Phase 3 data for Merck & Co. and Cologne Biotech’s antibody-drug conjugate sacituzumab tilmothecan (sac-TMT) suggest an intensifying race to establish a new standard of care in first-line non-small cell lung cancer.
In previously untreated PD-L1-positive NSCLC, the combination of TROP2-directed ADC and Keytruda significantly reduced the risk of disease progression or death by 65% compared with Keytruda alone, according to an abstract presented in advance of the ASCO 2026 Annual Meeting. The p-value was less than 0.0001, suggesting high statistical significance.
Although the important overall survival results underlying regulatory considerations in first-line NSCLC were not yet mature at the data cutoff of September 29, 2025, a strong preliminary trend of 45% improvement favoring combination therapy was observed.
Strong progression-free survival (PFS) results from the interim analysis of the planned OptiTROP-Lung05 trial in China mark the first randomized phase 3 victory for the combination of ADC and Keytruda in this favorable frontline NSCLC setting, escalating a potential showdown with another up-and-coming drug class, PD-(L)1xVEGF bispecific antibodies.
In this study, after a median follow-up of 10.5 months for patients receiving Keytruda alone, the median PFS was not reached for the combination therapy group, compared to 5.7 months. The study’s primary completion date is set for November, so the final PFS analysis is expected to occur in the second half of this year, according to ClinicalTrials.gov.
OptiTROP-Lung05 results demonstrate comparison with Akeso and Summit Therapeutics’ landmark Harmoni-2 study of PD-1xVEGF bispecific ivonescimab. Ivonecicimab alone improved PFS by 49% compared to Keytruda in the same first-line PD-L1-positive NSCLC setting in Chinese patients.
After a median follow-up of 8.7 months, the median PFS for Keytruda monotherapy in Harmoni-2 was 5.8 months, compared with 11.1 months for the ivonecicimab group. Although Keytruda’s performance in the two trials was similar, OptiTROP-Lung05 had a larger PFS effect size and longer follow-up, suggesting that the median PFS for sac-TMT/Keytruda is likely to be longer.
In approving ivonescimab for 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 disappointed investors by showing immature results with a 22.3% reduction in mortality risk compared to Keytruda.
Given that ivonescimab does not have a combination partner, side-to-side comparisons may not be fair. In a May 21 memo, Leerink Partners analysts acknowledged that the hurdles for single-agent ivonecimab were low, but argued that the comparison “remains valid given the targeted commercial market.”
Akeso has data from the Harmoni-6 trial for ivonescimab and chemotherapy in the first-line treatment of NSCLC. However, given that the ivonescimab trial targeted squamous NSCLC without PD-L1 restriction, and the comparison target was PD-1 plus chemotherapy rather than PD-1 monotherapy, it is difficult to directly compare it with sac-TMT here.
The therapeutic efficacy of Sac-TMT appears to be consistent across subgroups by PD-L1 expression and histology. The PFS improvement rate with this combination was 72% compared with Keytruda in PD-L1-low patients with a tumor proportion score (TPS) <50% and 53% in the PD-L1-high group. The numbers were 72% for nonsquamous tumors and 56% for squamous tumors.
Results for ivonescimab in Harmoni-2 were 46% in low PD-L1 patients, 52% in high PD-L1 patients, 45% in non-squamous patients, and 50% in squamous patients.
In Harmoni-6, ivonescimab plus chemotherapy improved PFS by 40% compared to tevinbra plus chemotherapy in PD-L1-positive squamous NSCLC. Akeso will share OS data from Harmoni-6 during the ASCO 2026 plenary session.
Overall study response rate (ORR) reached 70.2% with sac-TMT/Keytruda combination therapy, compared to 42% with Keytruda monotherapy. Leerink analysts said in a note Thursday that an ORR of over 65% and a median PFS of around 14 months could impress investors.
The data for Merck and Cologne’s regimen also looks competitive compared to AstraZeneca and Daiichi Sankyo’s rival TROP2 ADC, Dato-DXd. However, again, different study populations complicate direct comparisons between studies.
In the phase 1 Tropion-Lung02 trial, the combination of Datroway and Keytruda resulted in an ORR of 54.8% and median PFS of 11.2 months in 42 patients with first-line NSCLC, regardless of PD-L1 expression. PD-L1 subgroup data were categorized only by expression levels <50% or >50%.
On the safety front, sac-TMT and Keytruda exhibited what OptiTROP-Lung05 researchers called a “generally manageable” profile. According to the summary, treatment-emergent adverse events (TEAEs) of grade 3 or higher were 55.3% in the combination therapy group and 31.4% in the Keytruda monotherapy group.
TEAEs led to discontinuation of sac-TMT in 3.8% of treated patients. Keytruda discontinuation rates were 5.3% for combo and 4.9% for control.
Details of OptiTROP-Lung05 will be presented by Caicun Zhou, MD, of Tongji University, at ASCO 2026. He is also the principal investigator of ivonescimab, Harmoni-2, and the president of the International Association for Lung Cancer Research.
The Leerink team asserted that complete data are needed to properly assess OptiTROP-Lung05’s position in the first-line NSCLC market.
“We believe that treatment duration, response, and overall survival (OS) are the more important outcomes when replacing immuno-oncology (IO) standards,” the analysts noted.
Based on OptiTROP-Lung05 data, Chinese regulatory authorities are reviewing the application of Cologne in first-line NSCLC.
Globally, Merck is deeply committed to sac-TMT, as evidenced by 17 global Phase 3 trials and a Commissioner’s National Priority Coupon from the FDA to expedite future regulatory reviews.
The program’s first global trial yielded positive results. The TroFuse-005 study met both PFS and OS at interim analysis, as sac-TMT beat chemotherapy in previously treated endometrial cancer.
Merck does not have an exact worldwide replica of the China-only OptiTROP-Lung05 test. The New Jersey drugmaker’s TroFuse-007 study is evaluating sac-TMT plus Keytruda versus Keytruda alone in only previously untreated patients with high PD-L1 NSCLC.
