双抗CTLA-4和抗PD-1阻断剂用于罕见肿瘤的II期试验：SWOG/NCI的经验：肺浸润性黏液性或非黏液性鳞屑样腺癌（原细支气管肺泡癌）

Phase II trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors SWOG/NCI experience: invasive mucinous or non-mucinous lepidic adenocarcinoma of the lung (formerly bronchioloalveolar carcinoma).

作者信息

Chae Young Kwang, Othus Megan, Patel Sandip Pravin, Gerber David E, Tanvetyanon Tawee, Kim Hye Sung, Chung Liam Il-Young, McLeod Christine M, Lopez Gabby, Chen Helen X, Sharon Elad, Streicher Howard, Ryan Cristopher W, Blanke Charles D, Kurzrock Razelle

机构信息

Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 645 N. Michigan Avenue, Ste. 1006, Chicago, IL 60611, USA.

SWOG Statistics and Data Management Center, Seattle, WA, USA.

出版信息

Ther Adv Med Oncol. 2024 Nov 22;16:17588359241293401. doi: 10.1177/17588359241293401. eCollection 2024.

DOI:10.1177/17588359241293401

PMID:39583952

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11583498/

Abstract

BACKGROUND

Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies.

OBJECTIVES

This study presents the first results of ipilimumab-nivolumab in invasive mucinous or non-mucinous lepidic adenocarcinoma (invasive mucinous adenocarcinoma (IMA) or invasive non-mucinous lepidic adenocarcinomas (INLA), respectively) of the lung.

DESIGN

Dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks).

METHODS

Participants histologically diagnosed with advanced IMA or INLA, who had not responded to at least one line of therapy, were included in the bronchioloalveolar carcinoma cohort. The primary endpoint was the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (confirmed complete and partial responses (CR and PR)). Secondary endpoints were progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) ⩾ 6 months plus ORR), and toxicity.

RESULTS

Eight evaluable patients (median age: 77 years; the number of prior therapies ranged from 0 to 4; one patient with prior exposure to a PD-1 inhibitor; comprising six IMA and two INLA) were treated. One IMA had a 40% regression (PFS 45.2+ months, PD-L1 0%, KRAS G12C mutated, tumor mutational burden [TMB] 13 mut/Mb). One INLA had 66% regression (PFS 23.8 months, PD-L1 unknown, no actionable mutations, TMB 3 mut/Mb). Overall ORR was 25.0% (2/8) and CBR, 62.5% (5/8); PFS for the patients with SD > 6 months was 43.4+, 11.7+, and 8.3 months. The median PFS was 16 months (5.3-not reached) and the median OS was 32.2 months (14.6-not reached). The toxicity profile was similar to previous reports.

CONCLUSION

Ipilimumab plus nivolumab in the bronchioloalveolar carcinoma cohort (IMA, INLA) resulted in a durable ORR of 25.0% and CBR of 62.5% (PFS, 8.3 11.7+. 23.8 (PR), 43.4+ and 45.2+ (PR) months). Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies are warranted.

TRIAL REGISTRATION

ClinicalTrials.gov registry: NCT02834013.

摘要

背景

抗程序性死亡蛋白1（PD-1）/细胞毒性T淋巴细胞相关抗原4抗体在多种恶性肿瘤中有效。

目的

本研究展示了伊匹木单抗联合纳武单抗治疗肺浸润性黏液性或非黏液性鳞屑样腺癌（分别为浸润性黏液腺癌（IMA）或浸润性非黏液性鳞屑样腺癌（INLA））的首批结果。

设计

罕见肿瘤双重抗CTLA-4和抗PD-1阻断（DART）是一项前瞻性、开放标签、多中心（美国1016个地点）、多队列的II期试验，使用伊匹木单抗（每6周静脉注射（IV）1mg/kg）加纳武单抗（每2周IV 240mg）。

方法

组织学诊断为晚期IMA或INLA且对至少一线治疗无反应的参与者被纳入细支气管肺泡癌队列。主要终点是根据实体瘤疗效评价标准得出的总缓解率（ORR；确认的完全缓解和部分缓解（CR和PR））。次要终点是无进展生存期（PFS）、总生存期（OS）、临床获益率（CBR；疾病稳定（SD）⩾6个月加ORR）和毒性。

结果

8例可评估患者（中位年龄：77岁；既往治疗次数为0至4次；1例患者曾接触过PD-1抑制剂；包括6例IMA和2例INLA）接受了治疗。1例IMA出现40%的肿瘤退缩（PFS 45.2 + 个月，PD-L1 0%，KRAS G12C突变，肿瘤突变负荷[TMB] 13 mut/Mb）。1例INLA出现66%的肿瘤退缩（PFS 23.8个月，PD-L1未知，无可操作突变，TMB 3 mut/Mb）。总体ORR为25.0%（2/8），CBR为62.5%（5/8）；SD > 6个月的患者PFS分别为4,3.4 +、11.7 + 和8.3个月。中位PFS为16个月（5.3 - 未达到），中位OS为32.2个月（14.6 - 未达到）。毒性特征与既往报告相似。