At ASCO, Merck makes case for a ‘cornerstone’ cancer drug

Merck Presents Strong Phase 3 Data for Sac-TMT in Lung Cancer at ASCO

Merck presented promising Phase 3 data for its antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) in combination with Keytruda for lung cancer at the American Society of Clinical Oncology (ASCO) conference. The trial, conducted in China, showed the combination reduced the risk of disease progression or death by 65% compared to Keytruda alone after a median follow-up of 10.5 months. Median progression-free survival (PFS) was not reached for the sac-TMT arm, while the Keytruda-only group had a median PFS of 5.7 months. The positive results, observed across major subgroups, have bolstered Merck's confidence in sac-TMT as a potential "cornerstone" cancer drug, leading to a 5% rise in Merck's shares.

• Detailed data presented at ASCO revealed that the benefits of sac-TMT plus Keytruda were consistent across major subgroups of lung cancer patients, including those with squamous and non-squamous disease, and varying levels of PD-L1 expression. This broad efficacy profile suggests the combination's potential applicability to a diverse patient population, reinforcing Merck's conviction in its global development program, which includes 17 studies in various tumor types.
• The safety profile of sac-TMT was perceived by analysts as cleaner than anticipated, contributing significantly to investor optimism. Following the abstract release and detailed presentation, Merck's shares climbed over 5%, reflecting the market's positive outlook on the therapy's potential to become a significant asset as the company prepares for the eventual patent expiration of its blockbuster drug, Keytruda.
• Despite the positive data, sac-TMT faces a competitive landscape with other TROP2-targeting ADCs like AstraZeneca/Daiichi Sankyo’s Datroway and Gilead’s Trodelvy, as well as emerging PD-1/VEGF inhibitors. Challenges remain, including the need for global trial results and comparisons against standard-of-care Keytruda-chemotherapy combinations, which were not used as a control in the reported Chinese study. Merck, however, expresses confidence in sac-TMT's unique linker technology and consistent benefits observed.

Sac-TMT + Keytruda's Efficacy in Lung Cancer at ASCO

Recent clinical trials have demonstrated significant advances in lung cancer treatment across multiple therapeutic modalities. Key studies from 2025-2026 provide important insights into both targeted therapies and immunotherapy approaches, with several trials showing improved survival outcomes while others highlight the need for careful patient selection.

• KRYSTAL-12 Trial evaluated adagrasib versus docetaxel in 453 patients with KRAS-mutated NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/PD-L1 therapy. The study demonstrated significantly improved median PFS (5.5 vs 3.8 months; HR 0.58, 95% CI 0.45-0.76, p<0.0001), with grade ≥3 treatment-related adverse events occurring in 47% of adagrasib patients versus 46% receiving docetaxel.

• ALEX Trial Final Analysis compared alectinib to crizotinib in 303 treatment-naïve ALK-positive NSCLC patients, showing remarkable median OS benefit (81.1 vs 54.2 months; HR 0.78, 95% CI 0.56-1.08). Particularly notable were outcomes in CNS metastases patients (63.4 vs 30.9 months) and median duration of response (42.3 vs 11.1 months; HR 0.41, 95% CI 0.30-0.56).

• Antibody-Drug Conjugates Meta-Analysis of 13 studies involving 1,681 patients with advanced/metastatic NSCLC revealed pooled ORR of 30%, median PFS of 4.62 months, and median OS of 11.82 months. However, treatment-related adverse events occurred in 95% of patients with 44% experiencing grade ≥3 events, questioning clear superiority over standard chemotherapy.

• PD-1/PD-L1 Inhibitors in Elderly Patients meta-analysis across 12 RCTs with 3,078 patients demonstrated significant OS improvement (HR 0.76, 95% CI 0.69-0.84, p<0.001) and event-free survival benefit (HR 0.67, 95% CI 0.54-0.83, p<0.001), establishing efficacy in this vulnerable population.

• SAFFRON-301 Trial testing sitravatinib plus tislelizumab versus docetaxel in 377 patients was terminated early due to unfavorable risk-benefit assessment, with similar median OS (11.5 vs 11.4 months) but concerning safety signals including grade 5 hemoptysis in 1.6% of combination therapy patients.

Navigating the Crowded TROP2 ADC Landscape in Lung Cancer

Several TROP2-targeted ADCs and anti-PD-1 immune checkpoint inhibitors are being evaluated in similar combination strategies across multiple cancer types. The most notable example is enfortumab vedotin plus pembrolizumab, which achieved the first FDA approval for an ADC-ICI combination in locally advanced or metastatic urothelial carcinoma.

Unpacking the Sac-TMT Lung Cancer Trial Design and Implications

Recent lung cancer trials have employed diverse methodological approaches spanning systematic reviews, retrospective analyses, and prospective randomized controlled trials. Large-scale meta-analyses have become increasingly prevalent, with studies incorporating between 9-14 trials and encompassing 2,441-2,874 participants to evaluate targeted therapies and immunotherapies. Network meta-analyses utilizing Bayesian approaches have emerged as sophisticated tools for comparing multiple treatment modalities simultaneously, particularly in ALK-positive NSCLC where seven first-line treatments including ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy have been evaluated. Real-world evidence studies have gained prominence, with retrospective multicenter analyses examining patient cohorts ranging from 46 patients in Vietnamese hospitals to 355 patients in comparative effectiveness research studies spanning multiple years of follow-up.

Trial endpoints have demonstrated remarkable consistency across studies, with progression-free survival (PFS) and overall survival (OS) serving as primary efficacy measures in virtually all therapeutic areas. Objective response rate (ORR) assessed by RECIST criteria represents the third cornerstone endpoint, particularly emphasized in early-phase trials where regulatory approvals increasingly rely on single-arm phase II designs. Safety endpoints encompass comprehensive adverse event monitoring, with studies specifically tracking anemia, fatigue, elevated liver enzymes, and organ-specific toxicities including cardiac, spinal cord, and esophageal dosimetry in radiation-based interventions. Secondary endpoints have expanded to include health-related quality of life (HRQoL), one-year survival rates, central nervous system progression, and disease-free survival in adjuvant settings.

Contemporary trial designs reflect the molecular complexity of lung cancer, with patient stratification based on specific biomarkers including ALK rearrangements, KRAS mutations (particularly G12C), HER2 mutations, and PD-L1 expression levels. Real-world studies have incorporated novel prognostic markers such as neutrophil-to-lymphocyte ratios and eosinophil counts as stratification variables. Treatment protocols have evolved from single-agent approaches to combination strategies, exemplified by pembrolizumab plus platinum-based doublet chemotherapy regimens and bevacizumab combined with chemoradiotherapy. The integration of external comparator arms and matching-adjusted indirect comparisons has enabled single-arm trials to connect with broader evidence networks, facilitating regulatory pathways while maintaining scientific rigor in efficacy assessment.

Merck's Sac-TMT: A New Cornerstone in Lung Cancer

The recent Phase 3 data for sacituzumab tirumotecan (sac-TMT) in combination with Keytruda for lung cancer marks a pivotal moment in oncology, underscoring the evolving landscape of advanced non-small cell lung cancer (NSCLC) treatment. The impressive 65% reduction in the risk of disease progression or death, alongside an unreached median progression-free survival compared to Keytruda alone, signals a significant therapeutic advance. This outcome reinforces the growing understanding of how antibody-drug conjugates (ADCs), particularly those targeting TROP2 like sac-TMT, can synergize with immune checkpoint inhibitors (ICIs).

ADCs deliver highly potent cytotoxic payloads directly to tumor cells expressing specific targets, minimizing systemic toxicity. TROP2, a cell-surface antigen, is overexpressed in various solid tumors, including NSCLC, making it an attractive target. The literature suggests that some ADCs can induce immunogenic cell death and remodel the tumor microenvironment, potentially enhancing the efficacy of co-administered ICIs. This combination strategy, therefore, represents a sophisticated approach to cancer therapy, leveraging both targeted cytotoxicity and immune activation.

For Merck, these results are strategically vital. While Keytruda remains a dominant force, the addition of sac-TMT provides a powerful new asset, potentially establishing a new 'cornerstone' therapy that diversifies its oncology portfolio and extends its reach into new patient segments within the vast lung cancer market. This success could also catalyze further investment and research into ADC-ICI combinations across the industry, validating a promising new paradigm for drug development.

However, the path forward is not without considerations. ADCs, including TROP2-targeted agents, are associated with distinct adverse events such as myelosuppression (e.g., neutropenia), gastrointestinal toxicities (e.g., diarrhea, nausea), and potentially interstitial lung disease. Careful patient monitoring and proactive management of these toxicities will be crucial for optimal patient outcomes and broader adoption. Furthermore, the competitive landscape for TROP2-targeted ADCs is intensifying, with other agents already approved or in advanced development. Sac-TMT will need to demonstrate sustained differentiation and a favorable benefit-risk profile to carve out a significant market share. The trial's conduct in China also means that generalizability to diverse global populations will require further validation.