Phase 3 data for Merck & Co. and Kelun-Biotech’s antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) suggest the race is heating up to establish a new standard of care in first-line non-small cell lung cancer.
According to an abstract released ahead of the ASCO 2026 annual meeting, combining the TROP2-directed ADC with Keytruda slashed the risk of disease progression or death by a major 65% compared with Keytruda alone in treatment-naïve, PD-L1-positive NSCLC. The p-value is below 0.0001, suggesting high statistical significance.
Key overall survival results, which will underpin regulatory considerations in first-line NSCLC, were not mature at the Sept. 29, 2025, data cutoff, but a strong trend with a preliminary 45% improvement in favor of the combo arm was observed.
The strong progression-free survival (PFS) readout from a planned interim analysis of the OptiTROP-Lung05 study in China marks the first randomized phase 3 win for an ADC-Keytruda combo in this lucrative frontline NSCLC setting, escalating a potential showdown with another up-and-coming drug class, PD-(L)1xVEGF bispecific antibodies.
In the study, median PFS was not reached in the combination arm after a median follow-up of 10.5 months, versus 5.7 months for patients receiving Keytruda alone. The final PFS analysis is expected in the second half of this year, as the study’s estimated primary completion date is marked for November, according to ClinicalTrials.gov.
The OptiTROP-Lung05 results draw comparison to the landmark Harmoni-2 study of Akeso and Summit Therapeutics’ PD-1xVEGF bispecific ivonescimab. In the same first-line, PD-L1-positive NSCLC setting in Chinese patients, ivonescimab alone improved PFS by 49% versus Keytruda.
After a median follow-up of 8.7 months, the median PFS for ivonescimab landed at 11.1 months, versus 5.8 months for Keytruda alone in Harmoni-2. Similar Keytruda performance across the two trials—but a bigger PFS effect size and a longer follow-up for OptiTROP-Lung05—suggests sac-TMT/Keytruda’s median PFS will likely be longer.
In approving ivonescimab in first-line, PD-L1-positive NSCLC in April 2025, Chinese regulators requested an unplanned OS analysis of Harmoni-2. At the time, the PD-1xVEGF inhibitor showed an immature 22.3% death risk reduction versus Keytruda, disappointing investors.
The side-to-side comparison may not be fair for ivonescimab, given that it didn’t have a combination partner. Leerink Partners analysts, while acknowledging that single-agent ivonescimab represents a low bar to beat, argued that the comparison is still “valid when considering the intended commercial market,” according to a May 21 note.
Akeso does have data for ivonescimab plus chemo from the Harmoni-6 trial in first-line NSCLC. However, a direct comparison with sac-TMT here is challenging given that the ivonescimab trial was in squamous NSCLC without PD-L1 restrictions and its comparator was PD-1-plus-chemo rather than PD-1 monotherapy.
Sac-TMT’s treatment effect appears consistent in subgroups by PD-L1 expression and histology. The combo’s PFS improvement was 72% versus Keytruda in PD-L1-low patients with a tumor proportion score (TPS) of below 50% and 53% in the PD-L1-high group. The numbers were 72% for nonsquamous tumors and 56% for squamous.
In Harmoni-2, ivonescimab’s results were 46% in PD-L1-low, 52% for PD-L1-high, 45% among nonsquamous patients and 50% for squamous.
In Harmoni-6, ivonescimab and chemo led to a 40% improvement in PFS over Tevimbra and chemo in PD-L1-positive squamous NSCLC. Akeso will share OS data from Harmoni-6 during the plenary session of ASCO 2026.
Trial-wide overall response rate (ORR) reached 70.2% for the sac-TMT/Keytruda combo versus 42% for Keytruda alone. In their Thursday note, Leerink analysts said that an ORR of above 65% and a median PFS of roughly 14 months would be able to impress investors.
The Merck/Kelun regimen’s data also look competitive compared with AstraZeneca and Daiichi Sankyo’s rival TROP2 ADC, Datroway (Dato-DXd). But again, different trial populations complicate any direct cross-trial comparisons.
In the phase 1 Tropion-Lung02 study, Datroway plus Keytruda triggered an ORR of 54.8% and a median PFS of 11.2 months in 42 first-line NSCLC patients regardless of PD-L1 expression. PD-L1 subgroup data were only broken down by expression levels below or above 50%.
On the safety side, sac-TMT and Keytruda showed what OptiTROP-Lung05 investigators called a “generally manageable” profile. Grade 3 or above treatment-emergent adverse events (TEAEs) were 55.3% in the combo arm and 31.4% in the Keytruda monotherapy group, according to the abstract.
TEAEs led to discontinuation of sac-TMT in 3.8% of treated patients. The discontinuation rate for Keytruda was 5.3% for the combo and 4.9% for the control.
Full details from OptiTROP-Lung05 will be presented at ASCO 2026 by Caicun Zhou, M.D., Ph.D., from Tongji University. He was also the principal investigator of ivonescimab’s Harmoni-2 and serves as the president of the International Association for the Study of Lung Cancer.
The Leerink team argued that full data are required to properly assess OptiTROP-Lung05’s position in the first-line NSCLC market.
“In replacing an immuno-oncology (IO) standard, we believe duration of treatment and response and overall survival (OS) are more important outcomes,” the analysts noted.
Based on the OptiTROP-Lung05 data, Chinese regulators are reviewing Kelun’s application in first-line NSCLC.
Globally, Merck has made a deep commitment to sac-TMT, as manifested in its 17 global phase 3 trials and a Commissioner’s National Priority Voucher from the FDA to expedite its future regulatory review.
The first global trial from that program just read out positive. The TroFuse-005 study met both PFS and OS at an interim analysis, as sac-TMT beat chemo in previously treated endometrial cancer.
Merck doesn’t have an exact global replica of the China-only OptiTROP-Lung05 trial. The New Jersey pharma’s TroFuse-007 study is evaluating sac-TMT and Keytruda against Keytruda alone only in PD-L1-high patients with previously untreated NSCLC.