Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Columbia University Medical Center, New York, NY, USA.
Lancet Oncol. 2023 Oct;24(10):1073-1082. doi: 10.1016/S1470-2045(23)00358-3. Epub 2023 Sep 1.
The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma.
This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m bolus followed by 2400 mg/m over 48 h], leucovorin [400 mg/m], and oxaliplatin [85 mg/m]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete.
Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths.
Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned.
Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.
纳武利尤单抗联合化疗可改善晚期食管胃（食管、胃或胃食管交界处）腺癌患者的生存；然而，预后仍然较差。我们评估了regorafenib 联合 nivolumab 和化疗在 HER2 阴性转移性食管胃腺癌一线治疗中的安全性和活性。
这项由研究者发起的、单臂、2 期临床试验在未经治疗的 HER2 阴性、转移性食管胃腺癌的成年患者（年龄≥18 岁）中进行，该试验在纽约纪念斯隆凯特琳癌症中心（MSKCC）进行。合格患者具有可测量的疾病或不可测量的疾病，但可评估（根据实体瘤反应评估标准 1.1 版[RECIST]定义）且东部合作肿瘤学组的表现状态为 0 或 1。患者接受 FOLFOX 化疗（氟尿嘧啶[400mg/m 推注，随后 48 小时内 2400mg/m]、亚叶酸[400mg/m]和奥沙利铂[85mg/m]）和 nivolumab（240mg）静脉注射于第 1 天和第 15 天，口服regorafenib（80mg）于第 1 天至第 21 天，28 天为一个周期。治疗持续到疾病进展（根据 RECIST 1.1 版定义）、无法耐受的毒性或患者撤回同意。主要终点是方案人群（即接受所有研究治疗剂量的所有参与者）的 6 个月无进展生存期。如果至少 35 名患者中的 24 名在 6 个月时无进展，则该方案将被认为值得进一步研究。所有接受至少一剂任何研究治疗的参与者均进行了安全性评估。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT04757363，现已完成。
在 2021 年 2 月 11 日至 2022 年 5 月 4 日期间，共有 39 名患者入组，接受了至少一剂研究药物，并纳入安全性分析。35 名患者可评估 6 个月无进展生存期。中位年龄为 57 岁（IQR 52-66），9 名（26%）患者为女性，26 名（74%）为男性，28 名（80%）为白人，7 名（20%）为亚洲人。在数据截止日期（2023 年 3 月 3 日），中位随访时间为 18.1 个月（IQR 12.7-20.4）。主要终点达到，35 名患者中有 25 名（71%；95%CI 54-85）在 6 个月时无进展。35 名患者中有 9 名（26%）发生疾病进展，1 名（3%）患者死亡；死亡与治疗无关。任何级别的最常见不良事件是疲劳（39 名患者中的 36 名[92%]）。最常见的 3 级或 4 级不良事件是中性粒细胞计数减少（18 名患者[46%]）、高血压（6 名患者[15%]）、皮肤干燥、瘙痒或皮疹（5 名患者[13%]）和贫血（4 名患者[10%]）。10 名（26%）患者发生严重治疗相关不良事件，分别为急性肾损伤（3 名患者[8%]）、肝毒性（2 名患者[5%]）、脓毒症（2 名患者[5%]）、皮肤干燥、瘙痒或皮疹（1 名患者[3%]）、恶心（1 名患者[3%]）和胃穿孔（1 名患者[3%]）。没有治疗相关死亡。
regorafenib 联合 nivolumab 和化疗是安全的，并且在 HER2 阴性转移性胃食管腺癌中显示出有希望的活性。计划进行一项随机、3 期临床试验。
百时美施贵宝、拜耳和美国国立卫生研究院/美国国立癌症研究所。
