Data Sheet 1_A phase Ib/II study of modakafusp alfa alone and in combination with pembrolizumab in patients with advanced or metastatic solid tumors.docx

BackgroundModakafusp alfa is a novel immunocytokine comprising two attenuated interferon-α2b molecules fused to an anti-CD38 IgG4 monoclonal antibody. Modakafusp alfa has shown immune cell activation and antitumor activity in preclinical mouse models, including in combination with an anti-programmed cell death (PD-1) receptor in tumors that do not express CD38, and demonstrated clinical responses and immune activation in patients with relapsed/refractory multiple myeloma.
MethodsIn phase Ib, adult patients with advanced/metastatic solid tumors received escalating doses of modakafusp alfa 0.1–1.5 mg/kg intravenously every 3 weeks (Q3W) across six dosing cohorts. In phase II, patients with unresectable/metastatic cutaneous melanoma and resistance to ≤2 anti-PD-1 therapies in the metastatic setting received modakafusp alfa 1 mg/kg Q3W in combination with pembrolizumab Q6W. Primary objectives were to determine the safety/tolerability as a single agent in phase I, and efficacy in combination with pembrolizumab in phase II.
ResultsA total of 21 and 24 patients were enrolled across phases Ib and II, respectively. The recommended phase II dose of modakafusp alfa was 1 mg/kg. The most common drug-related adverse events were infusion-related reactions (IRRs; 52.4%) and thrombocytopenia (28.6%) in phase Ib; and headache (58.3%), fatigue (54.2%), IRRs (41.7%), neutropenia (37.5%), and nausea (33.3%) in phase II. In phase Ib, seven patients had a best response of stable disease (SD); in phase II, one patient had a confirmed complete response, one had a confirmed partial response, and seven had SD. All immunogenicity-evaluable patients were anti-drug antibodies (ADAs) positive following treatment with modakafusp alfa; neutralizing ADAs were reported in 82.4% and 90.9% of patients in phases Ib and II, respectively, which was associated with drug exposure reduction. Pharmacodynamic analyses demonstrated innate and adaptive immune activation in peripheral blood and within tumors. Paired biopsy analysis revealed two subgroups of patients defined by differences in CD38 upregulation, accompanied by differential intratumoral pharmacodynamic changes. Correlative analysis was inconclusive.
ConclusionsModakafusp alfa induces innate and adaptive immune responses, supporting its hypothesized mechanism of action (MoA) in patients with advanced solid tumors. High immunogenicity and the potentially limited treatment effect of the interferon MoA may have contributed to limited efficacy in these patients.
Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04157517, identifier NCT04157517.

背景
莫达卡司普α（Modakafusp alfa）是一种新型免疫细胞因子（immunocytokine），由两个减毒的干扰素-α2b（interferon-α2b）分子融合至抗CD38 IgG4单克隆抗体构成。该药物已在临床前小鼠模型中展现出免疫细胞激活与抗肿瘤活性，包括在不表达CD38的肿瘤中与抗程序性细胞死亡（PD-1）受体联合使用的场景，并在复发/难治性多发性骨髓瘤患者中展现出临床应答与免疫激活效应。
方法
在Ib期临床试验中，晚期/转移性实体瘤成年患者接受递增剂量的莫达卡司普α静脉输注，剂量范围为0.1~1.5 mg/kg，每3周一次（Q3W），共设置6个剂量队列。在II期临床试验中，不可切除/转移性皮肤黑色素瘤且在转移性治疗阶段中对≤2种抗PD-1疗法产生耐药的患者，接受莫达卡司普α 1 mg/kg Q3W联合帕博利珠单抗（pembrolizumab）每6周一次（Q6W）的治疗方案。本研究的主要终点为：I期单药治疗的安全性与耐受性，以及II期联合帕博利珠单抗治疗的有效性。
结果
Ib期与II期临床试验分别入组21例与24例患者。莫达卡司普α的II期推荐剂量为1 mg/kg。Ib期最常见的药物相关不良事件为输液相关反应（IRRs，52.4%）与血小板减少症（28.6%）；II期最常见的药物相关不良事件则为头痛（58.3%）、疲劳（54.2%）、输液相关反应（41.7%）、中性粒细胞减少症（37.5%）与恶心（33.3%）。Ib期有7例患者的最佳疗效为疾病稳定（SD）；II期有1例患者获得确认的完全缓解，1例获得确认的部分缓解，7例达到疾病稳定。所有可评估免疫原性的患者在接受莫达卡司普α治疗后均呈抗药物抗体（ADAs）阳性；Ib期与II期患者中分别有82.4%与90.9%检出中和性抗药物抗体，该情况与药物暴露量降低相关。药效学分析显示，外周血与肿瘤组织内均存在固有免疫与适应性免疫激活。配对活检分析发现两类患者亚群，其CD38上调水平存在差异，并伴随不同的瘤内药效学变化。相关性分析结果未明确。
结论
莫达卡司普α可诱导固有免疫与适应性免疫应答，支持其在晚期实体瘤患者中的作用机制（MoA）假说。高免疫原性与干扰素作用机制潜在的有限治疗效应，可能是导致该类患者疗效受限的原因。
临床试验注册信息
https://clinicaltrials.gov/study/NCT04157517，注册号为NCT04157517。