Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2021 Jun 1;27(11):3050-3060. doi: 10.1158/1078-0432.CCR-20-4118. Epub 2021 Mar 26.
As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy.
In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression.
Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer ( = 11), pancreatic cancer ( = 7), immunotherapy-resistant melanoma ( = 2), and human papillomavirus-negative head and neck cancer ( = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia.
No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
由于缺氧可介导对免疫疗法的耐药性，我们研究了联合应用前药埃伏磷酸酰胺（可减轻缺氧）与免疫检查点抑制剂伊匹单抗在免疫“冷”肿瘤（对免疫疗法固有不敏感）中的安全性、耐受性和疗效，以及在“热/温”转移性癌症（这种癌症对免疫疗法不典型耐药）中的疗效。
在一项 I 期、3+3 剂量递增试验（NCT03098160）中，埃伏磷酸酰胺（400-640mg/m ）和伊匹单抗（3mg/kg）在四个 3 周周期中给药。前药在周期 1-2 的第 1 和第 8 天给药，而后药在周期 1-4 的第 8 天给药。采用免疫相关 RECIST 评估反应，如果认为有获益，在完成第 4 周期或进展后允许重新治疗。
共纳入 22 例患者，其中 21 例可评估，包括去势抵抗性前列腺癌（n=11）、胰腺癌（n=7）、免疫治疗耐药性黑色素瘤（n=2）和人乳头瘤病毒阴性头颈部癌症（n=1）。>10%的患者出现与药物相关的血液学毒性、皮疹、发热、恶心、呕吐和肝酶升高。最常见的与药物相关的 3 级不良事件是丙氨酸氨基转移酶升高（33.3%）。2 例患者停止使用伊匹单抗，4 例因毒性需要降低埃伏磷酸酰胺剂量。在基线时有可测量疾病的 18 例患者中，3 例（16.7%）达到部分缓解，12 例（66.7%）达到疾病稳定。在 560mg/m 埃伏磷酸酰胺时观察到最佳反应。预先存在的免疫基因特征预测了对治疗的反应，而高代谢肿瘤则预测了进展。应答者还表现出外周 T 细胞增殖的改善和肿瘤内 T 细胞浸润到缺氧部位的增加。
联合应用埃伏磷酸酰胺和伊匹单抗未观察到新的或意外的安全性信号，且观察到了治疗活性。
