A phase III placebo-controlled study of eftilagimod alfa plus pembrolizumab and chemotherapy in metastatic non-small cell lung cancer.

1.
Introduction
1.1.
Background and rationale
Immune checkpoint inhibitors (ICIs) have become the backbone of the first-line treatment landscape for advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations, both as monotherapy (in patients with tumor proportion score [TPS] ≥ 50%) and in combination with chemotherapy (TPS 0–100%) [1]. The likelihood of experiencing an anti-ICI-induced response that is durable and translates into longer survival is often correlated with higher tumor programmed cell death protein (PD-L1) expression [2,3]. When this response is absent, these patients are considered primary resistant to anti-programmed cell death protein 1 (PD-1) therapy [4,5]. Therefore, there remains persistent unmet needs among those with low or negative PD-L1 expression (TPS < 50%) who are less likely to benefit from current ICI-based approaches [2,6].
An antigen-presenting cell (APC) activator such as eftilagimod alfa (efti) represents a distinct class of immuno-oncology agent that stimulates dendritic cells and monocytes, thereby independently initiating and sustaining a broad immune response without acting directly on the T cell. Preclinical and clinical data have demonstrated that efti promotes targeted, mild, and sustained activation of dendritic cells, monocytes, and T cells, suggesting its potential to complement the existing immune checkpoint blockade [7–9]. Distinct from traditional ICIs, efti functions upstream in the immune cascade, reengaging the innate immune system to support robust T cell-mediated anti-tumor activity [10–12]. Stimulating APCs with efti, and subsequent T cell priming and recruitment, may overcome primary resistance to anti-PD-1 therapies, thereby optimizing treatment outcomes (Figure 1).

Combining an APC activator such as efti with chemotherapy and pembrolizumab aims to synergistically target complementary steps of the cancer immunity cycle [13]. Cytotoxic chemotherapy firstly increases tumor antigen release and immunogenic cell death, thereby increasing the pool of antigens available for presentation [14,15]. Efti then improves priming and expansion of tumor-specific T cells. Pembrolizumab (anti-PD-1) finally reinvigorates exhausted peripheral T-cells and restores effector function, allowing newly primed T cells to mediate killing of cancer cells. Phase II clinical studies showing encouraging response rates and tolerability further supports similar approaches [10,16,17].
In one previous phase II study (NCT03625323), efti plus pembrolizumab as a first-line therapy for NSCLC subjects (squamous and non-squamous tumor histology) demonstrated an excellent safety profile and encouraging antitumor activity [10]. The subject population was not enriched for PD-L1 expression, with just over 20% of the subjects presenting with TPS ≥ 50%, reflecting real-world prevalence [10,18]. Subjects with TPS ≥ 1% had an objective response rate (ORR) of 48.3%, median progression-free survival (PFS) of 11.2 months, and median overall survival (OS) of 35.4 months. Antitumor effects were seen across all PD-L1 strata, including no PD-L1 expression (TPS < 1%) [10]. Translational results confirmed efti’s mechanism of action, demonstrating that early and sustained increases of IFN-γ and CXCL10/IP10 (markers for Th1 response) were significantly elevated at 3 and 6 months compared to baseline [19].
In a second independent study, efti plus chemotherapy and pembrolizumab (NCT03252938) was safely administered in non-squamous NSCLC subjects without any new clinically relevant safety finding. Early efficacy results were promising, particularly in subjects with TPS < 50% (ORR of 68.0%) [17].
These findings taken together provide the rationale for further investigation of efti plus SoC in a larger, randomized setting without restrictions on PD-L1 status.

2.
Methods
2.1.
Trial design
TACTI-004, Two ACTive Immunotherapies-004, is a global double-blinded, randomized, placebo-controlled phase III study designed to assess a novel first-line therapy strategy in advanced/metastatic NSCLC.
The study will enroll approximately 756 participants across over 25 countries in Asia, Australia, Europe, Latin America, and North America. Participants will be enrolled irrespective of PD-L1 status and randomized 1:1 to receive either efti plus SoC or placebo plus SoC (Figure 2). Participants will be stratified by PD-L1 expression level, tumor type, Eastern Cooperative Oncology Group performance status (ECOG PS), and geographical region.

Imaging will be performed q6w until week 18, q9w until week 54, and q12w thereafter.
An Independent Data Monitoring Committee (IDMC) will monitor ongoing unblinded safety data at regular intervals and review the unblinded data at planned interim analyses. The IDMC may recommend stopping or changing the trial if at any time during the trial there are unacceptable adverse events or safety concerns.

2.2.
Eligibility criteria
Prior to randomization, during the screening phase, participants’ tumor tissue will be centrally assessed for PD-L1 (using PD-L1 IHC 22C3 pharmDx assay) and actionable mutations (as needed). Key eligibility criteria are described in Table 1.

2.3.
Treatment
Participants will receive 30 mg efti subcutaneously every 2 weeks (q2w) for 24 weeks, then q3w and pembrolizumab intravenously at 200 mg q3w both for up to 2 years. Chemotherapy choice will be histology-dependent: participants with non-squamous NSCLC will intravenously receive cisplatin (75 mg/m2) or carboplatin (AUC 5 or 6) + pemetrexed (500 mg/m2) q3w for 3 months, then maintenance pemetrexed q3w. Participants with squamous NSCLC will intravenously receive carboplatin (AUC 5 or 6) + paclitaxel (175 or 200 mg/m2) q3w for 3 months. Treatment will be administered for a maximum of 2 years or until disease progression or intolerable toxicity.

2.4.
Study endpoints
The primary objective is to compare the efficacy of efti plus SoC versus placebo plus SOC, using dual primary endpoints of PFS by RECIST 1.1 (defined as the time from randomization to documented disease progression or death from any cause) and OS. All key study endpoints are summarized in Table 2.

2.5.
Statistical considerations
The overall type I error rate of the primary endpoints will be strongly controlled at a 2-sided alpha level of 0.05. This alpha will be split between the endpoints. The trial is mainly powered to show superiority in terms of OS at the final analysis and will be considered a success if one of the dual primary endpoints is positive.
Prior to the final analysis, there will be three interim analyses (one futility, one efficacy analysis for PFS, and one for OS). The timing of these analyses is predefined, driven by a prespecified number of events. Details of the timing of these analyses are described in the Statistical Analysis Plan (SAP).

3.
Discussion
The TACTI-004 study is recruiting participants who have all levels of PD-L1 expression (negative, low and high) and both major histological subtypes (squamous and non-squamous). Patients with tumors that are low or negative in PD-L1 expression or have squamous cell histology are often excluded or underrepresented in clinical trials due to historically poorer outcomes [2,20,21]. Our study seeks to enhance the clinical relevance of our findings by reflecting the real-world full spectrum of NSCLC.
However, potential limitations exist with this approach. We acknowledge that associated heterogeneity from introducing all PD-L1 levels and different chemotherapy backbones (selected on the basis of tumor histology) may obscure the true magnitude of benefit from the experimental treatment in any of these subgroups.
The TACTI-004 study explores an innovative first-line treatment strategy for treating NSCLC patients through the enhancement of existing SoCs with the addition of the first-in-class APC activator, efti. The anticipated results may expand the benefits of chemoimmunotherapy beyond the current PD-L1-driven treatment paradigm.
Study enrollment began in March 2025 with recruitment ongoing.

4.
Conclusion
The TACTI-004 trial has the potential to significantly impact clinical practice by providing an effective treatment option for patients, irrespective of their tumor PD-L1 status.