respectively. The ≤ 6-week responders gained 2.1 months of mean Q-TWiST. The median OS and PFS for the ≤ 12-week responders versus ≤ 12-week nonresponders were 16.3 versus 8.4 months and 5.3 versus 2.8 months (both P < .001), respectively, and the ≤ 12-week responders gained 3.2 months of mean Q-TWiST. The median OS was 13.1, 16.6, and 8.4 months (P < .001), the median PFS was 4.1, 6.7, and 2.8 months (P < .001), and the mean Q-TWiST was 10.2, 11.7, and 7.8 months for the early responders, late responders, and ≤ 12-week nonresponders, respectively. Both early and late responders had significantly longer Q-TWiST compared with the ≤ 12-week nonresponders (difference, +2.4 and +3.9 months, respectively; P < .05). ConclusionThese results underscore response as an important surrogate for assessment of long-term treatment outcomes in advanced NSCLC.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis

BackgroundIn this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. Patients and MethodsQuality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. ResultsIn the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], −0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). ConclusionIn its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer (mCRC) treated with fruquintinib in a phase II clinical trial.

765 Background: In a randomized phase II trial of mCRC patients who have failed at least 2 lines of standard therapy, fruquintinib has demonstrated superior progression free survival (PFS) and overall survival (OS) benefits over placebo. We further assessed the between-treatment difference of quality of life (QoL) using a Q-TWiST analysis, to elucidate the trade-off between adverse events and treatment benefits. Methods: Mean PFS and OS were estimated using the Kaplan-Meier method. OS in Q-TWiST analysis was partitioned into 3 health states: TOX (time with toxicity before progression), TWiST (time without symptoms or toxicity) and REL (time from progression until death). The algorism of Q-TWiST is the sum of the mean durations for the 3 health states, with each state weighted by its respective utility coefficient. The 95% confidence intervals of mean are calculated with z method and the standard error is generated by bootstrap method. The relative Q-TWiST gains of &gt; = 10% and &gt; = 15% are considered as a clinically important and clearly clinically important, respectively (Revicki, 2006). Results: A total of 71 patients were included in this post-hoc analysis. The 47 patients of fruquintinib arm had significant longer PFS, compared with the 24 patients in the placebo arm (mean: 5.0 vs. 2.2 months, difference [95% CI]: 2.8 [1.4, 4.3]). The benefit of OS was numerically superior (mean: 8.6 vs. 6.9 months, difference [95% CI]: 1.7 [-0.5, 4.0]). Patients treated with fruquintinib showed numerically longer overall Q-TWiST (mean: 5.8 vs. 4.4 months, difference [95% CI]: 1.4 [-0.1, 2.9] than those received placebo with the relative gain of 20.3% over OS, assuming the utility during TOX/REL period is 0.5 and that during the TWiST is 1.0. Sensitivity analysis demonstrated that the Q-TWiST gain may range from -0.7% to 41.2% at various utility assignments. Conclusions: In this phase II trial, mCRC patients treated with fruquintinib had clearly clinically important QoL benefit. Further studies with larger sample size are needed to confirm this finding. Clinical trial information: NCT02196688.