Novel ADC Shows Significant Survival Benefit in Pretreated EGFR-Mutated NSCLC

The novel antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) continues to show significant survival benefit for patients with previously treated advanced EGFR-mutated non-small cell lung cancer compared with docetaxel, according to final overall survival analysis from the OptiTROP-Lung03 trial. After a median follow-up of 23.8 months, the median overall survival was 20.0 months for patients assigned to receive sac-TMT compared with 13.5 months for patients assigned to docetaxel, translating into a hazard ratio for death of 0.63.

The difference in survival outcomes occurred despite the fact that 41% of patients assigned to the control group were crossed over to receive sac-TMT after disease progression on docetaxel. An analysis of overall survival adjusted for crossover of patients previously on docetaxel showed a median overall survival of 20.0 months versus 11.2 months, translating into a hazard ratio for death of 0.45.

The trial met its primary endpoint of objective response rate, with the ORR assessed by independent review significantly higher in the sac-TMT group at 45% versus 16% for docetaxel. After a median follow-up of 23.8 months, the median progression-free survival was 7.9 months in the ADC group compared with 2.8 months in the chemotherapy group, translating into a hazard ratio for progression or death of 0.23. The respective one-year progression-free survival rates were 30.2% and 2.2%.

Although the median duration of exposure was more than twofold higher in the sac-TMT group (7.1 vs. 2.8 months), the incidences of grade 3 or greater serious or treatment-related adverse events were markedly lower for patients treated with the ADC. The most common treatment-related adverse events in each group were hematologic toxicities. No cases of febrile neutropenia were reported in the ADC group compared with 19.6% of patients in the chemotherapy group. Interstitial lung disease/pneumonitis occurred in 2.2% of patients in each group.

The final overall survival results from OptiTROP-Lung03 trial are similar to the interim overall survival results from the OptiTROP-Lung04 study, in which sac-TMT was compared with platinum-based chemotherapy for patients with EGFR-mutated advanced NSCLC resistant to EGFR-directed tyrosine kinase inhibitors. In Lung04, the ADC was associated with a hazard ratio for death versus chemotherapy of 0.60. The 18-month overall survival rates were 65.8% with sac-TMT versus 48.0% with chemotherapy. That trial served as the basis for approval in China of sac-TMT for EGFR-mutated NSCLC.

Sac-TMT targets the trophoblast cell-surface antigen 2, which is highly expressed in EGFR-mutated NSCLC and is associated with resistance to EGFR-targeted TKIs. The ADC comprises the antibody conjugated via a bifunctional linker to a belotecan-derived topoisomerase 1 inhibitor as the toxic payload.

OptiTROP-Lung03 enrolled 137 patients with EGFR-mutated nonsquamous stage IV or stage IIIB–IIIC NSCLC who were ineligible for surgery or radical radiotherapy who had experienced disease progression after prior combination or sequential therapy with EGFR TKIs and platinum chemotherapy. After stratification by presence or absence of brain metastases, the patients were randomly assigned on a 2:1 basis to receive either sac-TMT (5 mg/kg intravenously every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Treatment continued until disease progression, intolerable toxicity, or another reason for discontinuation.