Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, USA.
Department of Medicine I, Medical University Vienna, Vienna, Austria.
ESMO Open. 2024 Nov;9(11):103931. doi: 10.1016/j.esmoop.2024.103931. Epub 2024 Oct 11.
Currently, there is no consensus definition for clinically meaningful outcomes in randomized clinical trials (RCTs) designed to evaluate new treatments for patients with refractory metastatic colorectal cancer (mCRC). Since 2014, recommended targets for improvements in overall survival and progression-free survival have been published by several societies, including those from the American Society of Clinical Oncology (ASCO) Clinically Meaningful Outcomes Working Group in 2014, the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) in 2015, and Colorectal Cancer Canada (CCC) consensus statements in 2019. However, evidence from several systematic reviews suggests that in a substantial proportion of RCTs that led to oncology drug approvals, the recommended thresholds of ASCO and ESMO-MCBS were not met. In addition to efficacy and safety, quality of life (QoL) is important to patients with mCRC, especially for those who are receiving later-line therapy or end-of-life care. As such, both ESMO-MCBS and CCC recommend the inclusion of QoL assessments in the design of mCRC clinical trials. Since the publication of the ASCO recommendations in 2014, there has been significant progress in the development of treatment options for patients with refractory mCRC; these include the approvals of trifluridine/tipiracil (FTD/TPI) as a single agent and in combination with bevacizumab, and the approval of fruquintinib. Among the phase III RCTs in third-line mCRC, only the SUNLIGHT trial of FTD/TPI plus bevacizumab met all recommended thresholds for clinically meaningful improvements, while also demonstrating a manageable safety profile and slower deterioration in multiple measures of QoL compared with FTD/TPI alone. The results from the SUNLIGHT study show that incremental gains in several clinically meaningful endpoints are achievable, thus raising the bar in defining clinically meaningful outcomes for emerging therapies in refractory mCRC.
目前，对于旨在评估新疗法治疗难治性转移性结直肠癌（mCRC）患者的随机临床试验（RCT），尚未就临床有意义的结局达成共识定义。自 2014 年以来，包括美国临床肿瘤学会（ASCO）临床有意义结局工作组（2014 年）、欧洲肿瘤内科学会-临床获益幅度量表（ESMO-MCBS）（2015 年）和加拿大结直肠癌共识声明（2019 年）在内的多个学会已发布了总生存期和无进展生存期改善的推荐目标。然而，多项系统评价的证据表明，在导致肿瘤药物批准的大量 RCT 中，ASCO 和 ESMO-MCBS 的推荐阈值并未得到满足。除了疗效和安全性之外，生活质量（QoL）对 mCRC 患者也很重要，尤其是对接受后线治疗或临终关怀的患者。因此，ESMO-MCBS 和 CCC 都建议将 QoL 评估纳入 mCRC 临床试验的设计中。自 2014 年 ASCO 建议发布以来，难治性 mCRC 患者的治疗选择取得了重大进展；这些进展包括批准氟尿嘧啶替匹嘧啶（FTD/TPI）作为单一药物和联合贝伐珠单抗，以及批准呋喹替尼。在三线 mCRC 的 III 期 RCT 中，只有 FTD/TPI 联合贝伐珠单抗的 SUNLIGHT 试验满足了所有临床有意义改善的推荐阈值，同时也显示出可管理的安全性特征和与单独使用 FTD/TPI 相比，多个 QoL 指标恶化更慢。SUNLIGHT 研究的结果表明，可实现多个临床有意义终点的增量收益，从而提高了难治性 mCRC 新兴疗法的临床有意义结局的定义标准。
