Sacituzumab Tirumotecan Improves Survival in Second-Line EGFR+ NSCLC

When assessed via BICR, the ORR with sac-TMT was 60.6% compared with 43.1% with chemotherapy; the DCR was 87.2% and 80.3%, respectively.

Sacituzumab tirumotecan (sac-TMT) led to a 51% reduction in the risk of death progression or death compared with chemotherapy in patients with nonsquamous EGFR-mutated non–small cell lung cancer (NSCLC) that developed EGFR-TKI resistance, according to phase 3 results of the OptiTROP-Lung04 study (NCT05870319) that were presented during the European Society of Medical Oncology (ESMO) Congress 2025.1

Results showed that, at a median follow-up of 18.9 months, the median progression-free survival (PFS) via blinded independent central review (BICR) was 8.3 months (95% CI, 6.7-9.9) with sac-TMT and 4.3 months (95% CI, 4.2-5.5) with chemotherapy (HR, 0.49; 95% CI, 0.39-0.62; P <.0001). The 12-month PFS rates were 32.3% (25.5%-39.2%) and 7.9% (95% CI, 4.4%-12.8%), respectively. The PFS benefit with sac-TMT was observed across all prespecified subgroups.

The investigator-assessed median PFS was 8.4 months (95% CI, 7.1-9.7) with sac-TMT and 4.8 months (95% CI 4.2-5.5) with chemotherapy (HR, 0.51; 95% CI, 0.41-0.65; P <.0001). The 12-month PFS rates were 34.7% (27.7%-41.7%) and 10.7% (95% CI, 6.5%-16.0%), respectively.

“Sac-TMT demonstrated statistically significant and clinically meaningful improvements in PFS and OS compared to platinum-based chemotherapy,” lead study author Li Zhang, MD, professor of medical oncology at Sun Yat-sen University Cancer Center in Guangzhou, China, said in an oral presentation of the data. “The results of the OptiTROP-Lung04 study support sac-TMT as a promising new treatment option for patients with EGFR-mutated NSCLC with EGFR-TKI resistance.”

Sac-TMT is a TROP2 antibody-drug conjugate (ADC) with a unique biofunctional linker that maximizes delivery of a belotecan-derivative topo I inhibitor payload to tumor cells. TROP2 is highly expressed in patients with EGFR-mutated NSCLC; preclinical data have shown that sac-TMT internalization and uptake are enhanced by EGFR mutations.2

Current standard options for patients who relapse on third-generation EGFR TKIs remains platinum-based chemotherapy, but more options are needed.

In the multicenter, open-label, phase 3 OptiTROP-Lung04 trial, 376 patients with nonsquamous stage IIIB/IIIC or IV NSCLC with EGFR-sensitive mutations were randomly assigned 1:1 to receive sac-TMT at 5 mg/kg intravenously (IV) every 2 weeks or pemetrexed at 500 mg/m2 plus carboplatin AUC 5 or cisplatin at 75 mg/m2 every 3 weeks for up to 4 cycles, followed by pemetrexed maintenance at 500 mg/m2 every 3 weeks. Treatment was given until disease progression, intolerable toxicity, or patient request to discontinue therapy.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1 and progression after third-generation TKI therapy or progression after first- or second-generation TKIs with T790M-negative mutations.

Stratification factors included prior EGFR TKI therapy (third-generation TKI in frontline vs second line vs no third-generation TKI) or brain metastases (yes vs no).

The primary end point was PFS assessed by BICR; secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety.

A total 148 patients on sac-TMT discontinued treatment due to disease progression (n = 125), patient or guardian withdrawal (n = 12), death (n = 6), adverse effects (AEs; n = 2), or other (n = 3). In the chemotherapy arm, 179 patients discontinued treatment due to disease progression (n = 140), patient/guardian withdrawal (n = 16), death (n = 9), AEs (n = 5), protocol deviation (n = 2), or other (n = 7). A total 69 and 102 patients in each arm, respectively, discontinued from the study due to death (n = 67 and 101) or were lost to follow-up (n = 2 and 1).

The data cutoff date was July 6, 2025.

Patient baseline characteristics were generally well balanced between the sac-TMT (n = 188) and chemotherapy arms (n = 188). The median age was 60 years (range, 31-75) and 59 years (range, 33-75), and 30.9% and 27.1%, respectively, were at least 65 years. Most had an ECOG performance status of 1 (81.4% and 77.1%), had no smoking history (77.1% and 71.8%), had stage IV disease (96.8% and 98.4%), and at least 3 metastatic sites (68.1% and 67.0%). A total 17.6% and 19.1% had brain metastases, and 13.3% and 17.6% had liver metastases. The majority in each arm had exon 19 deletions (56.4% and 62.8%), had unknown T790M mutation status (59.0% and 59.6%), and received a prior third-generation EGFR TKI in the frontline setting (62.8% and 62.2%).

The interim analysis showed that for sac-TMT, the median OS was not reached (NR; 95% CI, 21.5-NE) compared with 17.4 months (95% CI, 15.7-20.4) with chemotherapy, leading to a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.44-0.82; 2-sided P = .001). The 18-month OS rates were 65.8% (95% CI, 58.3%-72.3%) and 48.0% (95% CI, 40.2%-55.4%), respectively. OS was improved with sac-TMT across all prespecified subgroups.

Zhang also reported on subsequent anticancer treatment from the trial; 72.3% of patients on sac-TMT and 85.5% of those on chemotherapy received at least 1 subsequent treatment. In the sac-TMT and chemotherapy groups, respectively, these were comprised of chemotherapy (41.9%; 53.6%), and specifically pemetrexed-based chemotherapy (37.2%; 12.8%), an EGFR TKI (42.6%; 39.7%), an anti-angiogenic agent (34.5%; 48.0%), immunotherapy (16.9%; 24.6%), or an antibody-drug conjugate (1.4%; 19.6%).

Additionally, when censoring patients at the time of initiation of subsequent ADCs, sac-TMT significantly improved OS vs chemotherapy (HR, 0.56; 95% CI, 0.41-0.77).

When assessed via BICR, the ORR with sac-TMT was 60.6% (95% CI, 53.3%-67.7%) compared with 43.1% (95% CI, 35.9%-50.5%) with chemotherapy; the DCR was 87.2% (95% CI, 81.6%-91.6%) and 80.3% (95% CI, 73.9%-85.7%), respectively. The median DOR was 8.3 months (95% CI, 6.2-10.0) with sac-TMT and 4.2 months (95% CI, 3.0-4.4) with chemotherapy; the 12-month DOR rates were 36.3% (95% CI, 27.3%-45.3%) vs 8.1% (95% CI, 3.3%-15.8%), respectively.

Regarding safety, treatment-related AEs occurred in 100% and 98.4% of sac-TMT– and chemotherapy-treated patients, respectively. Grade 3 or higher TRAEs occurred in 58.0% and 53.8% of patients, and serious TRAEs occurred in 9.0% and 17.6% of patients, respectively. TRAEs that led to dose reductions and interruptions occurred in 30.3% and 36.7% of patients on sac-TMT; there were no TRAEs that led to discontinuation or death. In the chemotherapy arm, these rates were 22.5% and 33.0%; 1 patient each experienced TRAEs leading to discontinuation or death.

The median duration of exposure was 9.6 months (range, 0.5-23.5) with sac-TMT and 4.9 months (range, 0.7-22.6) with chemotherapy.

The most common TRAEs in both arms were hematologic events; sac-TMT had higher incidence of stomatitis that were mostly grade 1/2 (any-grade, 62%; grade ≥3, 5%). Ocular surface toxicities also occurred in 9.6% of patients on sac-TMT, all of which were grades 1/2. No cases of interstitial lung disease or pneumonitis were reported on the sac-TMT arm.

Phase 3 trials are currently exploring sac-TMT alone (NCT06305754; NCT06074588) and in combination with osimertinib (Tagrisso; NCT06670196) in patient with EGFR-mutant NSCLC.

Disclosures: Zhang cited personal declaration of interests with Akesobio and Sichuan Biokin Pharmaceutical as invited speakers; institutional declaration of interests with Akesokio, as trial chair; AZ as research grant and trial chair; China Shiyao Pharma as trial chair; Henrui Pharm as trial chair; Kelun Pharm as trial chair; Novartis as trial chair; Pierre-Fabre as trial chair; Pfizer as trial chair; QiLu pharm as trial chair; Roche with research grant; and Sichuan Biokin Pharmaceutical as trial chair.

References

1. Zhang L, Fang W, Wu L, et al. Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase 3 OptiTROP-Lung04 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA5.
2. 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.