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Abstract：
BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC).
METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W.
RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%.
CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab\'s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant.
BACKGROUND: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.
METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W.
RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%.
CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab\'s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant.
BACKGROUND: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.
摘要：
背景：肿瘤中CD73的上调导致局部免疫抑制。这个阶段I,首次在人类研究中评估了oleumumab（MEDI9447），抗CD73人IgG1λ单克隆抗体，单独或与Durvalumab一起治疗晚期结直肠癌（CRC）患者，胰腺导管腺癌（PDAC），或表皮生长因子受体突变的非小细胞肺癌（NSCLC）。
方法：患者每2周（Q2W）静脉内接受5-40mg/kg（剂量递增）或40mg/kg（剂量扩大）的oleumumab，单独（仅升级）或静脉注射Durvalumab10mg/kgQ2W。
结果：共纳入192例患者，升级期间为66，升级期间为126(42CRC，42PDAC,42NSCLC）扩增期间。在升级期间没有发生剂量限制性毒性。在单药治疗和联合治疗升级队列中，与治疗相关的不良事件（TRAEs）分别占55%和54%，分别,最常见的是疲劳（17％和25％）。在CRC中,PDAC,和NSCLC扩展队列，60％，57％和45％的患者患有TRAE，最常见的分别是疲劳(15%)，腹泻（9%），皮疹(7%)。游离可溶性CD73和CD73在外周T细胞和肿瘤细胞上的表达呈持续下降，伴有肿瘤细胞中CD73酶活性降低。升级期间的客观反应率为0%。CRC中的响应率，PDAC,NSCLC扩展队列为2.4%（1个完全缓解[CR]），4.8%（1CR，1部分响应[PR])，和9.5%(4个PR)，6个月无进展生存率分别为5.4%、13.2%和16.0%。
结论：Oleclumab±durvalumab具有可控的安全性，具有药效学活性，反映了oleumumab的作用机制。在通常具有免疫疗法抗性的肿瘤类型中观察到抗肿瘤活性的证据。
背景：Clinicaltrials.gov，NCT02503774；注册日期，2015年7月17日。
方法：患者每2周（Q2W）静脉内接受5-40mg/kg（剂量递增）或40mg/kg（剂量扩大）的oleumumab，单独（仅升级）或静脉注射Durvalumab10mg/kgQ2W。
结果：共纳入192例患者，升级期间为66，升级期间为126(42CRC，42PDAC,42NSCLC）扩增期间。在升级期间没有发生剂量限制性毒性。在单药治疗和联合治疗升级队列中，与治疗相关的不良事件（TRAEs）分别占55%和54%，分别,最常见的是疲劳（17％和25％）。在CRC中,PDAC,和NSCLC扩展队列，60％，57％和45％的患者患有TRAE，最常见的分别是疲劳(15%)，腹泻（9%），皮疹(7%)。游离可溶性CD73和CD73在外周T细胞和肿瘤细胞上的表达呈持续下降，伴有肿瘤细胞中CD73酶活性降低。升级期间的客观反应率为0%。CRC中的响应率，PDAC,NSCLC扩展队列为2.4%（1个完全缓解[CR]），4.8%（1CR，1部分响应[PR])，和9.5%(4个PR)，6个月无进展生存率分别为5.4%、13.2%和16.0%。
结论：Oleclumab±durvalumab具有可控的安全性，具有药效学活性，反映了oleumumab的作用机制。在通常具有免疫疗法抗性的肿瘤类型中观察到抗肿瘤活性的证据。
背景：Clinicaltrials.gov，NCT02503774；注册日期，2015年7月17日。
