Merck’s extensive clinical development program for the TROP2 antibody-drug conjugate (ADC) sac-TMT already includes 17 international Phase 3 trials. But one important part is missing.
The New Jersey drug company is not currently conducting registration trials for the drug in partnership with Cologne Biotech for first-line PD-L1-low or negative non-squamous non-small cell lung cancer. Instead, the company is conducting a Phase 3 to add sac-TMT to Keytruda in first-line maintenance squamous NSCLC regardless of PD-L1 expression, as well as a Phase 3 in non-squamous patients with high PD-L1 expression.
More than two years have passed since these two studies began. This is a glaring hole in Merck’s overall TroFuse clinical program, which the company touts as its “flagship” product, especially since its breakthrough Keynote-189 trial win in first-line non-squamous NSCLC helped propel Keytruda to the PD-1 kingship.
At the American Society of Clinical Oncology Annual Meeting in Chicago, Dr. Kern also presented positive results from the Chinese phase 3 clinical trial OptiTROP-Lung05 in PD-L1-positive NSCLC across both histologies, although the single-agent Keytruda comparison may not apply to the U.S. for PD-L1-low subpopulations.
Before Merck began the two first-line NSCLC trials mentioned above, OptiTROP-Lung05 data was not available to guide planning, and it was not clear whether sac-TMT was sufficient to replace chemotherapy for everyone, Marjorie Green, M.D., Merck’s head of oncology clinical development, told Fierce in an interview on the sidelines of ASCO.
US drug companies did not want to layer ADCs on Keytruda and chemotherapy. She explained that this approach has not been as successful in solid tumors as it has been in blood cancers, perhaps because dose intensity must be compromised to control toxicity.
“Everyone’s like, ‘When are we going to replace 189?'” Green said.
“We didn’t want to say, ‘Let’s throw the kitchen sink at the patient,’ because there’s fragmentation going on in lung cancer,” she says. “Think about how practice actually happens and design it that way.”
Let’s return to today. In addition to the positive results for OptiTROP-Lung05, Cologne plans to report results from its phase 3 OptiTROP-Lung06 trial in China at the European Society of Medical Oncology annual meeting in October, the Chinese company told Fierce.
This study compared sac-TMT and Keytruda to chemotherapy and Keytruda in first-line PD-L1-negative NSCLC. This provides a direct clue as to whether Merck’s global twin has the potential to cover the PD-L1 negative non-squamous population that is missing in the TroFuse program.
During a Q&A session at ASCO 2026, OptiTROP-Lung05’s principal investigator, Caicun Zhou, MD, of Tongji University, incorrectly referred to the upcoming ESMO data as being from OptiTROP-Lung14, which specifically focuses on non-squamous patients with PD-L1-negative tumors.
Separately, Merck is currently developing the PD-1xVEGF inhibitor MK-2010, which has the potential to be a more powerful immunotherapy, and which Green calls a “Phase 3-ready” asset. But she seems wary of a three-drug approach here too because of the risk of duplicating toxicity.
“It’s possible,” Green told Fiers. “Because someone drops a drug that improves survival, does it create more toxicity that limits its effectiveness? I think that’s an open question.”
Green declined to say whether Merck will initiate a next-generation phase 3 trial involving Keytruda and sac-TMT or MK-2010, an alternative to conventional chemotherapy, in non-squamous NSCLC with low or negative PD-L1, citing a “hypercompetitive environment.”
At least one thing seems clear. Despite promising early results with MK-2010 and other PD-(L)1xVEGF competitors, Green’s comments suggest that Merck is unlikely to pursue extensive first-line NSCLC research combining MK-2010 with chemotherapy, as competitors Summit Therapeutics, Pfizer, and the BioNTech/Bristol-Myers Squibb alliance do. Merck also seems unlikely to use this approach for sac-TMT, despite AstraZeneca and Daiichi Sankyo employing this strategy for their TROP2 ADC Datroway in the high-profile Avanzar trial.
“I don’t think the shotgun approach is the best approach in oncology,” Green said. “We’ve become spoiled with Keytruda and other drugs because they…act on the immune system, and it’s not tumor-specific.”
“We always want to plan our portfolio around what care will look like three to five years from now, rather than what care looks like now,” she said.
