Sacituzumab Tirumotecan Enhances Efficacy in Pretreated EGFR-Mutant NSCLC

When adjusted for crossover using the RPSFT model, the median OS in the investigational arm was NR vs 9.3 months with docetaxel, and the respective 12-month OS rates were 72.8% vs 43.2%.

Sacituzumab tirumotecan (sac-TMT) exhibited enhanced efficacy outcomes vs docetaxel in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) previously treated with combination therapies or sequential treatment with EGFR-tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy, according to findings from the open-label multi-center phase 2 OptiTROP-Lung03 trial (NCT05631262) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

Data from the trial revealed that among 91 efficacy evaluable patients treated with sac-TMT and 45 treated with docetaxel, the respective objective response rates (ORRs) were 45.1% (95% CI, 34.6%-55.8%) and 15.6% (95% CI, 6.5%-29.5%), for a statistically significant ORR improvement for the former of 28.9% (95% CI, 14.5%-43.2%; P = .0004). Additionally, the disease control rate (DCR) in each respective arm was 82.4% (95% CI, 73.0%-89.6%) vs 60.0% (95% CI, 44.3%-74.3%). Furthermore, the median duration of response (DOR) was 7.0 months (95% CI, 5.4-9.1) with sac-TMT vs 5.1 months (95% CI, 3.1-not evaluable [NE]) with docetaxel.

Further data revealed that a survival advantage was observed with the investigational agent vs docetaxel, with a median progression-free survival (PFS) by blinded independent review committee (BIRC) of 6.9 months (95% CI, 5.4-8.2) and 2.8 months (95% CI, 1.6-4.1), respectively (HR, 0.30; 95% CI, 0.20-0.46; P < .0001). The 6-month PFS rate with sac-TMT was 54.2% vs 14.6% with docetaxel. Investigator-assessed PFS elicited similar results with an HR of 0.23 (95% CI, 0.15-0.36; P <.0001).

Additionally, overall survival (OS) outcomes favored sac-TMT, with the investigational agent eliciting a 12-month OS rate of 72.8% vs 54.3% with docetaxel. OS events occurred in 27.5% of the sac-TMT arm vs 45.7% in the docetaxel arm, with a median OS not reached (NR) in the investigational arm (95% CI, NE-NE) or docetaxel arms (8.0-NE) as of the data cut-off date of December 31, 2024 (HR, 0.49; 95% CI, 0.27-0.88; P = .0070).

When adjusted for crossover using the rank-preserving structural failure time (RPSFT) model, the median OS in the investigational arm was NR (95% CI, NE-NE) vs 9.3 months (95% CI, 7.3-NE) with docetaxel (HR, 0.36; 95% CI, 0.20-0.66). The respective 12-month OS rates were 72.8% vs 43.2%.

“EGFR mutation is the most common driver alteration in NSCLC. The prevalence of EGFR mutations reaches 28.2% among patients [with NSCLC] in China,” Li Zhang, MD, national lead principal investigator, medical oncologist, and the deputy director of the Lung Cancer Research Centre at Sun Yat-Sen University, said in the news release on the study findings.2 “Although third-generation EGFR-TKIs have become the standard-of-care for advanced EGFR-mutant NSCLC and may significantly improve PFS, acquired resistance remains inevitable. Combining EGFR-TKIs with chemotherapy can offer additional survival benefits to some patients, but this approach is limited by safety concerns and may compromise future treatment options, posing significant clinical challenges.”

The phase 2 study randomly assigned patients 2:1 to receive 5 mg/kg of sac-TMT every 2 weeks (n = 91) or 75 mg/m2 of intravenous docetaxel every 3 weeks (n = 46). Treatment in both arms was received until disease progression, unacceptable toxicity, or meeting other discontinuation criteria. Patients who experienced disease progression with docetaxel were permitted to cross over and receive sac-TMT.

Patients eligible for enrollment had an ECOG performance score of 0 or 1 and nonsquamous histology including stage IIIB/IIIC disease ineligible for surgery or radical radiotherapy as well as stage IV disease. Additionally, patients with EGFR-sensitizing mutations, including 19 deletions and L858R were enrolled. Patients were stratified based on the presence of brain metastases.

Among patients in the sac-TMT and docetaxel arms, the median age was 57.0 years (range, 37-75) vs 55.0 years (range, 34-74), respectively. A total of 41.8% vs 47.8% of each arm were males, 100% of each arm had adenocarcinoma histology, and 97.8% of each arm had stage IV NSCLC. Furthermore, 83.5% of the sac-TMT arm and 80.4% of the docetaxel arm had an ECOG performance score of 1, 47.3% vs 69.6% had 19 deletions, and 57.1% vs 43.5% had 2 prior lines of anti-tumor therapy.

The primary end point of the trial was ORR assessed by BIRC. Secondary end points included PFS, OS, investigator-assessed ORR, DOR, DCR, time to response, and safety.

The overall safety analysis showed that treatment-related adverse effects (TRAEs) occurred at a rate of 97.8% in both arms. Furthermore, 56.0% of the investigational arm vs 71.7% of the chemotherapy arm experienced grade 3 or higher TRAEs, with serious TRAEs occurring in 16.5% vs 41.3%, respectively.

TRAEs leading to dose reduction or interruption occurred in 31.9% and 35.2% of the sac-TMT arm vs 43.5% and 28.3% of the chemotherapy arm. A single TRAE leading to dose discontinuation occurred in the chemotherapy arm and no fatal TRAEs occurred in either arm.

References

1. Zhang L, Fang W, Li XY, et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): results from the randomized OptiTROP-Lung03 study. J Clin Oncol. 2025;43(suppl 16):8507. doi:10.1200/JCO.2025.43.16_suppl.8507
2. The British Medical Journal Publishes study results on sacituzumab tirumotecan for previously treated EGFR-mutant advanced NSCLC. News release. Sichuan Kelun-Biotech Biopharmaceutical Co. June 9, 2025. Accessed June 9, 2025. https://tinyurl.com/2re4d839