Anti-PD1 Monotherapy in 1L Advanced NSCLC Patients With PD-L1 TPS > 50% and PTI=0
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- UNICANCER
- 入组人数
- 275
- 试验地点
- 4
- 主要终点
- The primary objective is to evaluate the rate of patients without early progression upon anti-PD1 monotherapy by selecting patients with a baseline plasma PTI score of 0 in patients with advanced/metastatic NSCLC with PD-L1 TPS >50%.
研究概览
简要总结
Anti-PD-1 monotherapy has demonstrated significant clinical efficacy in advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score [TPS] >50%), outperforming platinum-based chemotherapy in terms of objective response rate (ORR) and overall survival (OS). Pivotal randomized trials such as KEYNOTE-024 and EMPOWER-Lung 1 established the superiority of PD-1 blockade in this patient population, leading to regulatory approvals by both the FDA and EMA for first-line treatment. These studies confirmed that a subset of patients can achieve deep and durable responses with immunotherapy alone, highlighting the potential of immune checkpoint inhibition to provide long-term clinical benefit without the toxicities associated with cytotoxic chemotherapy.
Despite these successes, accumulating clinical evidence has revealed a clinically significant risk of hyperprogressive disease (HPD) in a subset of patients treated with anti-PD-1 monotherapy. HPD is characterized by an unexpected and rapid acceleration of tumor growth following treatment initiation and is associated with early clinical deterioration and increased mortality. This phenomenon likely contributes to the early crossover of survival curves frequently observed when comparing immunotherapy alone with chemotherapy in first-line NSCLC trials. In contrast, such early survival crossover is not observed in trials comparing chemotherapy-immunotherapy combinations with chemotherapy alone, including CheckMate-227, CheckMate-9LA, KEYNOTE-189, and KEYNOTE-407. These results have led many thoracic oncologists to favor combined chemo-immunotherapy regimens as first-line treatment, as they reduce the risk of HPD and increase initial ORR.
However, while chemotherapy combined with immunotherapy effectively mitigates the risk of hyperprogression and improves early response rates, it also appears to compromise the durability of antitumor immune responses. Clinical data indicate that the median duration of response with chemo-immunotherapy combinations is approximately 10-11 months, compared with more than 22 months for anti-PD-1 monotherapy alone. This difference is likely attributable to the cytotoxic effects of chemotherapy on immune effector cells, which may limit the persistence and depth of immune-mediated tumor control. Consequently, there remains a strong clinical need to identify patients who could safely and effectively benefit from anti-PD-1 monotherapy while avoiding unnecessary exposure to chemotherapy.
Multiple early-phase translational studies have independently identified soluble plasma biomarkers associated with response or resistance to PD-1 blockade in advanced NSCLC. Building on this body of evidence, translational analyses conducted at Gustave Roussy Cancer Center have identified a composite signature of circulating soluble factors, including interleukin-6 (IL-6), interleukin-8 (IL-8), soluble CD14 (sCD14), soluble CD25 (sCD25), and growth differentiation factor-15 (GDF-15). Together, these biomarkers define a Pro-Tumoral Inflammation (PTI) signature that is strongly associated with primary resistance to anti-PD-1 monotherapy. Elevated PTI scores reflect a systemic inflammatory state that promotes tumor progression and immune dysfunction, and have been linked to poor clinical outcomes, including non-response and hyperprogressive disease.
Within the META-1 sub-protocol of the METAREM master protocol, the investigators propose to integrate these soluble biomarkers into a single PTI score generated through baseline PORTRAIT immunoprofiling. The primary objective of this approach is to prospectively validate the predictive value of the PTI score for anti-PD-1 monotherapy efficacy in advanced NSCLC. By enabling early identification of patients at high risk of resistance or hyperprogression, this strategy aims to refine patient stratification and guide first-line treatment selection. Ultimately, the use of the PTI score could allow clinicians to identify patients most likely to benefit from anti-PD-1 monotherapy, preserving the potential for durable responses while sparing others from ineffective treatment and optimizing the overall therapeutic strategy in advanced NSCLC.
详细描述
Traditionally, anticancer drug development has been guided by tumor histology and largely focused on tissue-specific characteristics rather than the underlying biological mechanisms driving disease progression. Conventional anticancer therapies, which are often nonspecific, are associated with substantial toxicity and adverse events, and their efficacy frequently diminishes over time due to the emergence of drug resistance. These limitations have driven a paradigm shift toward the development of therapies that target the molecular and biological features of cancer rather than its anatomical origin.
Advances in tumor biology and immunology have profoundly transformed the oncology treatment landscape. Once considered speculative, biomarker-driven and tissue-agnostic therapeutic approaches are now supported by robust clinical evidence. Since 2017, regulatory approvals have validated this shift, beginning with the FDA approval of pembrolizumab for tumors characterized by high microsatellite instability (MSI-H), followed by additional tumor-agnostic agents. To date, seven therapies have received FDA approval for tissue-agnostic indications, underscoring the clinical relevance of shared biological features across cancer types.
A comprehensive understanding of drug mechanisms of action, together with an in-depth assessment of the tumor microenvironment and its inflammatory status, has emerged as a critical determinant of treatment efficacy, particularly in patients who fail to respond to conventional therapies. The increasing focus on immune-tumor interactions has led to the identification of key immune regulatory pathways that represent attractive targets for tumor-agnostic drug development. Among these, CD8⁺ T-cell immunophenotypes play a central role in mediating responses to immunotherapy. Unlike classical oncogenic driver alterations, immune checkpoint molecules such as PD-1 and PD-L1 are not mutated in PD-L1-positive tumors. Nevertheless, PD-L1 expression has been observed across multiple cancer types with otherwise unrelated genomic alterations, making the PD-1/PD-L1 axis a prototypical tumor-agnostic therapeutic target. Pharmacological blockade of this pathway using monoclonal antibodies can restore antitumor T-cell activity and induce meaningful clinical responses.
Anti-PD-1 monotherapy has demonstrated substantial clinical benefit in advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score [TPS] >50%) across multiple randomized clinical trials. In the KEYNOTE-024 study, pembrolizumab significantly improved objective response rate (ORR) and overall survival (OS) compared with platinum-based chemotherapy. At a median follow-up of 24 months, median OS was 26.3 months for pembrolizumab versus 13.4 months for chemotherapy, with a hazard ratio of 0.62. Notably, the estimated 5-year OS rate was 31.9% in the pembrolizumab arm compared with 16.3% in the chemotherapy arm, highlighting the potential for long-term disease control with immunotherapy.
Similarly, the EMPOWER-Lung 1 trial demonstrated the superiority of cemiplimab over chemotherapy in patients with PD-L1 TPS ≥50%. Median OS was not reached in the cemiplimab arm versus 14.2 months with chemotherapy, and progression-free survival (PFS) was significantly prolonged. Importantly, these benefits were observed despite a high crossover rate, reinforcing the robustness of the survival advantage conferred by PD-1 blockade.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In addition to the inclusion criteria of the METAREM master protocol, following additional criteria must be respected during patient inclusion in META-1 trial:
- •Patients with age ≥18 years
- •Patients in first-line therapy for advanced metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) >50%, without EGFR/ ALK/ ROS1 mutations and irrespective of their histological subtype (squamous or non-squamous).
- •Patients with a PTI score of zero in plasma on the baseline PORTRAIT report. Note: Patients with PTI score ≥ 1 who meet all other criteria will be followed up to 36 months or death according to standard of care.
排除标准
- •In addition to the Exclusion criteria of the METAREM master protocol, following additional criteria must be considered during patient exclusion from META-1 trial:
- •Patients who have previously received an anti-PD(L)1 or anti-CTLA4 or anti-LAG-3 or anti-TIM3 immunotherapy.
- •Patients with any Hypersensitivity to the active ingredient or to any of the excipients of Pembrolizumab or Cemiplimab.
研究组 & 干预措施
Single Arm Anti-PD1 monotherapy in 1L advanced NSCLC patients with PD-L1 TPS > 50% and PTI=0
Pembrolizumab or cemiplimab (anti-PD1) will be considered as investigational medical products (IMP) and will be used in accordance with their marketing authorization for the trial population.
干预措施: Pembrolizumab (Drug)
Single Arm Anti-PD1 monotherapy in 1L advanced NSCLC patients with PD-L1 TPS > 50% and PTI=0
Pembrolizumab or cemiplimab (anti-PD1) will be considered as investigational medical products (IMP) and will be used in accordance with their marketing authorization for the trial population.
干预措施: Cemiplimab (Drug)
结局指标
主要结局
The primary objective is to evaluate the rate of patients without early progression upon anti-PD1 monotherapy by selecting patients with a baseline plasma PTI score of 0 in patients with advanced/metastatic NSCLC with PD-L1 TPS >50%.
时间窗: 12 weeks
The primary endpoint is the rate of patients without disease progression at 12 weeks.
次要结局
未报告次要终点