As Kaplan-Meier (KM) analysis is limited to single unidirectional endpoints, most advanced cancer randomized clinical trials (RCTs) are powered for either progression free survival (PFS) or overall survival (OS). This discards efficacy information carried by partial responses, complete responses, and stable disease that frequently precede progressive disease and death. Chauhan Weighted Trajectory Analysis (CWTA) is a generalization of KM that simultaneously assesses multiple rank-ordered endpoints. We hypothesized that CWTA could use this efficacy information to reduce sample size requirements and expedite efficacy signals in advanced cancer trials. We performed 100-fold and 1000-fold simulations of solid tumour systemic therapy RCTs with health statuses rank ordered from complete response (Stage 0) to death (Stage 4). At increments of sample size and hazard ratio, we compared KM PFS and OS with CWTA for (i) sample size requirements to achieve a power of 0.8 and (ii) time-to-first significant efficacy signal. CWTA consistently demonstrated greater power, and reduced sample size requirements by 18% to 35% compared to KM PFS and 14% to 20% compared to KM OS. CWTA also expedited time-to-efficacy signals 2- to 6-fold. CWTA, by incorporating all efficacy signals in the cancer treatment trajectory, provides clinically relevant reduction in required sample size and meaningfully expedites the efficacy signals of cancer treatments compared to KM PFS and KM OS. Using CWTA rather than KM as the primary trial outcome has the potential to meaningfully reduce the numbers of patients, trial duration, and costs to evaluate therapies in advanced cancer.

翻译：由于Kaplan-Meier（KM）分析局限于单一单向终点，大多数晚期癌症随机对照试验（RCT）以无进展生存期（PFS）或总生存期（OS）作为统计效能依据。这忽略了常出现在疾病进展和死亡之前的部分缓解、完全缓解和疾病稳定所携带的有效性信息。Chauhan加权轨迹分析（CWTA）是KM分析的广义化方法，可同时评估多个有序等级终点。我们假设CWTA能利用这些有效性信息，减少晚期癌症试验的样本量需求并加速有效性信号获取。我们进行了100倍和1000倍的实体瘤全身治疗RCT模拟，将健康状态从完全缓解（0期）到死亡（4期）进行有序等级划分。在样本量和风险比递增的条件下，比较KM PFS、KM OS与CWTA在以下两方面的表现：（i）达到0.8统计效能所需的样本量，（ii）首次显著性有效性信号的出现时间。CWTA始终展现出更高的统计效能，相比KM PFS可减少18%至35%的样本量需求，相比KM OS可减少14%至20%。同时，CWTA将有效性信号获取时间加速了2至6倍。通过整合癌症治疗轨迹中的所有有效性信号，CWTA相较于KM PFS和KM OS，在临床相关层面降低了所需样本量，并显著加速了癌症治疗有效性信号的获取。将CWTA而非KM作为主要试验终点，有望在晚期癌症疗法评估中显著减少患者数量、缩短试验周期并降低成本。