Background Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up. Patients and methods EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported. Results Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis. Conclusion The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib. Trial Registration Number NCT00704730.

中文翻译：

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EXAM 的总体生存分析，这是一项卡博替尼治疗放射学进展性甲状腺髓样癌患者的 III 期试验。


背景 在晚期甲状腺髓样癌 (EXAM) 试验中对 XL184（卡博替尼）的双盲 III 期疗效进行初步分析表明，与安慰剂相比，卡博替尼对进展性甲状腺髓样癌 (MTC) 患者的无进展生存期有显着改善。对关键次要终点总生存期（OS）的最终分析是在长期随访后进行的。患者和方法 EXAM 在 330 名记录有转移性 MTC 影像学进展的患者中对卡博替尼与安慰剂进行了比较。患者被随机 (2:1) 接受卡博替尼（140 毫克/天）或安慰剂。报告最终操作系统和更新的安全数据。结果 最短随访时间为 42 个月。 Kaplan-Meier 分析显示，与安慰剂相比，卡博替尼的中位 OS 增加了 5.5 个月（26.6 个月与 21.1 个月），尽管差异未达到统计学显着性[分层风险比 (HR)，0.85； 95%置信区间（CI），0.64-1.12； P = 0.24]。在对 OS、无进展生存期和客观缓解率的探索性评估中，与不携带该突变的患者相比，卡博替尼似乎对 RET M918T 突变阳性肿瘤患者具有更大的治疗效果。对于 RET M918T 阳性疾病患者，卡博替尼组的中位 OS 为 44.3 个月，而安慰剂组为 18.9 个月 [HR，0.60； 95% CI，0.38-0.94； P = 0.03（未针对多个亚组分析进行调整）]，RET M918T 阴性亚组中的相应值为 20.2 个月与 21.5 个月（HR，1.12；95% CI，0.70-1.82；P = 0.63）。卡博替尼的中位治疗持续时间为 10.8 个月，安慰剂为 3.4 个月。卡博替尼的安全性与初步分析的安全性保持一致。 结论 在卡博替尼治疗转移性、放射学进展性 MTC 患者的最终 OS 分析中，未达到次要终点。与安慰剂相比，卡博替尼的 OS 增加无统计学意义。探索性分析表明，RET M918T 阳性肿瘤患者使用卡博替尼可能会获得更大的治疗益处。试用注册号 NCT00704730。