Merck ADC, licensed from China, hits mark in first big global trial

Merck's Sac-TMT Succeeds in Global Phase 3 Endometrial Cancer Trial

Merck & Co. announced positive results from a global Phase 3 trial of sacituzumab tirumotecan (Sac-TMT), an antibody-drug conjugate licensed from Kelun-Biotech, for endometrial cancer. The trial demonstrated statistically significant and clinically meaningful improvements in overall survival and progression-free survival compared to chemotherapy. This success marks a crucial step in Merck's strategy to diversify its revenue streams and achieve $70 billion in annual sales next decade, as its blockbuster immunotherapy Keytruda approaches patent expiry. Sac-TMT targets TROP2-expressing tumors and is being evaluated across 17 different cancer types.

• The global Phase 3 trial for Sac-TMT in endometrial cancer met its primary endpoints, showing statistically significant and clinically meaningful improvements in both overall survival and progression-free survival. Patients treated with Sac-TMT experienced delayed disease progression and extended lives compared to those receiving one of two common chemotherapies. The drug also demonstrated better remission rates, and its safety profile was consistent with prior observations, reinforcing its potential as a new treatment option for patients whose cancer had advanced despite previous platinum-based chemotherapy and immunotherapies.
• Sac-TMT is a cornerstone of Merck's long-term strategy to maintain revenue growth and achieve its ambitious goal of $70 billion in annual sales by the next decade, particularly as its top-selling cancer immunotherapy, Keytruda, faces patent expiration. The company aims to position Sac-TMT as a differentiated therapy in the competitive ADC landscape, distinguishing it from similar drugs like Gilead Sciences’ Trodelvy and AstraZeneca/Daiichi Sankyo’s Datroway, which are approved for certain breast and lung cancers. This trial success is vital for Merck's post-Keytruda portfolio.
• The positive endometrial cancer results are the first from a comprehensive development program evaluating Sac-TMT across 17 different tumor types, including breast and lung cancers. Earlier positive results from a lung cancer trial conducted by Kelun in China are slated for presentation at the upcoming American Society of Clinical Oncology (ASCO) meeting, and Kelun has already sought approval in China for non-small cell lung cancer. Analysts project significant market potential for Sac-TMT, with sales estimated to reach $2.6 billion by 2030 and $7.2 billion by 2034, underscoring its importance to Merck's future.

Sac-TMT's Landmark Phase 3 Success in Endometrial Cancer

Recent clinical trials demonstrate significant advances in endometrial cancer treatment, particularly with immunotherapy combinations and targeted therapies. These studies span from Phase 2 investigations of novel agents to landmark Phase 3 trials that have reshaped treatment standards. The data reveal differential efficacy based on molecular characteristics, particularly mismatch repair status.

• ASCENT-GYN-01 (GOG-3104/ENGOT-en26/APGOT-EN2) - Sacituzumab govitecan versus physician's choice chemotherapy in 640 patients with recurrent endometrial cancer after platinum and PD-(L)1 inhibitor therapy. Dual primary endpoints of progression-free survival and overall survival with estimated completion June 2029.

• KEYNOTE-775 5-year follow-up - Lenvatinib plus pembrolizumab versus chemotherapy in 827 patients with progressive disease after platinum-based therapy. Five-year overall survival rates of 16.7% versus 7.3% in mismatch repair-proficient disease and 36.5% versus 9.8% in mismatch repair-deficient disease. Treatment-related adverse events led to discontinuation in 32.3% versus 5.9%.

• RUBY Trial - Dostarlimab combined with chemotherapy in advanced endometrial cancer demonstrated substantial improvements in progression-free survival and overall survival when added to chemotherapy for stage III/IV dMMR patients, with updated analyses solidifying first-line immuno-chemotherapy role.

• NRG-GY018 Trial - Immune checkpoint inhibitors combined with chemotherapy showed substantial improvements in both progression-free survival and overall survival for stage III/IV dMMR endometrial cancer patients, with differential benefits according to mismatch repair status.

• Neoadjuvant Pembrolizumab Study - Pembrolizumab 100mg with low-dose paclitaxel and carboplatin in 8 patients with advanced disease achieved complete radiologic responses in 4 patients and pathological complete responses in 4 patients across diverse histologic subtypes, with no grade ≥3 adverse events.

• Real-world Lenvatinib plus Pembrolizumab Study - In 26 patients with recurrent disease, overall response rates were 33.3% in nonendometrioid versus 22.2% in endometrioid carcinoma, with median progression-free survival of 6.2 versus 11.5 months respectively. Most frequent adverse events were hypertension (92.3%) and hypothyroidism (65.4%).

Sac-TMT's Efficacy Against Standard of Care in Endometrial Cancer

Recent evidence demonstrates that immunotherapy combinations, particularly pembrolizumab with lenvatinib, have emerged as the new therapeutic standard in advanced endometrial cancer. Meta-analyses of 2,742 patients across eight studies show pembrolizumab significantly reduces progression risk (HR: 0.53; 95% CI: 0.44, 0.63; p < 0.00001), while the combination with lenvatinib reduces mortality risk (HR: 0.67; 95% CI: 0.59, 0.76; p < 0.00001). These regimens achieve superior objective response rates (OR: 3.61; 95% CI: 2.12, 6.13; p < 0.00001) and complete remission rates (OR: 2.7; 95% CI: 1.59, 4.57; p < 0.05) compared to standard chemotherapy controls. Current treatment selection is guided by clinical presentation, molecular status (particularly mismatch repair deficiency), disease aggressivity, and patient comorbidities.

Real-world data from 45 patients treated with lenvatinib plus pembrolizumab shows median progression-free survival of 8.5 months and overall survival of 15.6 months, though efficacy appears diminished in patients with performance status 1-2 or those ineligible for clinical trials. The safety profile reveals grade ≥3 adverse events in 78% of patients, necessitating lenvatinib dose reductions in 78% of cases, with median time to first reduction of 1.5 months. Novel PARP inhibitor rucaparib demonstrates promising efficacy in a phase II trial, achieving median PFS of 28.1 months versus 8.7 months with placebo (HR 0.45; 95% CI 0.24-0.87), particularly in patients with p53 activity loss.

Traditional adjuvant approaches remain relevant for specific patient populations, with post-surgical observation recommended for low-risk disease and vaginal brachytherapy for intermediate-risk cases. Network meta-analyses of progestin-based regimens identify mTOR inhibitor combinations and dual progestin regimens as effective options for hormone receptor-positive disease, with LNG-IUS-based dual therapy showing superior complete response rates (SUCRA=98.7%) and objective response rates (SUCRA=99.1%). However, PARP inhibitors are not currently recommended for maintenance therapy, and clinical trial enrollment should be prioritized when feasible, with selection guided by HER2 status and next-generation sequencing results.

Merck's Strategic Vision: Sac-TMT Beyond Endometrial Cancer

Sacituzumab tirumotecan is being evaluated across multiple tumor types beyond endometrial cancer, with the most advanced data emerging from breast, lung, and urothelial cancers. The intervention models vary from single-arm monotherapy studies to randomized controlled trials comparing against standard-of-care chemotherapy regimens.

Merck's TROP2 ADC: A New Growth Engine for Oncology

Merck's recent announcement of positive Phase 3 results for sacituzumab tirumotecan (Sac-TMT) in endometrial cancer marks a pivotal moment, not only for patients battling this challenging malignancy but also for the pharmaceutical giant's strategic future. This TROP2-targeted antibody-drug conjugate (ADC) demonstrated statistically significant and clinically meaningful improvements in overall survival and progression-free survival, offering a much-needed new therapeutic option where systemic treatments are often limited. The success of Sac-TMT reinforces the growing prominence of ADCs as a powerful modality in oncology, building on the established efficacy of other TROP2 ADCs like sacituzumab govitecan in metastatic triple-negative breast cancer and datopotamab deruxtecan in HR-positive, HER2-negative breast cancer.

For Merck, this achievement is a critical step in its ambitious strategy to diversify revenue streams as its blockbuster immunotherapy approaches patent expiry. A successful TROP2 ADC, with its broad potential across 17 different cancer types currently under evaluation, could become a significant new pillar for growth. However, the path forward is not without its challenges. The competitive landscape for TROP2 ADCs is rapidly intensifying, necessitating clear differentiation for Sac-TMT. Furthermore, while Sac-TMT has shown a manageable safety profile in other indications, the overall toxicity profile, including common adverse events like hematologic issues, diarrhea, and nausea, will require careful management in clinical practice. The inherent heterogeneity of TROP2 expression in tumors also presents a consideration, as TROP2 is not yet a predictive biomarker for ADC response, which could impact patient selection and overall efficacy in certain populations. This positive data, nonetheless, underscores the continued evolution of targeted therapies and the potential for ADCs to redefine treatment paradigms across a spectrum of solid tumors.