Sacituzumab tirumotecan versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: multicentre, open label, randomised controlled trial

Abstract

Objective: To compare the efficacy and safety of sacituzumab tirumotecan (sac-TMT) with docetaxel in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.

Design: Multicentre, open label, randomised controlled trial.

Setting: 48 centres in China, 1 September 2023 to 31 December 2024.

Participants: 137 adults (aged 18-75 years) with EGFR-mutated advanced or metastatic NSCLC after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.

Intervention: Patients were randomly assigned (2:1) to receive sac-TMT (5 mg/kg) on days 1 and 15 of each four week cycle, or docetaxel (75 mg/m²) on day 1 of each three week cycle. Patients in the docetaxel group were permitted to crossover to sac-TMT treatment on disease progression.

Main outcome measures: The primary endpoint was objective response rate as assessed by a blinded independent review committee (BIRC). The secondary endpoints included objective response rate assessed by the investigator; disease control rate, progression-free survival, time to response, and duration of response assessed by BIRC and the investigator; overall survival; and safety.

Results: 137 patients were randomised to receive sac-TMT (n=91) or docetaxel (n=46). Median follow-up was 12.2 months at the data cut-off for efficacy (31 December 2024). BIRC assessed objective response rate was significantly higher in the sac-TMT group (45% (41/91)) v docetaxel (16% (7/45)), with a difference of 29% (95% confidence interval (CI) 15% to 43%; one sided P<0.001). Median progression-free survival was longer with sac-TMT than with docetaxel assessed by BIRC (6.9 v 2.8 months; hazard ratio 0.30, 95% CI 0.20 to 0.46; one sided P<0.001) and the investigator (7.9 v 2.8 months; hazard ratio 0.23, 0.15 to 0.36; one sided P<0.001). The 12 month overall survival rate was 73% with sac-TMT and 54% with docetaxel (hazard ratio 0.49, 0.27 to 0.88; one sided P=0.007). After adjustment for crossover using the rank-preserving structural failure time model, sac-TMT also showed improved overall survival (hazard ratio 0.36, 0.20 to 0.66). Grade ≥3 treatment related adverse events were less frequent with sac-TMT than with docetaxel (56% v 72%), with no new safety signals identified.

Conclusions: Sac-TMT showed statistically significant and clinically meaningful improvements in objective response rate, progression-free survival, and overall survival compared with docetaxel, with a manageable safety profile in patients with EGFR-mutated locally advanced or metastatic NSCLC.

Trial registration: ClinicalTrials.gov NCT05631262.

Fig 1

Trial profile. *Four patients had radiology detected disease progression verified by blinded independent review committee (BIRC). sac-TMT=sacituzumab tirumotecan

Fig 2

Waterfall plots showing antitumour activity assessed by blinded independent review committee in patients with EGFR-mutated non-small cell lung cancer. EGFR=epidermal growth factor receptor; sac-TMT=sacituzumab tirumotecan

Fig 3

Time to response and duration of response in patients with EGFR-mutated non-small cell lung cancer according to treatment. PR=partial response; sac-TMT=sacituzumab tirumotecan

Fig 4

Kaplan-Meier curves for progression-free survival and overall survival in patients with EGFR-mutated non-small cell lung cancer receiving sac-TMT or docetaxel. (Panel A) Progression-free survival assessed by blinded independent review committee; (panel B) progression-free survival assessed by investigator; (panel C) overall survival; and (panel D) overall survival using RPSFT model to adjust for crossover effects. BIRC=blinded independent review committee; CI=confidence interval; EGFR=epidermal growth factor receptor; NE=not evaluable; NR=not reached; RPSFT=rank-preserving structural failure time; sac-TMT=sacituzumab tirumotecan