Furqan Muhammad, Malhotra Jyoti, Shergill Ardaman, Liu Li, Mott Sarah L, Pasquinelli Mary M, Hulbert Alicia, Kennedy Kathleen, Feldman Lawrence
Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
Transl Lung Cancer Res. 2024 Nov 30;13(11):2998-3009. doi: 10.21037/tlcr-24-346. Epub 2024 Nov 19.
Therapeutic strategies to engage anti-tumor innate immunity are still underdeveloped. Imprime PGG (imprime), a pathogen-associated molecular pattern (PAMP), through pattern recognition receptors, successfully illicit a broad-based innate immune response in preclinical models against various cancers. We aimed to study safety and efficacy of imprime in combination with pembrolizumab in advanced stage non-small cell lung cancer (NSCLC).
We conducted an investigator-initiated, multi-institutional, single-arm, phase Ib/II trial in previously treated, advanced stage NSCLC patients. Primary endpoints were maximum-tolerated dose (MTD) of imprime for the phase Ib, and progression-free survival (PFS) for the phase II study (NCT03003468).
All 33 eligible patients were included in the safety analysis. No dose-limiting toxicity was observed and the imprime dose of 4 mg/kg was determined as the MTD. Thirty patients treated at the MTD (phase Ib, 6; phase II, 24) were included in the efficacy analysis. Median length of follow-up was 10.8 months. Confirmed objective response rate was 10% [95% confidence interval (CI): 2-27%], with one complete and two partial responses. Median PFS was 2.6 months (95% CI: 1.4-7.0), and 6- and 12-month PFS rates were 37% and 17%, respectively. Median overall survival (OS) was 11.1 months, and 6- and 12-month OS rates were 75% and 46%. Univariate analysis was performed to assess the impact of age, sex, race, disease-stage, programmed death-ligand 1 (PD-L1) expression levels, and prior immunotherapy on PFS and OS. Of these, prior immunotherapy negatively influenced OS [hazard ratio (HR): 2.95, 95% CI: 1.21-7.24]. Overall, the combination was safe and tolerable.
The combination of imprime and pembrolizumab is tolerable but did not improve the outcome of advanced stage NSCLC patients who previously progressed on anti-programmed death 1 (PD-1)/PD-L1 immunotherapies. Further investigation is needed to understand the effects of therapeutic PAMPs to mount a strong innate immune response against cancer.
激活抗肿瘤固有免疫的治疗策略仍未充分发展。Imprime PGG（imprime）是一种病原体相关分子模式（PAMP），通过模式识别受体，在临床前模型中成功引发了针对各种癌症的广泛固有免疫反应。我们旨在研究imprime联合帕博利珠单抗治疗晚期非小细胞肺癌（NSCLC）的安全性和疗效。
我们在先前接受过治疗的晚期NSCLC患者中开展了一项由研究者发起的、多机构、单臂、Ib/II期试验。主要终点为Ib期的imprime最大耐受剂量（MTD）以及II期研究的无进展生存期（PFS）（NCT03003468）。
所有33例符合条件的患者均纳入安全性分析。未观察到剂量限制性毒性，4 mg/kg的imprime剂量被确定为MTD。30例接受MTD治疗的患者（Ib期6例；II期24例）纳入疗效分析。中位随访时间为10.8个月。确认的客观缓解率为10%[95%置信区间（CI）：2-27%]，包括1例完全缓解和2例部分缓解。中位PFS为2.6个月（95%CI：1.4-7.0），6个月和12个月的PFS率分别为37%和17%。中位总生存期（OS）为11.1个月，6个月和12个月的OS率分别为75%和46%。进行单因素分析以评估年龄、性别、种族、疾病分期、程序性死亡配体1（PD-L1）表达水平和既往免疫治疗对PFS和OS的影响。其中，既往免疫治疗对OS有负面影响[风险比（HR）：2.95，95%CI：1.21-7.24]。总体而言，该联合治疗安全且耐受性良好。
imprime与帕博利珠单抗联合治疗耐受性良好，但并未改善先前接受抗程序性死亡1（PD-1）/PD-L1免疫治疗后病情进展的晚期NSCLC患者的预后。需要进一步研究以了解治疗性PAMP对引发强大的抗癌固有免疫反应的作用。
