Sacituzumab Tirumotecan Improves Response vs Docetaxel in EFGR+ NSCLC

At the data cutoff date of December 31, 2024, the confirmed objective response rate assessed by blinded independent review committee was 45.1% vs 15.6% with sac-TMT and docetaxel, respectively.

Sacituzumab tirumotecan (sac-TMT; formerly SKB264/MK-2870) significantly improved response and survival rates compared with docetaxel in patients with locally advanced or metastatic EGFR-mutant nonsquamous non–small cell lung cancer (NSCLC) who experienced progression following combination or sequential treatment with EGFR-tyrosine kinase inhibition and platinum-based chemotherapy according to phase 2 OptiTROP-Lung03 trial (NCT05631262) results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

At the data cutoff date of December 31, 2024, the confirmed objective response rate (cORR) assessed by blinded independent review committee (BIRC) was 45.1% (95% CI, 34.6%-55.8%) vs 15.6% (95% CI, 6.5%-29.5%) with sac-TMT (n = 91) and docetaxel (n = 45), respectively, establishing a statistically significant difference of 28.9% (95% CI, 14.5%-43.2%; 1-sided P = .0004).

Responses with sac-TMT were observed regardless of TROP2 expression. Specifically in patients with TROP2-high disease, the cORR was 56.5% (95% CI, 41.1%-71.1%) vs 22.2% (95% CI, 6.4%-47.6%), demonstrating a 34.3% difference (95% CI, 10.3%-58.3%). In those with TRO2- low/medium disease, the cORR of 36.7% (95% CI, 19.9%-56.1%) vs 13.3% (95% CI, 1.7%-40.5%), with a difference of 23.3% (95% CI, –1.0% to 47.7%).

“Sac-TMT demonstrates statistically significant and clinically meaningful improvements in ORR, progression-free survival, and overall survival compared with docetaxel,” lead study author Li Zhang, professor in the Medical Oncology Department and deputy director of the Lung Cancer Research Center at Sun Yat-sen University in Guangzhou, China, said in a presentation at the meeting.

Diving into the Background and OptiTROP-Lung03 Study Design

In December 2024, the FDA granted a breakthrough therapy designation to sac-TMT as a potential option for the treatment of patients with advanced or metastatic nonsquamous NSCLC harboring EGFR mutations who experienced disease progression on or after a TKI and platinum-based chemotherapy.² Furthermore, the TROP2-directed ADC was approved by China’s National Medicinal Products Administration in March 2025 for the treatment of patients with EGFR-mutant locally advanced or metastatic nonsquamous NSCLC after disease progression on an EGFR TKI and platinum-based chemotherapy, based on the OptiTROP-Lung03 data.³

The open-label, randomized, multicenter OptiTROP-Lung03 study evaluated sac-TMT in patients with stage IIIB/IIIC nonsquamous NSCLC who are ineligible to receive surgery or radical radiotherapy for stage IV disease.¹ Patients also had to have EGFR-sensitizing mutations, including exon 19 deletions and L858R mutations, as well as disease progression after prior combination or sequential treatment with EGFR TKIs and platinum-based chemotherapy. An ECOG performance status of 0 or 1 was required. The presence of brain metastases was a stratification factor.

Following screening, patients were randomly assigned 2:1 (n = 137) to receive either intravenous (IV) sac-TMT at 5 mg/kg once every 2 weeks (n = 91) or IV docetaxel at 75 mg/m² once every 3 weeks (n = 46) until disease progression, intolerable toxicity, or other reasons to discontinue treatment. Those who had disease progression verified by BIRC were permitted to cross over to the sac-TMT arm. Of note, tumor assessments were performed every 6 weeks within 48 weeks following randomization, and after 48 weeks of randomization, tumor assessments were performed every 12 weeks.

The primary end point was BIRC-assessed ORR. Secondary end points included progression-survival, OS, investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), time to response (TTR), and safety.

Baseline Patient Characteristics

The median age was 57.0 years (range, 37-75) and 55.0 years (range, 34-74) in the sac-TMT and docetaxel arms, respectively, of which 20.9% and 17.4% of patients were aged 65 years or older, and 41.8% and 47.8% were male. Additionally, 100% of patients from both arms had adenocarcinoma. Clinical stage at enrollment was broken down by IIIB (2.2% each arm) and IV (97.8% each arm). Metastasis sites included brain (19.8% sac-TMT; 21.7% docetaxel) and liver (19.8%; 15.2%). Most patients had an ECOG performance status of 1 (83.5%; 80.4%).

Furthermore, EGFR mutation types included exon 19 deletions (47.3%; 69.6%) and L858R (52.7%; 30.4%).

T790M gene statuses included positive (20.9%; 21.7%), negative (35.2%; 28.3%), and unknown (44.0%; 50.0%). Patients previously received 1 (9.9%; 10.9%), 2 (57.1%; 43.5%), or more than 2 lines of treatment (33.0%; 45.7%), including an EGFR TKI. Prior EGFR TKIs included first-line third-generation EGFR TKI (59.3%; 56.5%), second-line third-generation EGFR TKI (33.0%; 39.1%), and no EGFR TKI (7.7%; 4.3%). A total 65.9% and 71.7% of patients from the respective arms received prior antiangiogenetic therapy; prior immunotherapy was received by 16.5% and 13.0% of patients.

Additional Efficacy Data With sac-TMT

The DCR was 82.4% (95% CI, 73.0%-89.6%) compared with 60.0% (95% CI, 44.3%-74.3%) in the sac-TMT and docetaxel arms, respectively, with a difference of 22.3% (95% CI, 6.0%-38.7%). Moreover, the DOR was 63.4% vs 85.7% in the respective arms, with a median DOR of 7.0 months (95% CI, 5.4-9.1) vs 5.1 months (95% CI, 3.1-not estimable [NE]).

The median PFS via BIRC was 6.9 months (95% CI, 5.4-8.2) with sac-TMT vs 2.8 months (95% CI, 1.6-4.1) with docetaxel (HR, 0.30; 95% CI, 0.20-0.46; P < .0001); the 6-month PFS rates were 54.2% vs 14.6%, respectively. The investigator-assessed median PFS was 7.9 months (95% CI, 6.2-9.5) with sac-TMT vs 2.8 months (95% CI, 1.5-3.8) with docetaxel (HR, 0.23; 95% CI, 0.15-0.36; P < .0001); the 6-month PFS rates were 63.0% vs 10.9%, respectively. The PFS benefit with sac-TMT was observed across all clinical and molecular subgroups.

At the prespecificed interim analysis, with a median follow-up of 12.2 months, the median OS was not reached (NR; 95% CI, NE-NE) vs NR (95% CI, 8.0-NE) in either arm, and the 12-month OS rate was 72.8% with sac-TMT vs 54.3% with docetaxel (HR, 0.49; 95% CI, 0.27-0.88; P = .0070).

Among 44 patients who discontinued docetaxel, 36.4% crossed over to the sac-TMT arm. When adjusted for crossover, the median OS was NR (95% CI, NE-NE) with sac-TMT vs 9.3 months (95% CI, 7.3-NE) with docetaxel, and the 12-month OS rate was 72.8% vs 43.2% (HR, 0.36; 95% CI, 0.20-0.66).

Safety Spotlight

In the sac-TMT arm, 68 patients discontinued treatment due to radiographic disease progression (n = 52), patient request (n = 10), adverse effects (AEs; n = 2), death (n = 1), and clinical progression (n = 3). Those in the docetaxel arm discontinued treatment due to radiographic disease progression (n = 40), patient request (n = 1), AEs (n = 1), and clinical progression (n = 2).

The median duration of exposure was 5.0 months (range, 0.5-9.2) and 2.8 months (range, 0.7-6.1) in the sac-TMT and docetaxel arms, respectively. Treatment-related AEs (TRAEs) occurred in 97.8% of patients in both arms; grade 3 or higher TRAEs were reported in 56.0% vs 71.7% of patients, with serious TRAEs occurring in 16.5% vs 41.3%.

TRAEs leading to dose reductions and dose interruptions occurred in 31.9% vs 43.5% and 35.2% vs 28.3% of patients, respectively. TRAEs leading to treatment discontinuation occurred in 2.2% of patients on docetaxel; no TRAEs leading to death were reported.

The most common TRAEs in the sac-TMT and docetaxel arms, respectively, included anemia (any grade, 77% vs 12%; grade ≥3, 67% vs 4%), decreased white blood cell count (68% vs 25%; 63% vs 52%), decreased neutrophil count (66% vs 43%; 59% vs 0%), stomatitis (62% vs 16%; 7% vs 2%), alopecia (47% vs 0%; 50% vs 0%), decreased platelet count (35% vs 5%; 20% vs 0%), asthenia (26% vs 0%; 30% vs 4%), decreased weight (21% vs 1%; 2% vs 0%), nausea (19% vs 0%; 28% vs 0%), decreased lymphocyte count (19% vs 7%; 22% vs 9%), hypoalbuminemia (14% vs 0%; 22% vs 0%), hypokalemia (9% vs 3%; 0%), pneumonia (grade ≥3, 1%; 7% vs 4%), and febrile neutropenia (0%; grade ≥3, 20%).

“Sac-TMT showed a manageable safety profile, with no unexpected safety signals identified,” Zhang concluded.

References

1. Zhang L, Fang W, Li XY, et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): results from the randomized OptiTROP-Lung03 study. J Clin Oncol. 2025;43(suppl 16):8507. doi: 10.1200/JCO.2025.43.16_suppl.850
2. 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 June 1, 2025. 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/
3. Kelun-Biotech’s TROP2 ADC sacituzumab tirumotecan (sac-TMT) approved for marketing in second indication by NMPA for EGFRm NSCLC. News release. Kelun-Biotech. March 10, 2025. Accessed June 1, 2025. https://www.prnewswire.com/news-releases/kelun-biotechs-trop2-adc-sacituzumab-tirumotecan-sac-tmt-approved-for-marketing-in-second-indication-by-nmpa-for-egfrm-nsclc-302396917.html