Phase 2 Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1 Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma

IF 10 1区 医学 Q1 ONCOLOGY
Sylvia Lee, Omid Hamid, Robert Jotte, Yousef Zakharia, Theresa Medina, Amanda Gillespie-Twardy, Inderjit Mehmi, Sunandana Chandra, Graham Watson, Patrick Ward, Marya Chaney, Hailing Lu, Jason Berndt, Brian P. O'Connor, Kapil Rathi, Eeman Shaikh, C. Lance. Cowey
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引用次数: 0

Abstract

Purpose: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells (Tregs) that express CD30 and re-sensitize tumors to anti-(PD-1) therapy. This study evaluated responses to BV+pembrolizumab post PD-1 and explored corresponding biomarkers. Methods: 55 patients with metastatic non-small cell lung cancer (NSCLC) and 58 with metastatic cutaneous melanoma received ≥1 dose of BV+pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor. Results: For the secondary refractory metastatic NSCLC cohort (RECIST v1.1), ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (iRECIST), ORR was 24%, median iPFS was 4.44 months, and median OS was 21.9 months. Overall, median duration of OS follow-up was 17.2 months (95% CI 14.62, 22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in Tregs. Paired tumor biopsies from baseline and Cycle 3 Day 1 showed a trend of increased CD8 T cell infiltration, especially in responding patients. Conclusions: BV+pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.
Brentuximab Vedotin联合Pembrolizumab治疗PD-1预处理的转移性非小细胞肺癌和转移性皮肤黑色素瘤的2期开放标签试验
目的:Brentuximab vedotin (BV)被假设选择性地消耗表达CD30的T调节细胞(Tregs),并使肿瘤对抗PD-1治疗重新敏感。本研究评估了PD-1后BV+pembrolizumab的应答,并探索了相应的生物标志物。方法:55例转移性非小细胞肺癌(NSCLC)患者和58例转移性皮肤黑色素瘤患者接受≥1剂量的BV+派姆单抗治疗。患者先前接受的系统治疗中位数为2.0(范围1-7)。主要终点为客观有效率(ORR)。探索性终点包括血液和肿瘤的总生存期(OS)和生物标志物分析。结果:对于继发性难治性转移性NSCLC队列(RECIST v1.1), ORR为14%,中位无进展生存期(PFS)为5.85个月,中位OS为14.4个月。对于继发性难治性转移性皮肤黑色素瘤队列(iRECIST), ORR为24%,中位iPFS为4.44个月,中位OS为21.9个月。总体而言,OS随访的中位持续时间为17.2个月(95% CI 14.62, 22.87)。没有发现新的安全信号。未见治疗相关的5级毒性。外周血纵向免疫表型显示Tregs的短暂下降。基线和周期3第1天的配对肿瘤活检显示CD8 T细胞浸润增加的趋势,特别是在有反应的患者中。结论:BV+派姆单抗治疗实体瘤恶性肿瘤具有临床意义,持久的应答,令人鼓舞的OS和PFS率支持该组合的免疫调节活性。在继发性难治性队列中观察到更强的抗肿瘤活性。该组合的安全性与单个药物的风险特征一致。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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