Hospital Ramon y Cajal, Madrid, Madrid, Spain; MD Anderson Cancer Center Madrid, Madrid, Spain.
Gregorio Maranon Hospital, Madrid, Spain.
Lancet Oncol. 2024 Jan;25(1):29-45. doi: 10.1016/S1470-2045(23)00540-5. Epub 2023 Dec 12.
IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C.
In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting.
Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy.
Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed.
F Hoffmann-La Roche.
在局部晚期或转移性尿路上皮癌患者中，与安慰剂加铂类化疗（C 组）相比，IMvigor130 研究中，一线阿替利珠单抗联合铂类化疗（A 组）在研究者评估的无进展生存期方面具有统计学显著获益。中期分析未改善总生存期。在此，我们报告了 A 组与 C 组的最终总体分析结果。
在这项全球性、部分盲法、随机、对照、3 期研究中，招募了 221 家医院和肿瘤中心的年龄≥18 岁、未经治疗的局部晚期或转移性尿路上皮癌患者，且东部肿瘤协作组体能状态为 0-2 分。患者以 1:1:1 的比例，采用随机区组方法（区组大小为 6）和交互式语音和网络响应系统，按 PD-L1 状态、Bajorin 风险因素评分和研究者选择的铂类化疗方案分层，随机分配（1:1:1）接受阿替利珠单抗联合铂类化疗（A 组）、阿替利珠单抗单药治疗（B 组）或安慰剂联合铂类化疗（C 组）。研究者、患者和赞助商均对阿替利珠单抗或安慰剂（即 A 组和 C 组）和阿替利珠单抗单药治疗（B 组）的分配情况设盲（即开放标签）。对于 A 组和 C 组，所有患者均接受吉西他滨（1000 mg/m 静脉输注；每 21 天周期的第 1 天和第 8 天）联合研究者选择的卡铂（曲线下面积 4.5 mg/mL·min 或 5 mg/mL·min；静脉输注）或顺铂（70 mg/m 静脉输注），加用阿替利珠单抗（1200 mg 静脉输注）或安慰剂，每周期第 1 天使用。该研究的主要终点是在意向治疗（ITT）人群（即所有随机患者）中，A 组与 C 组的研究者评估的无进展生存期和总生存期，以及 B 组与 C 组的总生存期，这是按层次进行检验的。在此报告 A 组与 C 组的最终总体生存和更新的安全性结果（安全性人群；所有接受任何剂量研究治疗药物的患者）。总体生存分析的最终预设显著性边界为单侧 p=0.021。该试验在 ClinicalTrials.gov 注册，编号为 NCT02807636，目前仍在进行，但不再招募患者。
2016 年 7 月 15 日至 2018 年 7 月 20 日期间，共纳入 1213 例患者，并随机分配至治疗组，其中 851 例分配至 A 组（n=451）和 C 组（n=400）。A 组 338 例（75%）和 C 组 298 例（75%）患者为男性，A 组 113 例（25%）和 C 组 102 例（25%）患者为女性，A 组 346 例（77%）和 C 组 304 例（76%）患者为白人。在数据截止日期（2022 年 8 月 31 日），中位随访 13.4 个月（6.2-30.8）后，A 组中位总生存期为 16.1 个月（95%CI 14.2-18.8；336 例死亡），C 组为 13.4 个月（12.0-15.3；310 例死亡）（分层风险比 0.85 [95%CI 0.73-1.00]；单侧 p=0.023）。最常见的 3-4 级治疗相关不良事件是贫血（454 例接受阿替利珠单抗联合化疗的患者中有 168 例[37%]，389 例接受安慰剂联合化疗的患者中有 133 例[34%]）、中性粒细胞减少症（167 例[37%]vs 115 例[30%]）、中性粒细胞计数降低（98 例[22%]vs 95 例[24%]）、血小板减少症（95 例[21%]vs 70 例[18%]）和血小板计数降低（92 例[20%]vs 92 例[24%]）。接受阿替利珠单抗联合化疗的 243 例（54%）患者和接受安慰剂联合化疗的 196 例（50%）患者发生了严重不良事件。9 例（2%；急性肾损伤、呼吸困难、肝功能衰竭、肝炎、中性粒细胞减少症、肺炎、呼吸衰竭、脓毒症和血小板减少症[各 1 例]）接受阿替利珠单抗联合化疗的患者和 4 例（1%；原因不明的死亡、腹泻、发热性中性粒细胞减少症和毒性肝炎[各 1 例]）接受安慰剂联合化疗的患者发生了治疗相关死亡。
在 IMvigor130 中，与安慰剂加铂类化疗相比，一线阿替利珠单抗联合铂类化疗的无进展生存获益并未转化为 ITT 人群总生存期的显著改善。需要进一步研究以了解哪些患者可能受益于一线联合治疗。没有观察到新的安全性信号。
F Hoffmann-La Roche。
