Abstract

Background

An ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study.

Methods

In the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019.

Results

Forty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs.

Conclusion

In heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity.

Clinical trial identification

NCT03179436.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.

中文翻译：

---

98P来自MK-1308（抗CTLA-4）加pembrolizumab在先前治疗的晚期小细胞肺癌中进行的I期研究的结果

抽象的

背景

一项正在进行的，开放标签，多臂，多中心，I期研究的抗CTLA-4抗体MK-1308结合派姆单抗治疗晚期实体瘤（NCT03179436），显示出可控的安全性和对晚期非肿瘤患者（pts）的有希望的疗效小细胞肺癌接受一线治疗[Perets等。J临床Oncol。2019; 37（suppl）：2558]。在这里，我们报告了来自这项研究的小细胞肺癌（SCLC）队列的数据。

方法

在剂量确认阶段，患有晚期SCLC的患者接受75 mg Q6W +派姆单抗200 mg Q3W的MK-1308（最多35个周期）。主要终点是安全性，次要终点是基于RECIST v1.1的基于盲目的独立中央评价（BICR）的ORR。基于RECIST v1.1和OS的BICR的PFS是探索性的终点。该分析的数据库截止日期为2019年6月3日。

结果

入组并给药40例先前治疗过的晚期SCLC（二线或更高剂量）的患者；中位随访时间为11个月。数据截断时，有32分（80％）的患者中止研究治疗-23％（58％）由于进展性疾病，4（10％）因AE而引起，2（5.0％）因临床进展而停止，3例（7.5％）退出同意。中位年龄为66岁。基线时60％的男性为男性，而ECOG PS 1为65％。根据BICR评估，有7分患者获得了部分缓解，ORR为18％（95％CI，7.3-33）。8例（20％）的患者对稳定疾病的总体反应最佳，21例（53％）的患者为进行性疾病。响应持续时间从2.9到8.4+ mo。截至数据截稿时，正在进行7项响应中的5项（71％）。中位反应时间为2.1 mo（范围1.1-12）。PFS中位数为2.0 mo（95％CI，1.9-3.9），6 mo PFS率为26％。OS的中位数为11个月（95％CI，未达到5.9），而6个月的OS率为66％。研究者确定的与治疗相关的不良事件（TRAE）发生在32分（80％）。3级TRAE报告为11分（28％）；没有报道4-5年级的事件。由于TRAE，三分（7.5％）的患者中止了治疗。

结论

在经过SCLC大量预处理的患者中，MK-1308 + pembrolizumab通常具有良好的耐受性，并具有令人鼓舞的抗肿瘤活性。

临床试验鉴定

NCT03179436。

编辑致谢

由ApotheCom pembrolizumab团队（美国宾夕法尼亚州亚德利）的Holly C. Cappelli博士，CMPP和Dana Francis博士提供医学写作和/或编辑帮助，并由默克子公司Merck Sharp＆Dohme Corp资助＆Co.，Inc.，美国新泽西州凯尼尔沃思。

负责研究的法人实体

默沙东和Dohme Corp.是位于美国新泽西州Kenilworth的默沙东公司的子公司。

资金

默沙东和Dohme Corp.是位于美国新泽西州Kenilworth的默沙东公司的子公司。

揭露

BC BC：Honoraria（个体经营），咨询/顾问，发言人局/专家证词，研究补助金/资金（个体经营）：诺华；酬金（个体经营），研究资助/资助（个体经营）：拜耳；酬金（个体经营），咨询/顾问，研究经费/资助（个体经营）：阿斯利康；酬金（自己），研究资助/资助（自己）：MOGAM研究所；酬金（个体经营），研究资助/资助（个体经营）：Dong-A ST; 酬金（个体经营），研究资助/资金（个体经营），许可/特许权使用费：冠军肿瘤学；酬金（个体经营），咨询/顾问，研究经费/资助（个体经营）：詹森；酬金（个体经营），咨询/顾问，研究经费/资助（个体经营）：Yuhan；酬金（个体经营），咨询/顾问，研究补助金/资金（个体经营）：小野；酬金（个体经营），研究资助/资助（个体经营）：Dizal Pharma；酬金（个体经营），咨询/顾问，研究资助/资助（个体）：MSD；咨询/顾问：勃林格殷格翰公司；咨询/顾问：罗氏；咨询/顾问：百时美施贵宝；咨询/顾问：辉瑞；咨询/顾问：礼来公司；咨询/顾问：武田；股东/股东/股票期权：TheraCanVac Inc; 股东/股东/股票期权：Bridgebio Therapeutics; 股东/股东/股票期权：Gencurix Inc. K. Yoh：研究资助/资金（机构）：MSD。J. Bar：咨询/顾问，研究补助金/资金（自己），研究补助金/资金（机构）：阿斯利康；咨询/顾问：MSD；咨询/顾问，研究资助/资助（机构）：勃林格殷格翰；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问，研究资助/资助（机构）：Bristol-Myers Squibb；咨询/顾问：武田；咨询/顾问，研究资助/资助（机构）：Abbvie；咨询/顾问：OncoHost；咨询/顾问：VBL；研究补助金/经费（机构）：辉瑞公司。A. Nagrial：酬金（自己），咨询/顾问，研究补助金/资金（机构）：Bristol-Myers Squibb；酬金（个体经营），咨询/顾问，研究资助/资助（机构）：MSD；酬金（个体经营），咨询/顾问，研究资助/资助（机构）：AZ；酬金（个体经营），咨询/顾问，研究经费/资助（机构）：Roche；研究经费/资助（机构）：Beigene；研究资助/资助（机构）：Incyte。Spigel博士：领导角色：百年医疗中心；旅行/住宿/费用：阿斯利康；旅行/住宿/费用：勃林格殷格翰；旅行/住宿/费用：Celgene; 旅行/住宿/费用：礼来；旅行/住宿/费用：EMD Serono；旅行/住宿/费用：百时美施贵宝；旅行/住宿/费用：Genentech；旅行/住宿/费用：Genzyme；旅行/住宿/费用：直观的手术；旅行/住宿/费用：默克；旅行/住宿/费用：辉瑞；旅行/住宿/费用：Purdue Pharma；旅行/住宿/费用：Spectrum Pharmaceuticals；差旅/住宿/费用：Sysmex。古铁雷斯（M. Gutierrez）：股东/股东/股票期权：COTA；咨询/顾问，发言人局/专家证词：礼来公司；咨询/顾问：Esanex；咨询/顾问：Guardant 360；发言人局/专家证词：默克；发言人办公室/专家证词：百时美施贵宝（Bristol-Myers Squibb）；发言人局/专家证词：基础医学。DW。Kim：研究资助/资助（机构）：Alpha Biopharma；研究资助/资助（机构）：阿斯利康/ Medimmune；研究补助金/经费（机构）：Hanmi；研究补助金/资金（机构）：Janssen；研究经费/资助（机构）：Merus；研究经费/资助（机构）：Mirati Therapeutics；研究经费/资助（机构）：MSD；研究经费/资助（机构）：诺华；研究经费/资助（机构）：ONO Pharmaceutical；研究补助金/资金（机构）：辉瑞公司；研究补助金/资金（机构）：Roche / Genentech；研究补助金/经费（机构）：武田；研究资助/资助（机构）：TP治疗学；研究补助金/资金（机构）：Xcovery；研究资助/资助（机构）：Yuhan。D. Rasco：研究资助/资助（机构）：Merck；研究经费/资助（机构）：Regeneron。M. Satouchi：Honoraria（自己），研究资助/资助（机构）：MSD。MJ。安（Ahn）：Honoraria（个体），咨询/顾问：百时美施贵宝（Bristol-Myers Squibb）；酬金（个体经营），咨询/顾问：ONO；酬金（个体经营），咨询/顾问：MSD；Honoraria（个体经营），咨询/顾问：AstraZeneca；酬金（个体经营），咨询/顾问：武田；咨询/顾问：礼来公司；咨询/顾问：Alpha Pharm。DH Lee：Honoraria（个体经营）：AbbVie；Honoraria（个体）：阿斯利康; Honoraria（个体经营）：Boehringer-Ingelheim；Honoraria（个体）：百时美施贵宝（Bristol-Myers Squibb）; Honoraria（个体经营）：ChongKunDang；Honoraria（个体经营）：CJ Healthcare；Honoraria（个体经营）：礼来公司；Honoraria（个体）：Janssen; Honoraria（个体）：Menarini; Honoraria（个体）：默克; Honoraria（个体）：MSD; Honoraria（个体）：Mundipharma; Honoraria（个体）：诺华; Honoraria（个体）：小野; Honoraria（个体）：辉瑞; Honoraria（个体）：罗氏; Honoraria（个体）：Samyang Biopharm; 酬金（个体经营），咨询/顾问：ST Cube；Honoraria（个体经营）：武田。C.莫里斯·德罗（Maurice-Dror）：旅行/住宿/费用：詹森；旅行/住宿/费用：辉瑞；旅行/住宿/费用：罗氏。S. Siddiqi：全职/兼职：Merck＆Co.，Inc. X. Li：全职/兼职：Merck＆Co.，Inc. J. Cyrus：领导作用，差旅/住宿/费用，股东/股东/股票期权，全职/兼职：Merck＆Co.，Inc.。RA Altura：差旅/住宿/费用，股东/股东/股票期权，全职/兼职：Merck＆Co.，Inc.。R. Perets：咨询/顾问：Karyopharm；咨询/顾问：BiolineRx。所有其他作者都声明没有利益冲突。