David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.
BHI of Omsk Region Clinical Oncology Dispensary, Omsk, Russia.
Lancet Oncol. 2021 Jan;22(1):51-65. doi: 10.1016/S1470-2045(20)30539-8. Epub 2020 Dec 4.
First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone.
CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872.
Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]).
First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC.
AstraZeneca.
在 CASPIAN 研究中，广泛期小细胞肺癌（ES-SCLC）患者一线使用度伐利尤单抗联合依托泊苷加顺铂或卡铂（铂类依托泊苷）与单独使用铂类依托泊苷相比，总生存期显著改善。这里我们报告了更新的结果，包括度伐利尤单抗联合替西木单抗加铂类依托泊苷与单独使用铂类依托泊苷相比的总生存期的主要分析。
CASPIAN 是一项正在进行的、开放性、研究者设盲、随机对照的 3 期临床试验，在全球 23 个国家的 209 个癌症治疗中心开展。纳入的患者年龄在 18 岁或以上（日本为 20 岁），组织学或细胞学证实为未经治疗的 ES-SCLC，WHO 体能状态评分为 0 或 1。患者按计划铂类药物、采用交互式语音或网络响应系统进行 1:1:1 随机分组，接受静脉注射度伐利尤单抗联合替西木单抗加铂类依托泊苷、度伐利尤单抗加铂类依托泊苷或铂类依托泊苷治疗。在所有组中，患者接受依托泊苷 80-100mg/m2，第 1-3 天使用研究者选择的卡铂 AUC 5-6mg/mL/min 或顺铂 75-80mg/m2，第 1 天。铂类依托泊苷组患者每 3 周接受最多 6 个周期的铂类依托泊苷，可选择进行预防性颅脑照射（研究者的判断）。免疫治疗组患者每 3 周接受 4 个周期的铂类依托泊苷加度伐利尤单抗 1500mg 加或不加替西木单抗 75mg，随后每 4 周接受维持剂量的度伐利尤单抗 1500mg。主要终点是度伐利尤单抗联合铂类依托泊苷与铂类依托泊苷、度伐利尤单抗联合替西木单抗加铂类依托泊苷与铂类依托泊苷相比的总生存期，在意向治疗人群中进行评估。所有接受至少一剂研究治疗的患者均进行安全性评估。该研究在 ClinicalTrials.gov 注册，NCT03043872。
2017 年 3 月 27 日至 2018 年 5 月 29 日，共筛选了 972 例患者，其中 805 例患者被随机分配（268 例接受度伐利尤单抗联合替西木单抗加铂类依托泊苷，268 例接受度伐利尤单抗加铂类依托泊苷，269 例接受铂类依托泊苷）。截至 2020 年 1 月 27 日，中位随访时间为 25.1 个月（IQR 22.3-27.9）。度伐利尤单抗联合替西木单抗加铂类依托泊苷与单独使用铂类依托泊苷相比，总生存期没有显著改善（风险比[HR]0.82[95%CI 0.68-1.00]；p=0.045）；中位总生存期为 10.4 个月（95%CI 9.6-12.0）与 10.5 个月（9.3-11.2）。度伐利尤单抗加铂类依托泊苷与单独使用铂类依托泊苷相比，总生存期持续改善（HR 0.75[95%CI 0.62-0.91]；名义 p=0.0032）；中位总生存期为 12.9 个月（95%CI 11.3-14.7）与 10.5 个月（9.3-11.2）。最常见的任何原因的 3 级或更高级别的不良事件是中性粒细胞减少症（度伐利尤单抗联合替西木单抗加铂类依托泊苷组 266 例患者中有 85 例[32%]，度伐利尤单抗加铂类依托泊苷组 265 例患者中有 64 例[24%]，铂类依托泊苷组 266 例患者中有 88 例[33%]）和贫血症（34 例[13%]、24 例[9%]和 48 例[18%]）。度伐利尤单抗联合替西木单抗加铂类依托泊苷组 121 例（45%）、度伐利尤单抗加铂类依托泊苷组 85 例（32%）和铂类依托泊苷组 97 例（36%）患者报告了任何原因的严重不良事件。度伐利尤单抗联合替西木单抗加铂类依托泊苷组发生 12 例（5%）治疗相关死亡（死亡、发热性中性粒细胞减少症和肺栓塞[各 2 例]；肠炎、一般身体健康恶化和多器官功能障碍综合征、肺炎、肺炎和肝炎、呼吸衰竭和猝死[各 1 例]），度伐利尤单抗加铂类依托泊苷组发生 6 例（2%）（心脏骤停、脱水、肝毒性、间质性肺病、全血细胞减少症和脓毒症[各 1 例]），铂类依托泊苷组发生 2 例（1%）（全血细胞减少症和血小板减少症[各 1 例]）。
一线度伐利尤单抗加铂类依托泊苷与单独使用铂类依托泊苷相比，总生存期有持续改善，但度伐利尤单抗加替西木单抗加铂类依托泊苷并未显著改善与铂类依托泊苷相比的结局。这些结果支持将度伐利尤单抗加铂类依托泊苷作为广泛期小细胞肺癌一线治疗的新标准。
阿斯利康。
