University of California San Diego, Moores Cancer Center, San Diego, California, USA
Hospital Universitario Ramón y Cajal, Madrid, Spain.
J Immunother Cancer. 2024 Feb 2;12(2):e007340. doi: 10.1136/jitc-2023-007340.
The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors.
Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8 T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8 and granzyme B cells were observed.
Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME.
NCT02671435.
莫那比拉珠单抗（抗 NKG2A/CD94）和度伐鲁单抗（抗程序性死亡配体 1）的联合治疗可能通过靶向固有和适应性免疫来促进抗肿瘤免疫。这项莫那比拉珠单抗和度伐鲁单抗的 1/2 期研究评估了晚期实体瘤患者的安全性、抗肿瘤活性和药代动力学。
入组了年龄≥18 岁、ECOG 体能状态为 0-1 分、复发/转移性疾病中接受过 1-3 线系统治疗的免疫治疗初治患者。在 1 部分（剂量递增）中，患者接受每 4 周（Q4W）一次的度伐鲁单抗 1500mg 联合莫那比拉珠单抗 Q2W/Q4W 的递增剂量（n=15）。1 部分的剂量扩展包括宫颈癌患者（n=15；度伐鲁单抗 1500mg Q4W 和莫那比拉珠单抗 750mg Q2W）或转移性微卫星稳定（MSS）-结直肠癌（CRC）患者（n=15；度伐鲁单抗 1500mg Q4W 和莫那比拉珠单抗 750mg Q4W）。在 2 部分（剂量扩展）中，MSS-CRC（n=40）、非小细胞肺癌（NSCLC；n=20）、MSS 子宫内膜癌（n=40）或卵巢癌（n=40）患者接受度伐鲁单抗 1500mg Q4W 和莫那比拉珠单抗 750mg Q2W。主要终点是安全性。次要终点包括按实体瘤反应评价标准 1.1 版（RECIST v1.1）评估的抗肿瘤活性。探索性分析包括外周血和肿瘤微环境（TME）中 T 细胞和自然杀伤（NK）细胞激活和增殖的评估。该研究入组了 185 名患者（1 部分，45 名；2 部分，140 名）。未观察到剂量限制毒性，也未达到最大耐受剂量。在 2 部分中，最常见的治疗相关不良事件是疲劳（12.1%）、乏力（9.3%）、腹泻（9.3%）、瘙痒（7.9%）和发热（7.1%）。在扩展队列中，缓解率分别为 0%（宫颈癌）、7.7%（MSS-CRC）、10%（NSCLC）、5.4%（卵巢癌）和 0%（MSS 子宫内膜癌）。观察到持续的 NK 细胞激活、CD8 T 细胞增殖、血清 CXCL10（C-X-C 基序趋化因子配体 10）和 CXCL11 水平升高，以及肿瘤内 CD8 和颗粒酶 B 细胞浸润增加。
尽管疗效温和，但莫那比拉珠单抗联合度伐鲁单抗耐受性良好，并在外周血和 TME 中观察到令人鼓舞的免疫激活。
NCT02671435。
