TROP2 ADC and PD-L1 mAb Show Promising Frontline Efficacy in NSCLC

Initial findings from the phase 2 OptiTROP-Lung01 study (NCT05351788), published in Nature Medicine, suggest that the combination of the novel TROP2 antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) and the PD-L1 monoclonal antibody (mAb) tagitanlimab demonstrates encouraging antitumor activity and a manageable safety profile as a first-line treatment for patients with advanced or metastatic non–small cell lung cancer (NSCLC).^1,2 This combination therapy was evaluated in patients without actionable genomic alterations, addressing a significant unmet need in this patient population.

Detailed Clinical Findings and Efficacy Data

The phase 2 OptiTROP-Lung01 study includes 2 cohorts of patients. Cohort 1A received sac-TMT at 5 mg/kg every 3 weeks in combination with tagitanlimab at 1200 mg every 3 weeks, while cohort 1B was treated with a different dosing regimen of sac-TMT at 5 mg/kg every 2 weeks and tagitanlimab at 900 mg every 2 weeks. The study followed a nonrandomized design with patients receiving treatment until disease progression or unacceptable toxicity.

The efficacy analysis included 40 patients in cohort 1A and 63 patients in cohort 1B. The results showed a notable difference in objective response rates (ORRs) between the 2 cohorts. Cohort 1A had a confirmed ORR of 40.0% (95% CI, 24.9%–56.7%), whereas cohort 1B demonstrated a higher confirmed ORR of 66.7% (95% CI, 53.7%–78.0%). This superior response in cohort 1B, which used a more frequent dosing schedule, is a key finding that may guide future therapeutic strategies.

Further subgroup analyses revealed consistent efficacy across various patient characteristics, including PD-L1 expression levels and histological subtypes. In cohort 1B, the ORRs were particularly strong, with confirmed responses of 57.1% in patients with a PD-L1 tumor proportion score (TPS) <1%, 63.2% for TPS 1–49%, and 78.3% for TPS ≥50%. These data suggest the combination may be effective regardless of PD-L1 status, a crucial consideration for clinical application. Efficacy was also consistent across both nonsquamous (64.7% ORR in cohort 1B) and squamous carcinoma (69.0% ORR in cohort 1B) subtypes.

Progression-free survival (PFS) data also underscored the potential of the regimen. The median PFS for cohort 1A was 15.4 months (95% CI, 6.7–17.9), while the median PFS for cohort 1B was not yet reached (NR; 95% CI, 9.6–NR), with a median follow-up of 13.0 months. This suggests a potentially durable and long-lasting response in patients treated with the cohort 1B regimen.

Safety Profile and Drug Mechanism

The safety profile of the combination therapy was deemed manageable, with the most common grade ≥3 treatment-related adverse events (TRAEs) across both cohorts being decreased neutrophil count, decreased white blood cell count, and anemia. These are well-known hematologic toxicities associated with many chemotherapy agents and ADCs. Notably, no treatment-related deaths were reported, highlighting a favorable risk-benefit balance.

Sac-TMT is a TROP2-directed ADC, a class of drugs that delivers a potent cytotoxic payload directly to tumor cells that express the TROP2 protein. The drug consists of an anti-TROP2 antibody linked to a derivative of the topoisomerase I inhibitor belotecan. Once the ADC binds to the TROP2 receptor on the tumor cell surface, it is internalized. The payload is then released inside the cell, where it induces DNA damage, leading to apoptosis. The drug also exhibits a "bystander effect," where the payload can diffuse out of the targeted cell to kill nearby tumor cells, potentially overcoming the issue of heterogeneous TROP2 expression within a tumor. The combination with tagitanlimab, a PD-L1 inhibitor, aims to enhance the antitumor immune response.

Implications and Future Direction

The positive outcomes from the OptiTROP-Lung01 study support the potential for sac-TMT to move from later-line to first-line therapy for advanced NSCLC. This could provide a new, effective treatment option for patients who currently have limited choices. The strong efficacy observed across different PD-L1 expression levels is particularly noteworthy, as it suggests this combination could be a versatile first-line treatment, bypassing the need for PD-L1 testing to determine eligibility.

In a press release, Kelun-Biotech's CEO, Michael Ge, MD, said, “The OptiTROP-Lung01 study supports the promising efficacy and safety of sacituzumab tirumotecan in combination with tagitanlimab as a first-line treatment for patients with advanced NSCLC. The results were observed across PD-L1/TROP2 expression levels and histological subtypes and support the advancement potential of sac-TMT from later-line to front-line therapy. The publication of results from several studies in top-tier international journals reflects the recognition of our innovation-driven development strategy. We will continue to work to address critical clinical challenges and unmet medical needs, striving to deliver more therapeutic options and improve quality of life for patients."²

REFERENCES:

1. Zhao S, Cheng Y, Wang Q, et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nat Med. 2025 Jun;31(6):1976-1986. doi: 10.1038/s41591-025-03638-2. Epub 2025 Apr 10.

2. Nature Medicine Publishes Results of Phase II Study of Sacituzumab Tirumotecan Plus Tagitanlimab as First-Line Therapy for NSCLC. News release. Sichuan Kelun-Biotech Biopharmaceutical Co Ltd. August 19, 2025. Accessed August 20, 2025. https://tinyurl.com/bp8j5zts