Sac-TMT Extends OS in Pretreated EGFR-Mutated NSCLC

March 27, 2026 | Kyle Doherty

The TROP2 antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) displayed a significant overall survival (OS) benefit compared with docetaxel in patients with pretreated EGFR-mutated non–small cell lung cancer (NSCLC) according to data from the final OS analysis of the phase 2 OptiTROP-Lung03 study (NCT05631262) presented during the 2026 European Lung Cancer Congress.¹

At a median follow-up of 23.8 months, patients who received sac-TMT (n = 91) achieved a median OS of 20.0 months (95% CI, 14.8-not evaluable [NE]) compared with 13.5 months (95% CI, 8.0-17.2) among patients who received docetaxel (n = 46; HR, 0.63; 95% CI, 0.40-0.98). The 18-month OS rates were 54.7% (95% CI, 43.9%-64.3%) and 34.0% (95% CI, 20.7%-47.7%), respectively.

“Sac-TMT is the first therapy to achieve long-term OS benefits in patients with advanced EGFR-mutated NSCLC who [have] progressed after EGFR TKI and platinum-based chemotherapy,” Yunpeng Yang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China

In December 2024, the FDA granted breakthrough designation to sac-TMT for the treatment of patients with advanced or metastatic nonsquamous NSCLC harboring EGFR mutations whose disease has progressed on or following a TKI and platinum-based chemotherapy.²

How was OptiTROP-Lung03 designed?

OptiTROP-Lung03 enrolled patients with nonsquamous NSCLC who had either stage IIIB/IIIC disease and were ineligible for surgery or radical radiotherapy, or stage IV disease.¹ Patients were also required to have an ECOG performance status of 0 or 1, EGFR-sensitizing mutations, and experienced disease progression following prior combination or sequential treatment with EGFR TKIs and platinum-based chemotherapy. Stratification occurred based on the presence of brain metastases (present vs absent).

Patients were randomly assigned 1:1 to receive intravenous (IV) sac-TMT at 5 mg/kg every 2 weeks or IV docetaxel at 75 mg/m² every 3 weeks. Treatment in both arms continued until disease progression, intolerable toxicity, or any other reason for discontinuation. Patients in the control arm who experienced disease progression per blinded independent central review (BICR) were allowed to crossover to the investigational arm.

The primary end point was overall response rate (ORR) per BICR. Secondary end points included progression-free survival (PFS), OS, investigator-assessed ORR, duration of response, disease control rate, time to response, and safety.

The data cutoff for the final OS analysis was December 11, 2025. At baseline, the median ages in the sac-TMT and docetaxel arms were 57.0 years (range, 37-75) and 55.0 years (range, 34-74), respectively; all patients in both arms had adenocarcinoma. Most patients in both arms had stage IV disease at enrollment (97.8% in the sac-TMT arm vs 97.8% in the docetaxel arm), an ECOG performance status of 1 (83.5% vs 80.4%), received a prior third-generation EGFR TKI in the frontline setting (59.3% vs 56.5%), and received prior antiangiogenic therapy (65.9% vs 71.7%).

What additional efficacy and safety data were reported?

Additional findings from OptiTROP-Lung03 revealed that the investigator-assessed median PFS in the investigational arm was 7.9 months (95% CI, 6.2-9.5) vs 2.8 months (95% CI, 1.5-3.8) in the control arm (HR, 0.23; 95% CI, 0.15-0.35). The respective 12-month PFS rates were 30.2% (95% CI, 20.6%-40.4%) and 2.2% (95% CI, 0.2%-10.0%).

After adjusting for crossover, the median OS in the sac-TMT arm was 20.0 months (95% CI, 14.8-NE) compared with 11.2 months (95% CI, 8.0-16.1) in the docetaxel arm (HR, 0.45; 95% CI, 0.28-0.73). The 18-month OS rates were 54.7% (95% CI, 43.9%-64.3%) and 9.1% (95% CI, 0.7%-31.7%), respectively.

In terms of safety, any-grade treatment-related adverse effects (TRAEs) occurred in 97.8% of patients in both the investigational and control arms. Patients in both arms experienced grade 3 or higher TRAEs (60.4% vs 73.9%), serious TRAEs (20.9% vs 41.3%), TRAEs leading to dose reduction (42.9% vs 43.5%), and TRAEs leading to dose interruption (46.2% vs 30.4%).

The most common any-grade TRAEs in the investigational arm included anemia (81.3%), decreased white blood cell count (74.7%), decreased neutrophil count (68.1%), and stomatitis (65.9%). The most common any-grade TRAEs in the control arm included anemia (67.4%), decreased white blood cell count (63.0%), decreased neutrophil count (58.7%), and alopecia (50.0%).

The median treatment durations in the sac-TMT and docetaxel arms were 7.1 months (range, 0.5-25.0) and 2.8 months (range, 0.7-13.1), respectively. In the sac-TMT arm, no TRAEs led to treatment discontinuation or death. Interstitial lung disease/pneumonitis occurred at a rate of 2.2% in both arms.

“Sac-TMT continues to have a manageable safety profile with no new safety signals after a median follow-up of [approximately] 2 years,” Yang said. “We believe that the results of the final OS analysis of [OptiTROP-Lung03] underscore sac-TMT as a promising new treatment option for [patients with] pretreated EGFR-mutated NSCLC.”

Disclosures: Yang shared no relevant financial disclosures.

References

Fang W, Li Z, Wang Q, et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC): final overall survival (OS) analysis from the randomized OptiTROP-Lung03 study. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract LBA4.

FDA grants breakthrough designation to sacituzumab tirumotecan (sac-TMT) for the treatment of certain patients with previously treated advanced or metastatic nonsquamous non-small cell lung cancer with EGFR mutations. News release. Merck. December 3, 2024. Accessed March 27, 2026. https://www.merck.com/news/fda-grants-breakthrough-therapy-designation-to-sacituzumab-tirumotecan-sac-tmt-for-the-treatment-of-certain-patients-with-previously-treated-advanced-or-metastatic-nonsquamous-non-small-cell-lung-ca/