Gilead's TROP2 ADC Sacituzumab Govitecan Plus Pembrolizumab Fails Phase III in First-Line NSCLC: Do Different TROP2 ADCs Yield Divergent Outcomes?

Gilead Sciences' TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan, when combined with pembrolizumab, failed to achieve statistical significance in its Phase III trial for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. The results raise questions about whether different TROP2 ADCs may yield divergent outcomes despite sharing the same target.

The Phase III EVOKE-03/KEYNOTE-D46 trial evaluated sacituzumab govitecan (SG) plus pembrolizumab versus pembrolizumab monotherapy in 620 previously untreated patients with metastatic NSCLC and PD-L1 tumor proportion scores (TPS) of 50% or higher. Patients in the trial had no EGFR, ALK, or ROS1 alterations.

According to results presented at the International Association for the Study of Lung Cancer's 2026 World Conference on Lung Cancer, the combination regimen demonstrated a median progression-free survival (PFS) of 11.8 months compared to 7.7 months for pembrolizumab alone. However, the hazard ratio of 0.81 (95% confidence interval, 0.66-1.00; P=0.0252) did not meet the pre-specified threshold for statistical significance.

"While sacituzumab govitecan plus pembrolizumab resulted in numerically longer progression-free survival and higher response rates, EVOKE-03/KEYNOTE-D46 failed to achieve statistical significance on its primary PFS endpoint, and overall survival was not significantly improved at this interim analysis," said Giannis Mountzios, MD, of Henry Dunant Hospital Center in Athens, Greece. "These findings provide important information as we continue to evaluate treatment strategies for patients with PD-L1 high-expressing metastatic NSCLC."

The dosing regimen in the trial consisted of SG 10 mg/kg administered intravenously on Days 1 and 8 of each 21-day cycle, with pembrolizumab 200 mg IV on Day 1 of each cycle. The trial's dual primary endpoints were PFS as assessed by blinded independent central review and overall survival.

At the interim analysis, median overall survival was 21.5 months in the combination arm versus 22.8 months in the pembrolizumab monotherapy arm (hazard ratio, 1.07; 95% CI, 0.85-1.35; P=0.7155). The combination group actually showed numerically shorter overall survival, meaning neither OS nor PFS achieved the design endpoints.

The combination regimen did demonstrate higher confirmed objective response rates: 55.6% for SG plus pembrolizumab versus 43.7% for pembrolizumab alone. Disease control rates were 83.3% and 73.1%, respectively, with median duration of response of 21.4 months and 21.3 months.

Treatment-related adverse events occurred in 93.2% of patients in the combination arm compared to 65.4% in the monotherapy arm. Grade 3 or higher treatment-related adverse events were reported in 55.7% of combination patients versus 16.5% of those receiving pembrolizumab alone. The most common treatment-related adverse events in the combination group included anemia, alopecia, neutropenia, diarrhea, and nausea. The safety profile was consistent with the known safety profiles of each agent alone, with no new or additional toxicities observed with the combination.

Sacituzumab govitecan targets TROP2 with a CL2A linker and SN-38 payload, achieving a drug-to-antibody ratio of 7.6. The ADC has a half-life of approximately 11.4 hours. Immunomedics, the original developer, selected a relatively less stable linkage site at the 20-hydroxyl position of SN-38. The company published related research as early as 2014 exploring different linker configurations and linkage sites to improve the therapeutic index in cancer therapy.

In contrast, sacituzumab tirumotecan (sac-TMT; SKB264/MK-2870), a TROP2 ADC developed by Kelun-Biotech that also uses a CL2A linker but with different conjugation methods and a relatively more potent toxin, has shown markedly different results.

The Phase III OptiTROP-Lung05 trial (NCT06448312) evaluated sac-TMT plus pembrolizumab versus pembrolizumab monotherapy as first-line treatment for patients with PD-L1 positive advanced NSCLC. The randomized, multicenter, open-label study enrolled patients with locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who had not received prior systemic anti-cancer therapy and had no sensitizing EGFR or ALK alterations. Other enrollment criteria included confirmed PD-L1 TPS of at least 1% by central laboratory immunohistochemistry 22C3 assay and ECOG performance status score of 1 or less.

Results presented at ASCO 2026 and published simultaneously in The Lancet showed that sac-TMT plus pembrolizumab reduced the risk of disease progression or death by 65% compared to pembrolizumab alone (hazard ratio, 0.35; 95% CI, 0.26-0.47; P<0.0001). Median PFS was not reached in the combination arm versus 5.7 months in the control arm.

The PFS benefit was consistent across PD-L1 TPS subgroups: hazard ratio of 0.47 for the TPS ≥50% subgroup and 0.28 for the TPS 1%-49% subgroup. Benefits were also consistent across histological subtypes: hazard ratio of 0.28 for non-squamous NSCLC and 0.44 for squamous NSCLC.

Objective response rates were 70.2% for the combination regimen versus 42.0% for pembrolizumab monotherapy, with deeper and more durable responses in the combination group. Overall survival data were not yet mature but showed a trend favoring the combination therapy (hazard ratio, 0.55; 95% CI, 0.36-0.85).

Following multiple positive Phase III readouts from sac-TMT studies in China, Merck has initiated nearly 20 global Phase III trials. In July, Kelun announced that the Phase III OptiTROP-Lung06 trial, evaluating sac-TMT plus pembrolizumab for first-line PD-L1 negative non-squamous NSCLC, also met its PFS endpoint with a favorable OS trend.

More recently, sac-TMT achieved its first global Phase III success: the TroFuse-005 trial in previously treated endometrial cancer patients met both PFS and OS endpoints.

Addressing the differences between the two TROP2 ADCs during an interview at ASCO 2026, Marjorie Green, MD, head of oncology clinical development at Merck, noted that different regional clinical practices and available treatment options may affect overall survival outcomes for the same drug across different geographic regions. In contrast, other endpoints such as tumor response rates and PFS are not affected by subsequent therapy and can serve as "reasonable surrogate indicators" for understanding ADC potential based on Chinese data.