Tislelizumab plus platinum and etoposide versus placebo plus platinum and etoposide as first-line treatment for extensive-stage small-cell lung cancer: patient-reported outcomes in the RATIONALE-312 trial

In the phase 3 RATIONALE-312 trial (ClinicalTrials.gov Identifier: NCT04005716), the addition of tislelizumab to chemotherapy as first-line treatment significantly improved overall survival and progression-free survival compared to placebo plus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC), with an acceptable safety profile. This analysis reports the patient-reported outcomes (PROs) from RATIONALE-312. Overall, 457 adults with ES-SCLC were randomized (1:1) to tislelizumab plus chemotherapy (n = 227) or placebo plus chemotherapy (n = 230). PROs were protocol-prespecified secondary end points that assessed health-related quality of life (HRQoL) using the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. PRO end points at Cycles 4 and 6 were analyzed using a mixed model for repeated measures. Time to deterioration (TTD) was evaluated. At Cycle 4, the tislelizumab arm demonstrated clinically meaningful improvement in coughing, hemoptysis, and chest pain. Clinically meaningful improvement was observed in the tislelizumab arm, but not in the placebo arm, for global health status (GHS)/QoL, dyspnea, and arm or shoulder pain. By Cycle 6, the tislelizumab arm achieved clinically meaningful improvement in GHS/QoL, with a statistically significant between-group difference favoring the tislelizumab arm. Clinically meaningful improvements in dyspnea, coughing, hemoptysis, and chest pain were maintained in the tislelizumab arm through Cycle 6. No between-group differences were observed in the TTD analysis. Tislelizumab plus chemotherapy maintained or improved HRQoL and patient-reported symptoms compared to placebo plus chemotherapy. Along with prior efficacy and safety data, these data support tislelizumab plus chemotherapy as first-line treatment in patients with advanced ES-SCLC. Small-cell lung cancer is a fast-growing cancer that often causes serious symptoms, such as coughing, shortness of breath, chest pain, and fatigue. Because many patients are diagnosed at an advanced stage, treatments should not only help people live longer, but also help them feel better during treatment. The RATIONALE-312 study compared two treatments for people with extensive-stage small-cell lung cancer who had not received treatment before. One group received standard chemotherapy. The other group received chemotherapy plus tislelizumab, a type of immunotherapy that helps the immune system attack cancer cells. Patients in the study regularly completed questionnaires about their quality of life and symptoms. These questionnaires asked how patients felt physically and how much symptoms affected their daily lives. Patients who received tislelizumab with chemotherapy reported improvements in their overall quality of life and in key lung cancer symptoms, including coughing, coughing up blood, chest pain, and shortness of breath. These improvements were seen during treatment and continued after chemotherapy ended. Importantly, adding tislelizumab did not make symptoms worse or cause patients to lose daily functioning sooner. Together with earlier results showing longer survival, these findings suggest that adding tislelizumab to chemotherapy can help patients live longer while also maintaining or improving how they feel during treatment.

在3期临床试验RATIONALE-312（临床试验.gov标识符：NCT04005716）中，针对广泛期小细胞肺癌（ES-SCLC）患者，将替雷利珠单抗（tislelizumab）作为一线治疗方案联合化疗，对比安慰剂联合化疗，可显著改善总生存期与无进展生存期，且安全性可接受。
本分析报告了RATIONALE-312试验的患者报告结局（PROs）。
总计457例ES-SCLC成人患者按1:1比例随机分组，分别接受替雷利珠单抗联合化疗（n=227）或安慰剂联合化疗（n=230）。
患者报告结局为试验方案预先设定的次要终点，采用欧洲癌症研究与治疗组织（EORTC）QLQ-C30及QLQ-LC13问卷评估健康相关生活质量（HRQoL）。
对第4周期和第6周期的患者报告结局终点采用重复测量混合效应模型进行分析，并评估了恶化时间（TTD）。
第4周期时，替雷利珠单抗组在咳嗽、咯血及胸痛方面出现了具有临床意义的改善。
替雷利珠单抗组在总体健康状况（GHS）/生活质量、呼吸困难以及手臂或肩部疼痛方面出现了具有临床意义的改善，而安慰剂组未观察到此类改善。
至第6周期时，替雷利珠单抗组在GHS/生活质量方面实现了具有临床意义的改善，组间差异具有统计学意义，且偏向替雷利珠单抗组。
截至第6周期，替雷利珠单抗组在呼吸困难、咳嗽、咯血及胸痛方面的临床意义改善得以维持。
恶化时间分析未观察到组间差异。
相较于安慰剂联合化疗，替雷利珠单抗联合化疗可维持或改善患者的健康相关生活质量及患者报告的症状。
结合已有的疗效与安全性数据，本研究结果支持替雷利珠单抗联合化疗作为晚期ES-SCLC患者的一线治疗方案。
小细胞肺癌是一种生长迅速的癌症，常引发咳嗽、呼吸困难、胸痛及乏力等严重症状。
由于多数患者确诊时已处于晚期，治疗不仅应帮助患者延长生存期，还应改善其治疗期间的生存体验。
RATIONALE-312研究对比了两种治疗方案，用于既往未接受过治疗的广泛期小细胞肺癌患者。
一组接受标准化疗，另一组接受化疗联合替雷利珠单抗——一种可帮助免疫系统攻击癌细胞的免疫治疗药物。
研究中的患者定期完成关于其生活质量与症状的问卷，问卷内容涵盖患者的躯体感受以及症状对其日常生活的影响程度。
接受替雷利珠单抗联合化疗的患者报告称，其总体生活质量及关键肺癌相关症状（包括咳嗽、咯血、胸痛及呼吸困难）均得到改善。
此类改善在治疗期间即可观察到，并在化疗结束后仍持续存在。
值得注意的是，加用替雷利珠单抗并未加重症状，也未导致患者更早丧失日常功能。
结合此前显示生存期延长的研究结果，本研究结果表明，在化疗基础上加用替雷利珠单抗，不仅可帮助患者延长生存期，还可维持或改善其治疗期间的生存质量。