Sacituzumab Govitecan , a Trop-2–directed antibody–drug conjugate, is being explored as part of chemotherapy-free strategies to improve first-line outcomes in metastatic non–small cell lung cancer (mNSCLC). The phase II EVOKE-02 study evaluated sacituzumab govitecan in combination with pembrolizumab in previously untreated patients with mNSCLC lacking actionable genomic alterations, stratified by PD-L1 tumor proportion score. The study assessed antitumor activity, progression-free survival, safety, and the role of Trop-2 expression, providing insight into the potential of ADC–immunotherapy combinations as an alternative to standard chemo-immunotherapy regimens.
Background
Metastatic non–small cell lung cancer (mNSCLC) remains a leading cause of cancer-related mortality worldwide, despite major advances in immunotherapy. For patients without actionable genomic alterations, immune checkpoint inhibitors targeting the programmed death-ligand 1 (PD-L1) pathway, either alone or combined with chemotherapy, are the current standard of care in the first-line setting. Pembrolizumab monotherapy is widely used in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥50%), while chemo-immunotherapy combinations are favored for lower PD-L1 expression.
However, a substantial proportion of patients experience primary resistance or early progression, and median overall survival with existing regimens remains under two years in real-world settings. This unmet need has driven interest in novel combination strategies that could improve efficacy while potentially reducing reliance on chemotherapy.
Sacituzumab govitecan (SG) is a first-in-class antibody–drug conjugate (ADC) targeting trophoblast cell surface antigen 2 (Trop-2), a transmembrane glycoprotein frequently overexpressed in both squamous and nonsquamous NSCLC. SG delivers SN-38, a potent topoisomerase I inhibitor, directly to tumor cells, enabling targeted cytotoxic activity. Preclinical data suggest potential synergy between ADCs and immune checkpoint inhibition, providing the rationale for combining SG with pembrolizumab in the first-line mNSCLC setting. The phase II EVOKE-02 study was designed to explore this strategy across different PD-L1 expression subgroups.
Methods
The EVOKE-02 trial (NCT05186974) is a global, open-label, multicenter, multicohort phase II study evaluating sacituzumab govitecan in combination with pembrolizumab, with or without chemotherapy, in previously untreated patients with metastatic NSCLC lacking actionable genomic alterations. The analysis summarized here focuses on two cohorts treated with SG plus pembrolizumab without chemotherapy, stratified by PD-L1 tumor proportion score.
The primary objective was to assess antitumor activity as measured by objective response rate (ORR) according to an independent review committee. Secondary objectives included progression-free survival (PFS), safety, and exploratory biomarker analyses, including the relationship between Trop-2 expression and clinical outcomes.
Study Design
Eligible patients were adults (≥18 years) with pathologically confirmed stage IV NSCLC, measurable disease per RECIST version 1.1, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients had received no prior systemic therapy for metastatic disease and were required to have no actionable genomic alterations, including EGFR or ALK alterations. PD-L1 expression was assessed using tumor proportion score and used to define cohort allocation.
Patients received sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle, combined with pembrolizumab 200 mg intravenously on day 1 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Two cohorts were analyzed:
- Cohort A: PD-L1 TPS ≥50%
- Cohort B: PD-L1 TPS <50%
Results
As of the data cutoff on June 3, 2024, a total of 92 patients had been enrolled and treated, including 30 patients in cohort A and 62 patients in cohort B. Baseline demographics and disease characteristics were generally balanced between cohorts. The median age of the overall population was 68 years (range, 32–80), with 72.8% of patients being male. Most patients had nonsquamous histology, and both squamous and nonsquamous subtypes were represented.
The confirmed objective response rate demonstrated clear differences by PD-L1 expression. In cohort A (PD-L1 TPS ≥50%), the ORR was 66.7% (95% confidence interval [CI], 47.2–82.7). In cohort B (PD-L1 TPS <50%), the ORR was 29.0% (95% CI, 18.2–41.9). These findings indicate substantially higher antitumor activity in patients with high PD-L1 expression, while still demonstrating clinically meaningful responses in the lower PD-L1 group.
Median progression-free survival also favored patients with higher PD-L1 expression. In cohort A, median PFS was 13.1 months (95% CI, 6.7–not reached). In cohort B, median PFS was 7.0 months (95% CI, 4.2–12.9). Notably, PFS benefit was observed across both squamous and nonsquamous histologies.
Exploratory biomarker analyses showed that Trop-2 expression levels did not correlate with improved ORR or PFS, suggesting that benefit from SG plus pembrolizumab was not dependent on the degree of Trop-2 expression in tumor tissue.
Safety analysis revealed that grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 76.1% of patients. The most common grade ≥3 TEAE was neutropenia, reported in 17.4% of patients. TEAEs led to discontinuation of any study drug in 27.2% of patients. Overall, the safety profile was consistent with the known toxicities of sacituzumab govitecan and pembrolizumab, with no new safety signals identified.
Key Findings
The EVOKE-02 study demonstrates that sacituzumab govitecan combined with pembrolizumab has clinically meaningful activity as first-line therapy in metastatic NSCLC. The highest efficacy was observed in patients with PD-L1 TPS ≥50%, with an ORR of nearly 67% and median PFS exceeding 13 months. Importantly, antitumor activity was also observed in patients with PD-L1 TPS <50%, a population that often requires chemotherapy-based combinations. The lack of correlation between Trop-2 expression and efficacy suggests that patient selection may not need to rely on Trop-2 biomarker thresholds. Safety findings were manageable and aligned with expectations for each agent.
Key Takeaway Messages
This study supports the feasibility of combining an ADC with immune checkpoint inhibition as chemotherapy-free first-line therapy in selected patients with mNSCLC. High PD-L1 expression identifies a subgroup with particularly robust benefit from SG plus pembrolizumab. Patients with lower PD-L1 expression also derived benefit, though to a lesser extent. The regimen demonstrated activity across histologic subtypes and did not require Trop-2 expression as a predictive biomarker. Toxicities were frequent but manageable and consistent with known safety profiles.
Conclusion
The phase II EVOKE-02 study provides compelling evidence that sacituzumab govitecan plus pembrolizumab is an active and tolerable first-line treatment option for patients with metastatic NSCLC without actionable genomic alterations. The magnitude of benefit in patients with PD-L1 TPS ≥50% is particularly notable and compares favorably with established first-line regimens. While further randomized studies are needed to define its role relative to current standards of care, these results reinforce the emerging role of ADC–immunotherapy combinations in lung cancer and support continued clinical development of sacituzumab govitecan in earlier lines of therapy.
For more information click here.