ASCO: Kelun-Merck ADC shines with differentiated overall survival in first-line lung cancer

Kelun-Merck TROP2 ADC Shows Differentiated OS in First-Line Lung Cancer

Merck and Chinese partner Kelun-Biotech presented positive Phase 3 interim overall survival (OS) data for their TROP2-directed antibody-drug conjugate, sacituzumab tirumotecan (sac-TMT), at the ASCO annual meeting. The trial, conducted in Chinese patients with first-line non-small cell lung cancer (NSCLC), showed that sac-TMT combined with Merck’s Keytruda (pembrolizumab) achieved an 80.4% 12-month OS rate, significantly outperforming Keytruda monotherapy's 68.9%. This data supports Merck's strategy to bolster its portfolio ahead of Keytruda's loss of exclusivity and positions sac-TMT as a strong contender in the competitive first-line NSCLC market, potentially differentiating it from rivals like Gilead's Trodelvy and AstraZeneca/Daiichi Sankyo's Datroway.

• The Phase 3 trial demonstrated a significant overall survival benefit for sacituzumab tirumotecan (sac-TMT) combined with Keytruda in first-line non-small cell lung cancer (NSCLC) patients in China. The 12-month OS rate was 80.4% for the combination, compared to 68.9% for Keytruda monotherapy, indicating a clear advantage over single-agent checkpoint inhibitor therapy. This outcome is crucial for Merck's strategy to navigate Keytruda's impending loss of exclusivity and provides strong support for its TROP2 ADC program.
• Beyond overall survival, the trial also showed consistent and significantly improved progression-free survival (PFS). Sac-TMT cut the risk of tumor progression by 65%, with hazard ratios of 0.35 (blinded independent central review) and 0.38 (investigator-assessed PFS). This consistency across different assessment methods reinforces the agent's efficacy and potential differentiation in a competitive TROP2 ADC market, highlighting its robust clinical profile in this challenging indication.
• The positive data strategically positions sac-TMT as a strong contender in the first-line NSCLC setting, an indication currently being pursued by competitors like Gilead's Trodelvy and AstraZeneca/Daiichi Sankyo's Datroway. While Merck's global Phase 3 trial for this indication has an estimated primary completion of January 2028, analysts suggest sac-TMT's differentiated efficacy, particularly in OS and consistent PFS, could give it an edge despite potentially being third to market in the U.S.

Sac-TMT + Keytruda's Promising Survival in First-Line NSCLC

The PAPILLON study evaluated amivantamab-chemotherapy combination versus chemotherapy alone in 308 patients with EGFR exon 20 insertion-mutated NSCLC. The combination demonstrated superior efficacy with median time to treatment discontinuation of 13.2 versus 7.5 months (HR 0.38, 95% CI 0.28-0.51) and median time to subsequent therapy of 17.7 versus 9.9 months (HR 0.35, 95% CI 0.25-0.49). Crossover-adjusted overall survival analysis showed favorable benefit with hazard ratios of 0.52-0.60, more pronounced than the planned interim intention-to-treat analysis (HR 0.67, 95% CI 0.42-1.09).

The MARIPOSA study randomized 1,074 patients with previously untreated EGFR-mutated, locally advanced/metastatic NSCLC to receive amivantamab-lazertinib versus osimertinib versus lazertinib. Overall survival demonstrated superiority with HR 0.75 (P=0.005) versus osimertinib. In Asian participants specifically, median overall survival was not reached for amivantamab-lazertinib versus 38.4 months for osimertinib (HR 0.74, 95% CI 0.56-0.97), with projections suggesting a >12-month prolongation in median OS. At 36 months, 61% of patients in the amivantamab-lazertinib arm remained alive versus 53% in the osimertinib arm.

Recent meta-analyses have provided comprehensive insights into established therapies. Tislelizumab demonstrated event-free survival improvement (RR=1.40, 95% CI: 1.19-1.65) with disease progression or death risk reduced by 41% (HR=0.59, 95% CI: 0.52-0.67) and overall survival risk reduced by 35% (HR=0.65, 95% CI: 0.59-0.73). Crizotinib showed superior objective response rates versus chemotherapy (OR=6.86; 95% CI, 4.39-10.73) with 6-month and 12-month PFS rates significantly favoring crizotinib treatment. Safety profiles across studies were generally manageable, with tislelizumab showing more frequent elevated ALT/AST, hypothyroidism, and rash but fewer cases of anemia and neutropenia compared to chemotherapy.

Unpacking the Phase 3 Design for Sac-TMT in NSCLC

Recent phase 3 trials in NSCLC have evolved to incorporate biomarker-driven patient selection and novel combination strategies. The trial designs demonstrate increasing sophistication in endpoint selection, with progression-free survival and overall survival remaining primary endpoints, while incorporating quality of life metrics and real-world evidence studies to complement traditional efficacy measures.

Navigating the TROP2 ADC Landscape in First-Line NSCLC

Several checkpoint inhibitors sharing pembrolizumab's anti-PD-1/PD-L1 mechanism of action are being extensively evaluated across multiple cancer indications. While no information was available regarding other TROP2-targeting ADCs like sacituzumab tirumotecan, numerous PD-1/PD-L1 inhibitors show promise in various oncology settings.

• Anti-PD-1 antibodies including nivolumab, cemiplimab, and dostarlimab are being tested across multiple indications - nivolumab is approved for third-line gastric cancer treatment in Asian patients and shows efficacy in renal cell carcinoma when combined with ipilimumab, while dostarlimab received accelerated FDA approval for advanced/recurrent dMMR/MSI-H endometrial cancer

• Anti-PD-L1 agents such as atezolizumab, avelumab, and durvalumab demonstrate clinical activity across various tumor types - atezolizumab received FDA accelerated approval for locally advanced or metastatic urothelial carcinoma with a confirmed objective response rate of 23.5%, and shows superior efficacy when combined with bevacizumab plus chemotherapy in NSCLC

• Combination strategies are extensively explored, particularly in NSCLC where network meta-analyses of 16 studies involving 8,278 patients show pembrolizumab plus chemotherapy provides optimal overall survival benefit for patients without PD-L1 selection, while nivolumab plus ipilimumab plus chemotherapy demonstrates best outcomes in PD-L1 <1% patients

• Intervention models primarily consist of randomized controlled trials for late-phase studies, single-arm phase I/II trials for dose-finding and efficacy evaluation, and network meta-analyses comparing multiple immunotherapy combinations - specific examples include single-arm two-stage phase 2 trials for pembrolizumab combinations and parallel-group randomized trials for head-to-head comparisons with standard chemotherapy

A New Horizon for First-Line NSCLC with TROP2 ADC-ICI

The recent presentation of positive Phase 3 interim overall survival data for sacituzumab tirumotecan (sac-TMT) in combination with pembrolizumab in first-line non-small cell lung cancer (NSCLC) represents a significant stride in the treatment landscape. Achieving an 80.4% 12-month OS rate, a notable improvement over pembrolizumab monotherapy, underscores the potential of this TROP2-directed antibody-drug conjugate (ADC) to redefine initial therapy for a challenging disease. This outcome is particularly impactful given the high unmet need in NSCLC, especially for patients without specific actionable genomic alterations.

This success validates the strategic approach of combining ADCs with immune checkpoint inhibitors, a therapeutic avenue that research suggests can enhance immune responses and overcome tumor resistance. For companies like Merck, this development is crucial for future growth and portfolio diversification, providing a powerful new asset as key products approach patent expiration. The data positions sac-TMT to potentially carve out a leading role in the first-line NSCLC market, differentiating itself from other TROP2 ADCs that are also emerging in the oncology space.

However, the path forward is not without considerations. ADCs, while highly effective, are known to carry specific toxicities. Evidence from other ADCs highlights risks such as myelosuppression and, notably, interstitial lung disease (ILD) or pneumonitis, which can be severe. Careful patient selection and robust safety monitoring will be paramount. Furthermore, the TROP2 ADC landscape is becoming increasingly crowded, with several agents in development or already approved for various indications. While sac-TMT's combination with pembrolizumab in the first-line setting offers a unique differentiator, ongoing competitive pressures will demand continued demonstration of superior benefit-risk profiles across diverse patient populations. Future research will likely focus on refining patient selection through biomarker identification and optimizing combination strategies to maximize efficacy while minimizing adverse events, ensuring these innovative therapies reach the patients who can benefit most.