Efficacy, safety and biomarkers of SG001 for patients with previously treated recurrent or metastatic cervical cancer: an open-label, multicenter, phase Ib trial

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-07-23 DOI:10.1002/cac2.12578
Jing Zuo, Wei Duan, Mingxuan Zhao, Zhendong Chen, Jie Lin, Huaqiu Shi, Ou Jiang, Youzhong Zhang, Meiyu Fang, Li Wang, Wei Wang, Yong Huang, Junyan Yu, Xiaoxue Zhang, Weiqing Pu, Deshun Hao, Fenglin She, Xiugao Yang, Ying Chen, Qizhi Tang, Xiao Zhang, Miao Niu, Yan'e Song, Lingying Wu
{"title":"Efficacy, safety and biomarkers of SG001 for patients with previously treated recurrent or metastatic cervical cancer: an open-label, multicenter, phase Ib trial","authors":"Jing Zuo,&nbsp;Wei Duan,&nbsp;Mingxuan Zhao,&nbsp;Zhendong Chen,&nbsp;Jie Lin,&nbsp;Huaqiu Shi,&nbsp;Ou Jiang,&nbsp;Youzhong Zhang,&nbsp;Meiyu Fang,&nbsp;Li Wang,&nbsp;Wei Wang,&nbsp;Yong Huang,&nbsp;Junyan Yu,&nbsp;Xiaoxue Zhang,&nbsp;Weiqing Pu,&nbsp;Deshun Hao,&nbsp;Fenglin She,&nbsp;Xiugao Yang,&nbsp;Ying Chen,&nbsp;Qizhi Tang,&nbsp;Xiao Zhang,&nbsp;Miao Niu,&nbsp;Yan'e Song,&nbsp;Lingying Wu","doi":"10.1002/cac2.12578","DOIUrl":null,"url":null,"abstract":"<p>Cervical cancer (CC) is one of the most common gynecological cancers, ranking fourth in incidence and mortality rates among women worldwide and second in China [<span>1</span>]. Approximately 15%-61% of patients with CC develop recurrent or metastatic (r/m) disease in the first two years after initial therapy completion, with a 5-year survival rate of 17% [<span>2</span>]. Platinum-based chemotherapy is the first-line treatment for r/mCC.</p><p>The immune checkpoint inhibitors targeting the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway have provided promising therapeutic choices [<span>3, 4</span>]. Based on the results from the KEYNOTE-158 [<span>5</span>] and KEYNOTE-826 trials [<span>3</span>], pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) as first-line (in combination with chemotherapy, with or without bevacizumab) and second-line or subsequent treatments for patients with PD-L1-positive r/mCC. However, the objective response rate (ORR) of PD-L1 inhibitor monotherapies rarely exceeds 30% in patients with PD-L1-positive r/mCC [<span>4, 6, 7</span>].</p><p>SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets PD-1 to block its interaction with the ligands PD-L1 and PD-L2. Here, we present the results from an expansion cohort (previously treated r/mCC) of an open-label, multicenter, phase Ib trial of SG001 monotherapy in patients with multiple advanced cancers (NCT03852823). Patients with histologically confirmed r/mCC who had progressed or were intolerant after one or more lines of chemotherapy and had at least one measurable lesion per the Response Evaluation Criteria in Advanced Solid Tumors (RECIST, version 1.1) were enrolled. SG001 (240 mg) was administered intravenously every 2 weeks until progressive disease, intolerable toxicity, or withdrawal. The methods for this study are described in detail in the Supplementary Material file.</p><p>A total of 91 patients were enrolled (Supplementary Figure S1). Ninety (98.9%) patients had received prior platinum-based therapy and 83 (91.2%) patients had undergone previous radiotherapy. In addition, 73 (80.2%) patients had squamous cell carcinoma (SCC), and 78 (85.7%) patients had distant metastasis. Forty-three (47.3%) patients had PD-L1-positive tumors (combined positive score ≥ 1). The baseline characteristics are summarized in Supplementary Table S1.</p><p>The Independent Review Committee (IRC)-assessed ORR was 25.3% (95% CI, 16.7-35.5), 29 (31.9%) of patients had stable disease (SD), and the disease control rate (DCR) was 63.7% (95% CI, 53.0-73.6) (Figure 1A and Supplementary Table S2). The median time to response (TTR) was 1.4 months (95% CI, 1.4-2.7). The median duration of response (DoR) had not been reached, with a 12-month DoR rate of 62.4% (95% CI, 35.7-80.5) (Supplementary Table S2). Thirty-nine patients exhibited a reduction in the target lesion size from baseline (Figure 1B). Similar results of the ORR, DCR, DoR and TTR by the investigators were also observed (Supplementary Table S2).</p><p>The median progression-free survival (PFS) was 5.5 months (95% CI, 4.1-6.9), with a 6-month PFS rate of 43.8% (95% CI, 31.6-55.4) per the IRC (Figure 1C). A total of 66 patients (72.5%) were still alive at the data cut-off date, with a 12-month overall survival (OS) rate of 65.8% (95% CI, 52.3-76.3) (OS curve with censored data was shown in Figure 1D). In the 78 patients with distant metastasis, 8.8% patients (<i>n</i> = 8) with liver metastasis showed a significantly shorter median PFS than those without liver metastasis (IRC: 2.6 months versus 5.4 months, <i>P</i> = 0.027; investigator: 2.1 months versus 4.2 months, <i>P</i> = 0.021) (Figure 1E, Supplementary Figure S2A). Compared to patients with non-SCC, patients with SCC showed a longer median PFS (IRC: 5.7 months versus 4.1 months, <i>P</i> = 0.091; investigator: 5.7 months versus 3.2 months, <i>P</i> = 0.027) (Figure 1F, Supplementary Figure S2B).</p><p>In the subset of patients with PD-L1-positive tumors (<i>n</i> = 43), the IRC-assessed ORR was 30.2%, with a median PFS of 7.1 months (Supplementary Figure S3A). Confirmed responses were also observed in those with PD-L1-negative tumors (<i>n</i> = 45), with an ORR of 20.0% and a median PFS of 4.3 months (Supplementary Figure S3A-B). To the best of our knowledge, our study revealed a relatively high ORR of PD-1 inhibitor monotherapy for ≥ second-line treatments in this setting in either the PD-L1-positive population or the PD-L1-negative population compared to the previous studies [<span>6, 7</span>]. Next-generation sequencing (NGS) testing data were obtained from 55 patients. Patients with high tumor mutational burden (TMB ≥ 4.92 mutations/Mb, <i>n</i> = 45) showed a higher ORR and longer median PFS than those with low TMB (<i>n</i> = 10) (IRC-assessed ORR: 33.3% versus 20.0%, <i>P</i> = 0.416; median PFS: 6.8 months versus 4.1 months, <i>P</i> = 0.022) (Supplementary Figure S3C-D). For the definition of TMB-high, the pre-specified threshold is 10 mutations/Mb in the KEYNOTE 158 study; accordingly, only 16% of patients in the CC cohort were regarded as TMB high [<span>8</span>]. In this study, the cut-off value of TMB was determined to be 4.92 mutations/Mb, resulting in more patients (81.8%) being classified as TMB-high. Our cut-off value was similar to that reported in a previous study [<span>9</span>].</p><p>Furthermore, the efficacy of combining PD-L1 and TMB was also investigated. No response was observed in patients with PD-L1-negative/TMB-low tumors (<i>n</i> = 6), whereas the IRC-assessed ORRs were 32.1%, 35.3% and 50.0% in patients with PD-L1-positive/TMB-high tumors, PD-L1-negative/TMB-high tumors, and PD-L1-positive/TMB-low tumors, respectively (Supplementary Figure S3E). The median PFS was longer in pooled patients with either PD-L1-positive tumors or TMB-high tumors or both than in those with PD-L1-negative/TMB-low tumors (IRC: 5.7 months versus 4.1 months, <i>P</i> = 0.081, Supplementary Figure S3F; investigator: 6.8 months versus 2.8 months, <i>P</i> = 0.023). Our combination analysis showed that patients with either PD-L1-positive tumors or high TMB or both had a benefit, with ORRs all over 30%, which is consistent with the results of the CLAP study [<span>9</span>], showing that the combination of TMB status and PD-L1 expression has a better prediction value.</p><p>A total of 74.7% (<i>n</i> = 68) of patients experienced one or more treatment-related adverse events (TRAEs). TRAEs of grade 3-4 were reported in 18.7% of patients (Supplementary Table S3), which was comparable to other similar studies with a reported rate of 12.2%-21.1% [<span>4, 5, 10</span>]. Grade ≥ 3 TRAEs that occurred in three or more patients were anemia (4.4%) and decreased lymphocyte count (3.3%). Three (3.3%) patients discontinued treatment because of TRAEs (abnormal hepatic function, interstitial lung disease, and toxic epidermal necrolysis) and one patient discontinued treatment due to AE assessed as not related to the SG001. No TRAEs leading to death occurred. Immune-related AEs of any grade associated with SG001 occurred in 36.3% (<i>n</i> = 33) patients, and 7.7% (<i>n</i> = 7) experienced at least one or more immune-related AEs of ≥ grade 3. The grade ≥ 3 immune-related AE that occurred in two or more patients was abnormal hepatic function (2.2%). The immune-related AEs (i.e., hypothyroidism and hyperthyroidism) reported here were consistent with those of other PD-1 inhibitors [<span>8, 9</span>].</p><p>This study was limited by a single-arm trial with no historical or concurrent control group. Despite this limitation, our exploration of PD-1 inhibitor monotherapy may still provide some theoretical basis for the role played by PD-1 inhibitors in later combination therapy for synergistic activities and greater clinical benefits [<span>6</span>]. The benefit of SG001 monotherapy in PD-L1-positive r/mCC has been further verified in an ongoing phase II study (NCT04886700). A phase III study of SG001 plus chemotherapy with/without bevacizumab in patients with PD-L1-positive r/mCC is underway (NCT05715840).</p><p>In summary, SG001 monotherapy exhibited clinically meaningful efficacy with minimal safety concerns in previously treated r/mCC patients. Of note, not only PD-L1 expression but also TMB could be predictors of the effectiveness of PD-1 inhibitor monotherapy. The encouraging response results and manageable safety profiles of SG001 revealed its significant potential in combination therapy for r/mCC.</p><p><i>Conception and design</i>: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao and Xiugao Yang. <i>Acquisition, analysis, and interpretation of the data</i>: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao, Zhendong Chen, Jie Lin, Huaqiu Shi, Ou Jiang, Youzhong Zhang, Meiyu Fang, Li Wang, Wei Wang, Yong Huang, Junyan Yu, Xiaoxue Zhang, Weiqing Pu, Deshun Hao, Fenglin She, Xiugao Yang, Xiao Zhang, Miao Niu, and Yan'e Song. <i>Administrative, technical, and material support</i>: Jing Zuo, Lingying Wu, Wei Duan, Deshun Hao, Fenglin She, Ying Chen, and Qizhi Tang. <i>Supervision</i>: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao, Zhendong Chen, Jie Lin, Huaqiu Shi, Ou Jiang, Youzhong Zhang, Meiyu Fang, Li Wang, Wei Wang, Yong Huang, Junyan Yu, Xiaoxue Zhang and Weiqing Pu. <i>Writing—review and editing</i>: Jing Zuo, Lingying Wu, Wei Duan and Mingxuan Zhao.</p><p>This study was supported by the CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.</p><p>Xiaoxue Zhang, Weiqing Pu, Deshun Hao, Fenglin She, Xiugao Yang, Ying Chen, Qizhi Tang, Xiao Zhang, Miao Niu, and Yan'e Song are employees of CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. The others have no conflicts of interest to declare.</p><p>The study was approved by the independent ethics committee National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (ID. 20/353-2137) and each participating center and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All patients signed informed consent in advance of participation. ClinicalTrials.gov identifier: NCT03852823.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":20.1000,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12578","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.12578","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Cervical cancer (CC) is one of the most common gynecological cancers, ranking fourth in incidence and mortality rates among women worldwide and second in China [1]. Approximately 15%-61% of patients with CC develop recurrent or metastatic (r/m) disease in the first two years after initial therapy completion, with a 5-year survival rate of 17% [2]. Platinum-based chemotherapy is the first-line treatment for r/mCC.

The immune checkpoint inhibitors targeting the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway have provided promising therapeutic choices [3, 4]. Based on the results from the KEYNOTE-158 [5] and KEYNOTE-826 trials [3], pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) as first-line (in combination with chemotherapy, with or without bevacizumab) and second-line or subsequent treatments for patients with PD-L1-positive r/mCC. However, the objective response rate (ORR) of PD-L1 inhibitor monotherapies rarely exceeds 30% in patients with PD-L1-positive r/mCC [4, 6, 7].

SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets PD-1 to block its interaction with the ligands PD-L1 and PD-L2. Here, we present the results from an expansion cohort (previously treated r/mCC) of an open-label, multicenter, phase Ib trial of SG001 monotherapy in patients with multiple advanced cancers (NCT03852823). Patients with histologically confirmed r/mCC who had progressed or were intolerant after one or more lines of chemotherapy and had at least one measurable lesion per the Response Evaluation Criteria in Advanced Solid Tumors (RECIST, version 1.1) were enrolled. SG001 (240 mg) was administered intravenously every 2 weeks until progressive disease, intolerable toxicity, or withdrawal. The methods for this study are described in detail in the Supplementary Material file.

A total of 91 patients were enrolled (Supplementary Figure S1). Ninety (98.9%) patients had received prior platinum-based therapy and 83 (91.2%) patients had undergone previous radiotherapy. In addition, 73 (80.2%) patients had squamous cell carcinoma (SCC), and 78 (85.7%) patients had distant metastasis. Forty-three (47.3%) patients had PD-L1-positive tumors (combined positive score ≥ 1). The baseline characteristics are summarized in Supplementary Table S1.

The Independent Review Committee (IRC)-assessed ORR was 25.3% (95% CI, 16.7-35.5), 29 (31.9%) of patients had stable disease (SD), and the disease control rate (DCR) was 63.7% (95% CI, 53.0-73.6) (Figure 1A and Supplementary Table S2). The median time to response (TTR) was 1.4 months (95% CI, 1.4-2.7). The median duration of response (DoR) had not been reached, with a 12-month DoR rate of 62.4% (95% CI, 35.7-80.5) (Supplementary Table S2). Thirty-nine patients exhibited a reduction in the target lesion size from baseline (Figure 1B). Similar results of the ORR, DCR, DoR and TTR by the investigators were also observed (Supplementary Table S2).

The median progression-free survival (PFS) was 5.5 months (95% CI, 4.1-6.9), with a 6-month PFS rate of 43.8% (95% CI, 31.6-55.4) per the IRC (Figure 1C). A total of 66 patients (72.5%) were still alive at the data cut-off date, with a 12-month overall survival (OS) rate of 65.8% (95% CI, 52.3-76.3) (OS curve with censored data was shown in Figure 1D). In the 78 patients with distant metastasis, 8.8% patients (n = 8) with liver metastasis showed a significantly shorter median PFS than those without liver metastasis (IRC: 2.6 months versus 5.4 months, P = 0.027; investigator: 2.1 months versus 4.2 months, P = 0.021) (Figure 1E, Supplementary Figure S2A). Compared to patients with non-SCC, patients with SCC showed a longer median PFS (IRC: 5.7 months versus 4.1 months, P = 0.091; investigator: 5.7 months versus 3.2 months, P = 0.027) (Figure 1F, Supplementary Figure S2B).

In the subset of patients with PD-L1-positive tumors (n = 43), the IRC-assessed ORR was 30.2%, with a median PFS of 7.1 months (Supplementary Figure S3A). Confirmed responses were also observed in those with PD-L1-negative tumors (n = 45), with an ORR of 20.0% and a median PFS of 4.3 months (Supplementary Figure S3A-B). To the best of our knowledge, our study revealed a relatively high ORR of PD-1 inhibitor monotherapy for ≥ second-line treatments in this setting in either the PD-L1-positive population or the PD-L1-negative population compared to the previous studies [6, 7]. Next-generation sequencing (NGS) testing data were obtained from 55 patients. Patients with high tumor mutational burden (TMB ≥ 4.92 mutations/Mb, n = 45) showed a higher ORR and longer median PFS than those with low TMB (n = 10) (IRC-assessed ORR: 33.3% versus 20.0%, P = 0.416; median PFS: 6.8 months versus 4.1 months, P = 0.022) (Supplementary Figure S3C-D). For the definition of TMB-high, the pre-specified threshold is 10 mutations/Mb in the KEYNOTE 158 study; accordingly, only 16% of patients in the CC cohort were regarded as TMB high [8]. In this study, the cut-off value of TMB was determined to be 4.92 mutations/Mb, resulting in more patients (81.8%) being classified as TMB-high. Our cut-off value was similar to that reported in a previous study [9].

Furthermore, the efficacy of combining PD-L1 and TMB was also investigated. No response was observed in patients with PD-L1-negative/TMB-low tumors (n = 6), whereas the IRC-assessed ORRs were 32.1%, 35.3% and 50.0% in patients with PD-L1-positive/TMB-high tumors, PD-L1-negative/TMB-high tumors, and PD-L1-positive/TMB-low tumors, respectively (Supplementary Figure S3E). The median PFS was longer in pooled patients with either PD-L1-positive tumors or TMB-high tumors or both than in those with PD-L1-negative/TMB-low tumors (IRC: 5.7 months versus 4.1 months, P = 0.081, Supplementary Figure S3F; investigator: 6.8 months versus 2.8 months, P = 0.023). Our combination analysis showed that patients with either PD-L1-positive tumors or high TMB or both had a benefit, with ORRs all over 30%, which is consistent with the results of the CLAP study [9], showing that the combination of TMB status and PD-L1 expression has a better prediction value.

A total of 74.7% (n = 68) of patients experienced one or more treatment-related adverse events (TRAEs). TRAEs of grade 3-4 were reported in 18.7% of patients (Supplementary Table S3), which was comparable to other similar studies with a reported rate of 12.2%-21.1% [4, 5, 10]. Grade ≥ 3 TRAEs that occurred in three or more patients were anemia (4.4%) and decreased lymphocyte count (3.3%). Three (3.3%) patients discontinued treatment because of TRAEs (abnormal hepatic function, interstitial lung disease, and toxic epidermal necrolysis) and one patient discontinued treatment due to AE assessed as not related to the SG001. No TRAEs leading to death occurred. Immune-related AEs of any grade associated with SG001 occurred in 36.3% (n = 33) patients, and 7.7% (n = 7) experienced at least one or more immune-related AEs of ≥ grade 3. The grade ≥ 3 immune-related AE that occurred in two or more patients was abnormal hepatic function (2.2%). The immune-related AEs (i.e., hypothyroidism and hyperthyroidism) reported here were consistent with those of other PD-1 inhibitors [8, 9].

This study was limited by a single-arm trial with no historical or concurrent control group. Despite this limitation, our exploration of PD-1 inhibitor monotherapy may still provide some theoretical basis for the role played by PD-1 inhibitors in later combination therapy for synergistic activities and greater clinical benefits [6]. The benefit of SG001 monotherapy in PD-L1-positive r/mCC has been further verified in an ongoing phase II study (NCT04886700). A phase III study of SG001 plus chemotherapy with/without bevacizumab in patients with PD-L1-positive r/mCC is underway (NCT05715840).

In summary, SG001 monotherapy exhibited clinically meaningful efficacy with minimal safety concerns in previously treated r/mCC patients. Of note, not only PD-L1 expression but also TMB could be predictors of the effectiveness of PD-1 inhibitor monotherapy. The encouraging response results and manageable safety profiles of SG001 revealed its significant potential in combination therapy for r/mCC.

Conception and design: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao and Xiugao Yang. Acquisition, analysis, and interpretation of the data: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao, Zhendong Chen, Jie Lin, Huaqiu Shi, Ou Jiang, Youzhong Zhang, Meiyu Fang, Li Wang, Wei Wang, Yong Huang, Junyan Yu, Xiaoxue Zhang, Weiqing Pu, Deshun Hao, Fenglin She, Xiugao Yang, Xiao Zhang, Miao Niu, and Yan'e Song. Administrative, technical, and material support: Jing Zuo, Lingying Wu, Wei Duan, Deshun Hao, Fenglin She, Ying Chen, and Qizhi Tang. Supervision: Jing Zuo, Lingying Wu, Wei Duan, Mingxuan Zhao, Zhendong Chen, Jie Lin, Huaqiu Shi, Ou Jiang, Youzhong Zhang, Meiyu Fang, Li Wang, Wei Wang, Yong Huang, Junyan Yu, Xiaoxue Zhang and Weiqing Pu. Writing—review and editing: Jing Zuo, Lingying Wu, Wei Duan and Mingxuan Zhao.

This study was supported by the CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.

Xiaoxue Zhang, Weiqing Pu, Deshun Hao, Fenglin She, Xiugao Yang, Ying Chen, Qizhi Tang, Xiao Zhang, Miao Niu, and Yan'e Song are employees of CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. The others have no conflicts of interest to declare.

The study was approved by the independent ethics committee National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (ID. 20/353-2137) and each participating center and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All patients signed informed consent in advance of participation. ClinicalTrials.gov identifier: NCT03852823.

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SG001对既往接受过治疗的复发性或转移性宫颈癌患者的疗效、安全性和生物标志物:一项开放标签、多中心、Ib期试验。
宫颈癌(CC)是最常见的妇科癌症之一,其发病率和死亡率在全球妇女中排名第四,在中国排名第二[1]。约 15%-61%的宫颈癌患者在初始治疗结束后的两年内出现复发或转移,5 年生存率为 17%[2]。针对程序性死亡-1(PD-1)/PD-配体1(PD-L1)通路的免疫检查点抑制剂提供了很有前景的治疗选择[3, 4]。根据KEYNOTE-158[5]和KEYNOTE-826试验[3]的结果,美国食品和药物管理局(FDA)已批准pembrolizumab作为PD-L1阳性r/mCC患者的一线治疗(联合化疗,联合或不联合贝伐珠单抗)、二线治疗或后续治疗。SG001 是一种全人源化的高亲和力免疫球蛋白 G4 单克隆抗体,以 PD-1 为靶点,阻断其与配体 PD-L1 和 PD-L2 的相互作用。在此,我们展示了一项开放标签、多中心、Ib 期 SG001 单药治疗多种晚期癌症患者试验(NCT03852823)的扩增队列(既往接受过治疗的 r/mCC)的结果。组织学确诊的r/mCC患者在接受了一种或多种化疗后病情进展或不耐受化疗,并且根据晚期实体瘤反应评估标准(RECIST,1.1版)至少有一个可测量病灶。每 2 周静脉注射一次 SG001(240 毫克),直到疾病进展、出现不可耐受的毒性或停药为止。本研究的方法详见补充材料文件。共有 91 名患者入选(补充图 S1)。90名患者(98.9%)曾接受过铂类治疗,83名患者(91.2%)曾接受过放疗。此外,73 名(80.2%)患者患有鳞状细胞癌(SCC),78 名(85.7%)患者有远处转移。43例(47.3%)患者的肿瘤为PD-L1阳性(合并阳性评分≥1)。独立审查委员会(IRC)评估的ORR为25.3%(95% CI,16.7-35.5),29例(31.9%)患者病情稳定(SD),疾病控制率(DCR)为63.7%(95% CI,53.0-73.6)(图1A和补充表S2)。中位应答时间(TTR)为 1.4 个月(95% CI,1.4-2.7)。中位应答持续时间(DoR)尚未达到,12 个月的 DoR 率为 62.4%(95% CI,35.7-80.5)(补充表 S2)。39例患者的靶病灶面积较基线有所缩小(图1B)。中位无进展生存期(PFS)为 5.5 个月(95% CI,4.1-6.9),根据 IRC,6 个月的 PFS 率为 43.8%(95% CI,31.6-55.4)(图 1C)。截至数据截止日,共有 66 名患者(72.5%)仍然存活,12 个月的总生存率(OS)为 65.8%(95% CI,52.3-76.3)(图 1D 中为带删减数据的 OS 曲线)。在78例远处转移患者中,8.8%的肝转移患者(n = 8)的中位生存期明显短于无肝转移患者(IRC:2.6个月对5.4个月,P = 0.027;研究者:2.1个月对4.2个月,P = 0.021)(图1E,补充图S2A)。与非 SCC 患者相比,SCC 患者的中位 PFS 更长(IRC:5.7 个月对 4.1 个月,P = 0.091;研究者:5.7 个月对 3.2 个月,P = 0.091):在 PD-L1 阳性肿瘤患者子集中(n = 43),IRC 评估的 ORR 为 30.2%,中位 PFS 为 7.1 个月(补充图 S3A)。在PD-L1阴性肿瘤患者(n = 45)中也观察到了确认的反应,ORR为20.0%,中位PFS为4.3个月(补充图S3A-B)。据我们所知,与之前的研究[6, 7]相比,我们的研究发现,在这种情况下,无论是PD-L1阳性人群还是PD-L1阴性人群,PD-1抑制剂单药治疗≥二线治疗的ORR都相对较高。从 55 例患者中获得了新一代测序(NGS)检测数据。肿瘤突变负荷高的患者(TMB ≥ 4.92突变/Mb,n = 45)比TMB低的患者(n = 10)显示出更高的ORR和更长的中位PFS(IRC评估的ORR:33.3%对20.0%,P = 0.416;中位PFS:6.8个月对4.1个月,P = 0.022)(补充图S3C-D)。对于TMB-high的定义,KEYNOTE 158研究中预先指定的阈值为10个突变/Mb;因此,CC队列中只有16%的患者被视为TMB-high[8]。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
期刊最新文献
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