Tislelizumab Treatment And Quality Of Life In Lung Cancer Patients
Overview
In the Phase 3 trial RATIONALE-303 (NCT03358875), the study evaluated the health-related quality of life (HRQoL) among patients with advanced non-small cell lung cancer (NSCLC) who were treated with either tislelizumab or docetaxel. The assessment utilized three measurement instruments: EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L. The analysis primarily focused on changes in HRQoL from baseline to Week 12 and Week 18 using longitudinal analysis of covariance. Additionally, a time-to-deterioration analysis was performed, employing the Kaplan–Meier method.
The study involved the randomization of 805 patients, with 535 receiving tislelizumab and 270 receiving docetaxel. The results demonstrated notable enhancements in HRQoL for patients treated with tislelizumab when compared to those who received docetaxel. Specifically, the tislelizumab group exhibited significant improvements in the QLQ-C30 global health status/quality of life (QoL) scale score by Week 18. Moreover, patients receiving tislelizumab reported reduced fatigue at both Week 12 and Week 18, along with improvements in the QLQ-LC13 symptom index score during the same time frames. Importantly, tislelizumab-treated patients experienced a reduction in coughing symptoms at both Week 12 and Week 18 compared to those treated with docetaxel.
Furthermore, the analysis revealed that patients who received tislelizumab had a lower risk of experiencing clinically meaningful deterioration across various aspects, including the overall lung cancer symptom index scale, dyspnea, coughing, and peripheral neuropathy.
In summary, the administration of tislelizumab, as opposed to docetaxel, was associated with significant improvements in HRQoL and the alleviation of lung cancer-related symptoms among patients with advanced NSCLC who had previously shown resistance to platinum-containing chemotherapy. These findings underscore the potential advantages of tislelizumab in enhancing the well-being of patients facing advanced NSCLC.
Introduction
Patients diagnosed with advanced non-small cell lung cancer (NSCLC) at Stage IIIB and Stage IV typically face a grim prognosis, with 5-year survival rates of less than 5% and 2%, respectively. For these individuals, the burden of debilitating symptoms related to lung cancer and compromised health-related quality of life (HRQoL) is a significant challenge. Disease progression and proximity to death often exacerbate these issues, emphasizing the importance of managing patient-reported lung cancer symptoms and maintaining or improving HRQoL. Traditionally, docetaxel has been employed to treat patients who have progressed after a platinum-based regimen, but it hasn’t shown substantial benefits in terms of reducing symptom burden and enhancing HRQoL.
Recent clinical trials have investigated the efficacy of therapies targeting the programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway, known as PD-(L)1 inhibitors, for advanced refractory NSCLC patients. These studies have demonstrated clinical benefits and improvements in HRQoL when PD-(L)1 inhibitors were used as second-line therapy compared to docetaxel. Furthermore, clinical trials involving tislelizumab, a PD-1 inhibitor, in combination with chemotherapy have shown promise, especially in terms of HRQoL improvements.
The RATIONALE 303 study (NCT03358875), a Phase 3, randomized, open-label, multi-center clinical trial, investigated the effectiveness and safety of tislelizumab compared to docetaxel in NSCLC patients who had experienced disease progression following previous platinum-containing regimen treatment. Tislelizumab monotherapy was found to extend overall survival (median difference of 5.3 months), improve progression-free survival (median 4.2 vs. 2.6 months), and achieve a higher objective response rate. Importantly, tislelizumab was associated with lower rates of treatment-emergent adverse events compared to docetaxel.
The study’s secondary objective was to assess HRQoL using patient-reported outcomes. This analysis revealed that tislelizumab treatment was linked to positive changes in HRQoL and a reduction in patient-reported lung cancer symptoms for NSCLC patients who had experienced disease progression after prior platinum-containing chemotherapy. These findings underscore the potential benefits of tislelizumab in enhancing the well-being of this patient population.
Method
In the RATIONALE 303 study, eligible patients were randomly assigned in a 2:1 ratio to receive either tislelizumab 200 mg every 3 weeks (Q3W) or docetaxel 75 mg/m2 Q3W until disease progression, intolerable toxicity, consent withdrawal, or death. Patients receiving tislelizumab were allowed to continue treatment beyond disease progression based on protocol-defined conditions.
The study included adults aged 18 or older with locally advanced or metastatic squamous (sq-) or non-squamous (nsq-) NSCLC, confirmed through histological analysis, regardless of tumor PD-L1 expression. These patients had previously experienced progressive disease during or after at least one platinum-containing chemotherapy regimen (with a maximum of two prior systemic treatment lines) and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients with treated, stable brain metastases were also included, while those with prior docetaxel treatment for metastatic disease or known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation were excluded.
The study adhered to ethical principles outlined in the Declaration of Helsinki, Good Clinical Practice guidelines, and clinical trial registration requirements. Institutional Review Boards or Independent Ethics Committees at each study site approved the study, and written informed consent was obtained from all participants.
To assess health-related quality of life (HRQoL), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the EuroQoL Five-Dimensions Five-Levels (EQ-5D-5L) questionnaire were used. Key patient-reported outcome (PRO) endpoints included the global health status/quality of life (GHS/QoL), physical functioning, and fatigue scales of the EORTC QLQ-C30. For the QLQ-LC13, multiple lung cancer-related symptoms were evaluated, including dyspnea, coughing, peripheral neuropathy, chest pain, arm or shoulder pain, and hemoptysis. The EQ-5D-5L included the Visual Analogue Scale (VAS) score for self-rated health.
PRO assessments were conducted at baseline and on day 1 of every treatment cycle until the end of treatment. The primary clinical cycles for PRO evaluation were at week 12 (cycle 4) and week 18 (cycle 6), aligning with the completion of chemotherapy (week 12) and the post-chemotherapy period (week 18) close to scheduled tumor assessments. A longitudinal analysis of covariance was employed to assess differences in mean score changes between treatment arms from baseline to weeks 12 and 18 in the PRO endpoints. Changes between ±2 were considered maintenance, while ±2 indicated improvement or worsening.
Time to deterioration (TTD) analysis used the QLQ-LC13 symptom index scale and relevant lung cancer symptoms to assess when a worsening score of ≥10 points occurred. The Kaplan–Meier method estimated deterioration curves, and the stratified log-rank test assessed treatment differences in TTD. Descriptive analysis was performed for EQ-5D-5L’s VAS, considering factors like histology, lines of therapy, and PD-L1 expression in the analysis.
In conclusion, this study aimed to evaluate HRQoL in NSCLC patients treated with tislelizumab compared to docetaxel, focusing on several PRO endpoints and employing rigorous methodology to provide valuable insights into the impact of these treatments on patients’ well-being.
Result
In the RATIONALE 303 study, a total of 805 patients were randomly assigned to either the tislelizumab arm (n=535) or the docetaxel arm (n=270). The characteristics of these patients were similar between the two treatment arms, making them representative of the target patient population. The data for this analysis were collected until July 2021.
The analysis focused on 789 patients for health-related quality of life (HRQoL) assessment, with 533 in the tislelizumab arm and 256 in the docetaxel arm. Compliance with HRQoL assessments was high in both arms at various time points throughout the study. The key findings regarding HRQoL included:
Global Health Status/Quality of Life (GHS/QoL)
– At week 12, the GHS/QoL remained stable in the tislelizumab arm and declined in the docetaxel arm.
– At week 18, GHS/QoL improved in the tislelizumab arm while continuing to worsen in the docetaxel arm.
– The difference in GHS/QoL change from baseline between the two arms was statistically significant at both week 12 and week 18, favoring tislelizumab.
Physical Functioning
– In the tislelizumab arm, physical functioning remained stable at week 12 and week 18.
– In contrast, the docetaxel arm experienced worsening physical functioning at both time points.
– The difference in change from baseline in physical functioning between the two arms was statistically significant at week 18, favoring tislelizumab.
Fatigue
– Tislelizumab-treated patients experienced reduced fatigue at both week 12 and week 18.
– In contrast, fatigue increased in the docetaxel arm at these time points.
– The difference in fatigue scores between the two arms was statistically significant at both week 12 and week 18, favoring tislelizumab.
Symptom Index Scale
– The tislelizumab arm exhibited improvement in the symptom index scale score at both week 12 and week 18.
– Conversely, patients in the docetaxel arm experienced worsening of symptoms at these time points.
– The difference in change from baseline in the symptom index scale score between the two arms was statistically significant at both week 12 and week 18, favoring tislelizumab.
Other Symptoms (Dyspnea, Coughing, Peripheral Neuropathy, Pain in Chest, Pain in Arm or Shoulder, Hemoptysis)
– Tislelizumab demonstrated either maintenance or improvement in these symptoms at week 12 and week 18.
– In contrast, the docetaxel arm generally exhibited worsened symptoms.
– Statistically significant differences in favor of tislelizumab were observed for coughing and peripheral neuropathy at both week 12 and week 18.
Visual Analogue Scale (VAS) Score
– Maintenance in the VAS score was observed in both the tislelizumab and docetaxel arms at weeks 12 and 18.
Additionally, the tislelizumab arm had a significantly lower risk of experiencing deterioration in various HRQoL aspects compared to the docetaxel arm. These aspects included GHS/QoL, symptom index scale, dyspnea, coughing, and peripheral neuropathy.
In summary, the study showed that tislelizumab was associated with notable improvements in HRQoL and symptom management compared to docetaxel, demonstrating its potential benefit in enhancing the well-being of patients with advanced non-small cell lung cancer (NSCLC) who had previously not responded well to platinum-containing chemotherapy.
Conclusion
In the RATIONALE 303 study, it was observed that tislelizumab monotherapy outperformed docetaxel in terms of clinical efficacy for non-small cell lung cancer (NSCLC) patients who had previously failed platinum-containing chemotherapy. Additionally, patient-reported outcomes (PROs) indicated that patients treated with tislelizumab also experienced more favorable Health-Related Quality of Life (HRQoL) and a reduced burden of lung cancer-related symptoms, as evaluated through the QLQ-C30 and QLQ-LC13 questionnaires. Key findings from the study include:
Global Health Status/Quality of Life (GHS/QoL)
– Patients in the tislelizumab arm showed improved GHS/QoL at week 18, whereas those in the docetaxel arm experienced a decline.
Physical Functioning
– Tislelizumab-treated patients maintained their physical functioning, while docetaxel-treated patients saw a decline at both weeks.
Fatigue
– Fatigue symptoms decreased at weeks 12 and 18 in the tislelizumab group, but increased in the docetaxel group during the same periods.
Overall Lung Cancer Symptoms
– Patients receiving tislelizumab reported improved overall lung cancer symptoms at weeks 12 and 18, whereas those on docetaxel experienced worsening.
Coughing
– Improvements in coughing were significantly larger in the tislelizumab group at weeks 12 and 18.
Peripheral Neuropathy
– Tislelizumab-treated patients maintained or slightly improved peripheral neuropathy, while docetaxel patients experienced worsening
Time to Deterioration (TTD) Analysis
– Tislelizumab-treated patients had a lower risk of experiencing clinically meaningful worsening in overall lung cancer symptom index scale, dyspnea, coughing, and peripheral neuropathy during treatment.
The study’s findings contribute to the growing body of evidence highlighting the positive impact of PD-(L)1 inhibitors on HRQoL in advanced NSCLC patients. Comparisons with previous studies, such as CheckMate 017, KEYNOTE-010, and OAK, indicate consistent trends in improved HRQoL and symptom burden associated with PD-(L)1 inhibitors.
However, several limitations should be noted, including the open-label design, the absence of an investigation into the relationship between PRO endpoints and clinical outcomes or adverse events, and the need for further analysis to explore stratification and missing data assumptions.
In conclusion, the study underscores tislelizumab’s potential to enhance HRQoL and alleviate lung cancer-related symptoms in NSCLC patients who have previously failed platinum-containing chemotherapy. These findings, in conjunction with tislelizumab’s demonstrated clinical benefits and safety profile, support its favorable risk-benefit ratio as a second-line therapy for this patient population. Future research may consider additional stratification and data analysis to provide a more comprehensive understanding of tislelizumab’s impact on patient outcomes.
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