The effects of tislelizumab treatment on the health‐related quality of life of patients with advanced non‐small cell lung cancer

Abstract This study examined the health‐related quality of life (HRQoL) of patients with advanced non‐small cell lung cancer (NSCLC) receiving tislelizumab versus docetaxel in the open‐label, multicenter, Phase 3 trial called RATIONALE‐303 (NCT03358875). HRQoL was assessed with the EORTC QLQ‐C30, EORTC QLQ‐LC13, and the EQ‐5D‐5L instruments. A longitudinal analysis of covariance assessed the change from baseline to Week 12 and from baseline to Week 18. A time to deterioration analysis was also performed using the Kaplan–Meier method. Eight hundred and five patients were randomized to either tislelizumab (n = 535) or docetaxel, respectively (535 and 270 to tislelizumab and docetaxel, respectively). The tislelizumab arm improved while the docetaxel arm worsened in the QLQ‐C30 global health status/QoL scale score (difference LS mean change Week 18: 5.7 [95% CI: 2.38, 9.07, p = 0.0008]), fatigue (Week 12: ‐3.2 [95% CI: −5.95, −0.37, p < 0.0266]; Week 18: −4.9 [95% CI: −8.26, −1.61, p = 0.0037]), and QLQ‐LC13 symptom index score (Week 12: −5.5 [95% CI: −6.93, −4.04, P < 0.0001]; Week 18: −6.6 [95% CI: −8.25, −4.95, p < 0.0001]). The tislelizumab arm had improvements in coughing versus the docetaxel arm (Week 12: −4.7 [95% CI: −8.57, −0.78, p = 0.0188]; Week 18: −8.3 [95% CI: −13.02, −3.51, p = 0.0007]). The patients who received tislelizumab were less at risk for clinically meaningful worsening in the overall lung cancer symptom index scale (hazard ratio (HR): 0.24 [95% CI: 0.162, 0.356], p < 0.0001), dyspnea (HR: 0.74 [95% CI: 0.567, 0.958], p = 0.0109), coughing (HR: 0.74 [95% CI: 0.534, 1.019], p = 0.0309), and peripheral neuropathy (HR: 0.55 [95% CI: 0.370, 0.810] p = 0.0011). In general, tislelizumab versus docetaxel was associated with improved HRQoL and symptoms of lung cancer in patients who previously failed treatment with platinum‐containing chemotherapy.


| INTRODUCTION
Patients diagnosed with advanced non-small cell lung cancer (NSCLC) at Stage IIIB and Stage IV have a relatively poor overall prognosis, with 5-year survival rates of less than 5% and 2%, respectively. 13][4][5][6][7] Furthermore, an increase in symptom burden due to NSCLC disease progression and proximity to death leads to further deterioration of patients' HRQoL. 2,4,7,8Particularly in patients with advanced NSCLC who have experienced disease progression after a platinum-based regimen, a reduction or maintenance of patient-reported lung cancer-related symptoms are important goals of systemic therapies. 9reatment with docetaxel, which has been considered the conventional approach of treating patients who have progressed after a platinum-based regimen, has not produced significant benefits in HRQoL via reduction in symptom burden. 10,113][14][15][16][17] Along with clinical improvements, a reduction in some of the lung cancerrelated symptoms and improved HRQoL have also been reported in patients who received a PD-(L)1 inhibitor as a second-line therapy compared to those who were treated with docetaxel. 12,18,19revious clinical studies have shown that patients with advanced squamous (sq-) and non-squamous (nsq-) NSCLC who were administered tislelizumab in combination with chemotherapy have experienced clinical benefits compared to those who received chemotherapy alone. 20,21ith respect to HRQoL, the addition of tislelizumab to platinum-based chemotherapy in a first-line setting was associated with improvements in global health status and quality of life, relative to chemotherapy alone in patients with sq-NSCLC and nsq-NSCLC. 22,23In patients with sq-NSCLC, the combination of tislelizumab and platinumbased chemotherapy has been linked with a decrease in lung cancer-specific symptoms including coughing, dyspnea, and hemoptysis 23 ; and for patients with nsq-NSCLC, a reduction in symptoms such as coughing, chest pain, and dyspnea were reported. 22he RATIONALE 303 (NCT03358875) study was a Phase 3, randomized, open-label, multicenter clinical trial that examined the effectiveness and safety of tislelizumab compared to docetaxel for NSCLC patients who had experienced disease progression after a previous treatment involving a platinum-containing regimen. 24Compared with docetaxel, tislelizumab monotherapy prolonged overall survival (OS; median difference of 5.3 months), improved progression-free survival (PFS; median 4.2 vs. 2.6 months; hazard ratio [HR]: 0.63 [95% confidence interval [CI]: 0.53-0.75];p < 0.0001), and had a higher objective response rate (ORR; difference of 15.6%, 95% CI: 11.0-20.03;p < 0•0001). 24Furthermore, the rates of treatment-emergent adverse events (TEAEs) were lower in the tislelizumab arm versus the docetaxel arm (≥ Grade 3 TEAE: 42.1% vs. 74.8%;Treatment Related ≥ Grade 3 TEAE; 15.7% vs. 66.3%),despite the median treatment duration being twice as long for the former.
The assessment of HRQoL using patient-reported outcome (PRO) was a prespecified secondary objective in RATIONALE 303.The current analysis evaluated HRQoL and changes in patient-reported lung cancer symptoms in patients treated with tislelizumab compared with docetaxel in patients with NSCLC who had experienced disease progression following a prior chemotherapy regimen containing platinum.

| Study design and population
Eligible patients from RATIONALE 303 were randomly assigned in a 2:1 ratio to receive either tislelizumab 200 mg every 3 weeks (Q3W) or docetaxel 75 mg/m 2 Q3W until disease progression, intolerable toxicity, withdrawal of consent, or death. 24Patients in the tislelizumab arm were allowed to continue treatment beyond disease progression under protocol-defined conditions, as deemed appropriate by the investigators.
Patients who were eligible for inclusion in the study were adults aged 18 years or older with locally advanced or metastatic sq-or nsq-NSCLC, confirmed by histological analysis, regardless of tumor PD-L1 expression, who docetaxel, health-related quality of life, non-small cell lung cancer, patient-reported outcomes, programmed cell death protein-1 inhibitor experienced progressive disease during or after at least one platinum-containing chemotherapy regimen (with no more than two prior systemic treatment lines) and had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients who had treated, stable brain metastases were also included.Exclusion criteria included: prior docetaxel treatment for metastatic disease or prior immune checkpoint inhibitor treatment; known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation.
The study adhered to the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, as well as the requirements of the public registration of clinical trials and approved by the relevant Institutional Review Board or Independent Ethics Committee for each study site.Prior to participating in the study, written informed consent was obtained from all participants.Additional information on study design, efficacy, and safety data is reported elsewhere. 24

| Patient-reported endpoints
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), 25 the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13) 26 and the EuroQoL Five-Dimensions Five-Levels (EQ-5D-5L) questionnaire 27 were used to assess HRQoL.Key PRO endpoints were the global health status/quality of life (GHS/QoL), physical functioning, and fatigue scales of the EORTC QLQ-C30.Higher scores on the GHS/QoL scale and physical functioning scales indicated better outcomes, while higher scores on the fatigue scale indicated worse outcomes.For the QLQ-LC13, the symptom index scale, dyspnea, coughing, peripheral neuropathy, pain in chest, pain in arm or shoulder, and hemoptysis items were used with higher scores indicating worse outcomes.The symptom index scale was calculated by taking the mean of all symptom scale scores.The Visual Analogue Scale (VAS) score of EQ-5D-5L recorded the patient's self-rated health, where higher scores reflected better perceived health.These endpoints were selected due to their relevance to lung cancer and treatmentrelated side effects, as well as their use in previous studies. 4,5,7,12,18The PROs were collected at baseline and on day 1 at every treatment cycle until to the end of treatment.
The key clinical cycles were week 12 (cycle 4) and week 18 (cycle 6) and were selected to measure change in PRO endpoints at the end of chemotherapy (week 12) and after chemotherapy treatment (week 18) close to the clinical scheduled visit for tumor assessment.At the start of each visit, patients were requested to answer the questionnaires before clinical assessments or intervention.

| Statistical analyses
The PRO analyses consisted of all patients who were randomized and received at least one dose of the study drug and completed at least one assessment of HRQoL.The analysis included HRQoL assessments up to point of investigator-assessed progressive disease (PD), as patients had the option to receive additional therapy following the assessment.If patients completed at least one item on a PRO instrument, they were deemed to have completed one HRQoL assessment.Compliance with the PRO assessments was determined as the proportion of questionnaires that were actually received out of the expected number (i.e., number of patients on treatment and are alive).
A longitudinal analysis of covariance was conducted to evaluate differences between the arms regarding mean score changes from baseline to week 12 and week 18 in the PRO endpoints.In line with the missing at random assumption, the response variable was the PRO score, while the covariates were treatment, study visit, treatment by study visit interaction, and randomization stratification factors (PD-L1 expression in tumor cells and disease stage).Between-group comparisons were reported as differences in the least square (LS) mean change from baseline with the 95% confidence interval (CI) and nominal p-value.Changes from baseline that were between ±2 were considered to reflect maintenance, while a change of ±2 was considered improvement or worsening.
Time to deterioration (TTD) was examined using the QLQ-LC13 symptom index scale, and the most relevant lung cancer symptoms of dyspnea, coughing, peripheral neuropathy, pain in chest, pain in arm or shoulder, and hemoptysis symptoms.TTD threshold was defined as time to first onset of ≥10points 28 toward a worsening direction (e.g., increase score in symptom scales) from randomization to the first occurrence of a worsening score confirmed at the subsequent visit or death from any cause.The Kaplan-Meier method was used to estimate the deterioration curve in each group and the stratified log-rank test was used to assess the treatment difference in TTD; one-sided p-value from stratified log-rank test is presented.Efron's method of tie handling was used to assess between-group differences.The stratification factors considered in the analysis included histology (squamous vs. non-squamous), lines of therapy (second versus third), and PD-L1 expression (≥25% vs. <25% tumor cells).Additionally, a descriptive analysis was performed for the EQ-5D-5L's VAS.

| RESULTS
A total of 805 patients were randomly assigned to either the tislelizumab arm (n = 535) or the docetaxel arm (n = 270).The demographics and clinical characteristics were similar between the two treatment arms and were representative of the target patient population (Table 1).The data cutoff date for the present analysis was July 2021.

| EORTC QLQ-C30
Baseline means for the QLQ-C30 are presented in Table S1.The GHS/QoL maintained at week 12 in the tislelizumab

| EQ-5D-5L
Maintenance in the VAS score at weeks 12 and 18 were observed for the both the tislelizumab and docetaxel arms (Table 3).

| DISCUSSION
In RATIONALE 303, tislelizumab monotherapy demonstrated superior clinical efficacy compared to docetaxel in NSCLC patients who previously failed a platinumcontaining chemotherapy. 24Here we report that patients treated with tislelizumab also had more favorable HRQoL and a reduced lung cancer symptom burden, as assessed by the QLQ-C30 and QLQ-LC13, than patients who received docetaxel.Specifically, improvements were observed for the global health status and quality of life index scale in the tislelizumab arm relative to docetaxel at week 18.Physical functioning maintained in tislelizumab-treated patients while worsening in the patients treated with docetaxel at both weeks.Fatigue symptoms decreased at week 12 and week 18 in patients treated with tislelizumab, while increasing at both weeks 12 and 18 in the docetaxel arm.
Overall lung cancer symptoms, as assessed by the QLQ-LC13 symptom index score, improved at weeks 12 and 18 in the tislelizumab arm, while worsening at weeks 12 and 18 in the docetaxel arm.Improvements in coughing were significantly larger in tislelizumab-treated patients relative to the docetaxel arm at both weeks 12 and 18.The tislelizumab arm also maintained (week 12) or slightly improved (week 18) in peripheral neuropathy while docetaxel patients worsened at both weeks 12 and 18.Time to deterioration analysis further showed that patients in the tislelizumab arm had a lower risk of experiencing clinically meaningful worsening in overall lung cancer symptom index scale, as well as for specific symptoms such as dyspnea, coughing, and peripheral neuropathy, over the course of treatment.
The findings of this study add to the expanding body of literature on the positive impact of PD-(L)1 inhibitors on HRQoL of patients with advanced NSCLC. 12,18,19Similar to the current study, the Phase 3 CheckMate 017 study found significant improvements in the average symptom burden index of the Lung Cancer Symptom Scale associated with nivolumab compared to docetaxel, although the samples consisted of patients with sq-NSCLC. 19In the Phase 2/3 KEYNOTE-010 study, pembrolizumab was associated with improvements in the EORTC QLQ-C30's GHS/QoL scale score relative to docetaxel, but unlike the current study these differences were nonsignificant. 12imilarly, the Phase 3 OAK study reported a nonsignificant improvement in the EORTC QLQ-C30's GHS/ QoL index scale score for atezolizumab as compared to docetaxel. 18Previous studies have also reported a decrease in overall lung cancer symptoms, including fatigue and coughing, which are consistent with the findings of the current study. 18,19Finally, unlike several previous studies, TTD differences were not found for pain in chest, pain in arm or shoulder, and hemoptysis; however, significant differences in TDD were found in the tislelizumab arm in other lung cancer-specific symptoms which were not observed in the previous studies.
The following limitations should be considered.First, an open-label design was used and therefore patients were not blinded to treatment which could have impacted their responses to the PROs.Second, analysis did not investigate the relationship between PRO endpoints and clinical outcomes or adverse events.Previous studies have found that patients with disease progression experienced less worsening in HRQoL and lung cancer symptoms if treated with a PD-(L)1 inhibitor compared to patients who received chemotherapy. 12,18Moreover, a previous study of patients with NSCLC reported a 9% increase in survival with every 10-point increase in global QOL as assessed by the EORTC QLQ-C30. 29Taken together, these studies suggest that PROs assessing HRQoL and lung cancer symptoms may serve as a valid surrogate endpoints for diseases progression and overall survival.Though the tislelizumab arm experienced more improvements in HRQoL relative to the docetaxel arm, these changes did not reach clinical significance.Future analyses should consider additional stratification such as ethnic and/or regional differences endpoints, ECOG score, and/or other comorbidities within the current study population when possible.Finally, the missing at random assumption in the longitudinal analysis of covariance could be investigated.Future research will look at models that include reasons for treatment discontinuation and relationships to PRO outcomes.
Previous studies have found that when tislelizumab was added to platinum-based chemotherapy as a firstline treatment for sq-NSCLC and nsq-NSCLC, there were improvements in global health status, quality of life, and symptoms related to lung cancer. 22,23The findings of the current study significantly extend tislelizumab's growing evidence as an agent that improves HRQoL and alleviates symptom burden to an even more at-risk group of patients with NSCLC.In addition to tislelizumab's superior clinical benefits and safety profile compared to docetaxel, 24 patient-reported outcomes provide additional evidence supporting the favorable risk-benefit ratio of tislelizumab as a second-line therapy for patients with NSCLC who had

T A B L E 3
Change from Baseline for EQ-5D-5L VAS Scores at Week 12 and Week 18.
Compliance Rates for HRQoL Assessments.
T A B L E 4Abbreviations: CI, confidence interval; EORTC QLQ-LC13, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 items; GHS/QOL, global health status/quality of life; HR, hazard ratio; NE, not estimated; NR, not reached.a Stratification factors: histology (squamous versus non-squamous), lines of therapy (second versus third), and PD-L1 expression (≥25% versus <25% tumor cells).