With a phase 3 win for a combination of its TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) and Keytruda, Merck & Co.’s partner Kelun-Biotech is the latest to claim that it has a potential new first-line treatment for non-small cell lung cancer.
Treatment with the combination of sac-TMT and Keytruda led to a “statistically significant and clinically meaningful” improvement in progression-free survival versus Keytruda alone in a phase 3 trial in patients with first-line PD-L1-positive NSCLC, Kelun said Monday.
The phase 3 study, coded OptiTROP-Lung05, has therefore met its primary endpoint at an interim analysis. The trial is being conducted in Chinese patients with previously untreated NSCLC that expresses the PD-L1 biomarker at a tumor proportion score (TPS) of at least 1.
Based on the results, Kelun said it plans to talk to Chinese regulators about a potential application for approval. Just last month, sac-TMT was cleared in China to treat second-line EGFR-mutant NSCLC, the drug’s third indication in the country, following a strong phase 3 showing in both PFS and OS versus chemotherapy.
OptiTROP-Lung05 is the first phase 3 trial of an ADC combined with an immune checkpoint inhibitor to achieve its primary endpoint in first-line NSCLC, Kelun noted. However, thanks to its design, the study is less informative for the U.S. or the broader first-line NSCLC landscape.
Keytruda plus chemo—rather than Keytruda monotherapy—is the more widely accepted standard treatment in first-line PD-L1-positive NSCLC. Therefore, a comparison against Keytruda-chemo would provide a more illustrative view of sac-TMT’s potential in this setting.
Drugmakers’ propositions for ADCs are focused on leveraging these molecules’ targeted delivery of cytotoxic agents to replace existing systemic delivery of chemotherapies, so it doesn’t come as a complete surprise that the combo managed to outperform the chemo-less regimen in OptiTROP-Lung05.
Previously, Akeso and Summit Therapeutics’ PD-1xVEGF bispecific ivonescimab already showed a whopping 49% improvement in PFS compared with Keytruda in the landmark HARMONi-2 trial. Like OptiTROP-Lung05, which was conducted in Chinese patients with first-line PD-L1-positive NSCLC.
Although a cross-trial comparison suggests that sac-TMT appears to work better than ivonescimab in second-line EGFR-mutant NSCLC, that tumor type puts ivonescimab at a disadvantage because it’s rather insensitive to immunotherapy.
Second, OptiTROP-Lung05, being conducted in China, will not be able to support a regulatory filing in the U.S. As Kelun noted, sac-TMT is being evaluated in ten registrational studies in various lung cancer settings, including five global phase 3 studies conducted by Merck, which hasn’t yet decided to pit a cocktail of Keytruda and sac-TMT against Keytruda-chemo in first-line NSCLC.
In a more targeted indication than OptiTROP-Lung05, Merck’s TroFuse-007 trial is testing whether adding sac-TMT to Keytruda works better than Keytruda alone in first-line PD-L1-high NSCLC with TPS of at least 50%. This is a patient population for whom chemo has historically not shown much additional efficacy on top of Keytruda.
Merck and Kelun are aggressively advancing sac-TMT. Merck, having already registered 15 phase 3 trials for the drug, recently reached a $700 million royalty deal with Blackstone to help fund the development of sac-TMT.
The race is heating up in the TROP2 ADC field. Gilead Sciences’ first-to-market Trodelvy, after failing in second-line NSCLC, is awaiting readout from the phase 3 Evoke-03 trial, which is sponsored by Merck in the same PD-L1-high population as TroFuse-007.
Meanwhile, AstraZeneca recently slightly pushed back a highly anticipated readout from the phase 3 Avanzar trial for its Daiichi Sankyo-partnered Datroway. The ambitious study will see if AZ’s Imfinzi, plus Datroway and chemo, can beat Keytruda and chemo in first-line NSCLC. The trial will evaluate PFS and OS as co-primary endpoints in both the entire population and in a TROP2 biomarker-enriched subgroup. AZ expects a readout in the first half of 2026.