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）分析仅限于单一单向终点，大多数晚期癌症随机临床试验（RCT）仅针对无进展生存期（PFS）或总生存期（OS）进行效能计算。这种方法丢弃了在疾病进展和死亡前常出现的部分缓解、完全缓解和疾病稳定所携带的疗效信息。Chauhan加权轨迹分析（CWTA）是KM方法的一种推广，可同时评估多个有序分级终点。我们假设CWTA能够利用这些疗效信息来降低样本量需求并加速晚期癌症试验中的疗效信号出现。我们对实体瘤全身治疗RCT进行了100次和1000次模拟，健康状况按从完全缓解（阶段0）到死亡（阶段4）的顺序分级。在不同样本量和风险比的增量下，我们比较了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）首次出现显著疗效信号的时间。与KM PFS相比，CWTA始终表现出更高的统计效能，并将样本量需求降低了18%至35%；与KM OS相比，样本量需求降低了14%至20%。同时，CWTA将疗效信号出现时间加速了2至6倍。通过整合癌症治疗轨迹中的所有疗效信号，CWTA相比KM PFS和KM OS，能够实现临床相关的样本量减少，并显著加速癌症治疗的疗效信号出现。采用CWTA而非KM作为主要试验终点，有望显著减少晚期癌症治疗评估所需的患者数量、试验持续时间和成本。