September 17, 2026 | OncLive Staff
Sacituzumab tirumotecan (sac-TMT) elicited an objective response rate (ORR) of 34.4% (95% CI, 24.7%-45.2%) in previously treated patients with advanced non–small cell lung cancer (NSCLC) harboring actionable genomic alterations (AGAs) other than classic EGFR mutations, according to data from the phase 2 OptiTROP-Lung03 trial (NCT05631262) presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).1
At a data cutoff of December 11, 2025, with a median follow-up of 21.2 months (95% CI, 20.1-22.2) across the overall population (n = 90), the disease control rate (DCR) was 85.6% (95% CI, 76.6%-92.1%) and the median duration of response (DOR) was 12.7 months (95% CI, 7.6-14.9). The median progression-free survival (PFS) was 9.4 months (95% CI, 5.7-11.5), with a 12-month PFS rate of 38.9% (95% CI, 28.0%-49.5%). Median overall survival (OS) was not reached (95% CI, 19.1-not evaluable [NE]), and the 18-month OS rate was 64.7% (95% CI, 53.7%-73.7%).
Sac-TMT is a TROP2-directed antibody-drug conjugate (ADC) composed of sacituzumab, a humanized anti-TROP2 monoclonal antibody, joined via a proprietary bifunctional linker to a novel, belotecan-derived topoisomerase I inhibitor payload at a drug-to-antibody ratio of 7.4 (range, 7-8). Sac-TMT previously demonstrated antitumor activity and an OS benefit in patients with previously treated, EGFR-mutant NSCLC, findings that supported the agent’s regulatory approval for this indication in China.2,3,5 Effective treatment options remain limited for patients with NSCLC harboring other AGAs who progress after targeted therapy. Sac-TMT is also being evaluated earlier in the treatment course; a related phase 3 trial of frontline sac-TMT plus pembrolizumab (Keytruda) recently met its PFS end point in patients with PD-L1–negative, nonsquamous NSCLC.4
Fang and coinvestigators concluded that sac-TMT monotherapy showed clinical activity across cohorts with AGAs beyond classic EGFR mutations and that the findings warrant further investigation of the agent in this population.1
How was the OptiTROP-Lung03 trial designed?
OptiTROP-Lung03 is a phase 2, open-label, multicohort study conducted in China. The cohort reported here enrolled patients with advanced NSCLC harboring AGAs other than classic EGFR mutations, including non-classic EGFR mutations (eg, G719X, S768I, L861Q), EGFR exon 20 insertions, ALK fusions, KRAS mutations, ROS1 or RET fusions, MET exon 14 skipping mutations, or BRAF V600E mutations, who had progressed after standard therapy and had an ECOG performance status of 0 or 1. Patients received sac-TMT at 5 mg/kg intravenously every 2 weeks until loss of clinical benefit, intolerable toxicity, withdrawal, or another discontinuation criterion was met. The primary end points were ORR and safety; secondary end points included DCR, DOR, time to response, PFS, and OS. Tumor response was assessed per RECIST v1.1 every 8 weeks for the first 48 weeks and every 12 weeks thereafter.
Of the 90 enrolled patients, cohorts included non-classic EGFR mutations (n = 23), EGFR exon 20 insertions (n = 20), ALK fusions (n = 20), KRAS mutations (n = 16), and ROS1/RET fusions, MET exon 14 skipping, or BRAF V600E mutations (n = 11). The median patient age was 59.0 years (range, 36.0-74.0), 56.7% of patients were female, and 81.1% had an ECOG performance status of 1. Nearly all patients (97.8%) had stage IV disease, and 53.3% had 3 or more metastatic sites. Patients had received a median of 2 prior anti-tumor regimens (range, 1-7); 74.4% had received corresponding targeted therapy, 68.9% platinum-based chemotherapy, and 28.9% immunotherapy. At data cutoff, 15 patients remained on treatment and 75 had discontinued, most often for radiographic disease progression (n = 56).
How did efficacy vary across genomic subgroups?
Responses were observed across all 5 genomic subgroups assessed.
Efficacy by Genomic Subgroup (ORR / DCR / Median PFS)
- Non-classic EGFR mutations (n = 23): 39.1% / 91.3% / 10.9 months
- EGFR exon 20 insertions (n = 20): 35.0% / 75.0% / 9.0 months
- ALK fusion (n = 20): 40.0% / 95.0% / 9.4 months
- KRAS mutation (n = 16): 25.0% / 75.0% / 9.6 months
- ROS1/RET fusion, MET exon 14 skipping, or BRAF V600E (n = 11): 27.3% / 90.9% / 7.1 months
Median OS was not reached in the non-classic EGFR mutation cohort (18-month OS rate, 78.3%) or the ROS1/RET fusion, MET exon 14 skipping, or BRAF V600E cohort (18-month OS rate, 54.5%). Median OS was 23.3 months in the ALK fusion cohort, 21.3 months in the EGFR exon 20 insertion cohort, and 12.3 months in the KRAS mutation cohort. Median DOR ranged from 7.6 months in the ALK fusion cohort to 14.7 months in the ROS1/RET fusion, MET exon 14 skipping, or BRAF V600E cohort; median DOR was not reached in the KRAS mutation cohort.
What did the safety analysis show?
Among all 90 treated patients, treatment-related adverse effects (TRAEs) of any grade occurred in 98.9%, and grade 3 or higher TRAEs occurred in 56.7%; serious TRAEs occurred in 18.9%. No TRAEs led to treatment discontinuation or death. The median duration of exposure was 8.8 months (range, 0.5-25.5). The most common TRAEs, reported in at least 20% of patients, were hematologic toxicities, including anemia (78.9%; grade ≥3, 17.8%), decreased white blood cell count (76.7%; grade ≥3, 24.4%), and decreased neutrophil count (74.4%; grade ≥3, 42.2%), along with stomatitis (52.2%; grade ≥3, 7.8%). Pneumonitis occurred in 2 patients (2.2%), graded as grade 1 and grade 2, respectively; no cases of interstitial lung disease were reported.
What are the next steps for sac-TMT in NSCLC?
Investigators concluded that sac-TMT monotherapy demonstrated clinical activity and a manageable safety profile in this heavily pretreated population with AGAs beyond classic EGFR mutations, warranting further investigation. A global phase 3 trial, TroFuse-004 (NCT06074588), is ongoing to evaluate sac-TMT vs chemotherapy in patients with NSCLC harboring EGFR mutations or other genomic alterations.
References
Fang W, Zhang X, Yang R, et al. Sacituzumab tirumotecan (sac-TMT) in patients with previously treated advanced NSCLC with actionable genomic alterations other than classic EGFR Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract OA10.03.
Fang W, Li X, Wang Q, et al. Sacituzumab tirumotecan versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: multicentre, open label, randomised controlled trial. BMJ. 2025;389:e085680. doi:10.1136/bmj-2025-085680
Fang W, Wu L, Meng X, et al. Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):13-26. doi:10.1056/NEJMoa2512071.
Frontline sac-TMT plus pembrolizumab meets PFS end point in PD-L1–negative, nonsquamous NSCLC. OncLive. Published July 15, 2026. Accessed September 16, 2026. https://www.onclive.com/view/frontline-sac-tmt-plus-pembrolizumab-meets-pfs-end-point-in-pd-l1-negative-nonsquamous-nsclc
Sac-TMT extends OS in pretreated EGFR-mutated NSCLC. OncLive. Published March 27, 2026. Accessed September 16, 2026. https://www.onclive.com/view/sac-tmt-extends-os-in-pretreated-egfr-mutated-nsclc
