The race to bring TROP2 antibody-drug conjugates (ADCs) to first-line non-small cell lung cancer (NSCLC) patients has narrowed following another failure in a Phase 3 trial of Gilead Sciences’ Trodelvy.
On Monday, Merck and Gilead announced they were discontinuing the Phase 3 Evoke-03 trial, also known as Keynote-D46, following the recommendation of an external data monitoring board.
This study evaluated Trodelvy in combination with Keytruda versus Keytruda alone as first-line treatment for patients with PD-L1-high NSCLC.
The companies said that although positive trends were observed in the trial, the endpoint of progression-free survival was not met in the final analysis. Furthermore, an interim analysis of overall survival suggested that the trial was unlikely to achieve statistical significance on this metric.
The failure of Evoke-03 is another major blow to the first-in-class TROP2 ADC, following a setback in a second-line NSCLC trial more than two years ago. Gilead stock was down about 2.7% as of Tuesday morning’s announcement.
Without a win in first-line NSCLC, Trodelvy’s commercial future will depend primarily on its use in triple-negative breast cancer, which would not justify the $21 billion price tag Gilead paid for the drug’s developer, Immunomedics. Gilead has already posted significant losses related to the failure of Trodelvy’s second-line NSCLC treatment and its exit from the bladder cancer market in 2024.
Trodelvy’s latest PFS mistake surprised analysts at Jefferies and Leerink Partners. For the broader oncology industry, Evoke-03’s failure serves as a warning that “breaking the standard of care (SoC) of easy (Keytruda) monotherapy as an entry into 1L NSCLC may not be as easy as it seems,” the Leerink team wrote in a June 8 note.
Nevertheless, both teams of analysts remain hopeful that Merck’s rival TROP2 ADC, sac-TMT, can be successful in the same first-line NSCLC setting.
In a subgroup analysis of the positive OptiTROP-lung05 trial conducted by Merck partner Cologne Biotech, sac-TMT plus Keytruda was associated with a 53% greater PFS benefit than Keytruda alone in patients with previously untreated PD-L1-high NSCLC. Merck’s Phase 3 TroFuse-007 study is testing the regimen in people around the world.
Sac-TMT acknowledged that a complete head-to-head comparison between the two drugs in NSCLC does not exist, but the two analysis teams noted that Sac-TMT demonstrated numerically superior efficacy to Trodelvy in this setting.
Potentially longer treatment durations could also benefit sac-TMT, the teams noted. In Gilead’s Phase 2 Evoke-02 trial, Trodelvy showed much higher treatment-related discontinuations (24%) than Kelun reported in OptiTROP-Lung05 (less than 10%), Leerink noted.
Besides Merck, AstraZeneca and Daiichi Sankyo are also targeting the lucrative first-line NSCLC market, with the high-profile Phase 3 Avanzer trial of their TROP2 ADC Datroway expected to be announced this year. AZ has developed a TROP2-based biomarker that has the potential to increase the probability of success in the partner’s primary NSCLC trial. One study, Tropion-Lung08, is testing Datroway alongside Keytruda in patients with first-line non-squamous PD-L1-rich NSCLC.
Meanwhile, for Gilead, there is one Phase 3 left in Trodelvy. Data from the Ascent-GYN study in second-line endometrial cancer is expected later this year.
As competition from Trodelvy intensifies, including in breast cancer, Gilead investors’ attention will begin to shift to other areas. The California company recently agreed to buy ADC Biotechnology’s Tubulis for a much cheaper deal than Immunomedics. For $3.15 billion upfront, Gilead will acquire TUB-040, a NaPi2b ADC that analysts believe has the best disease potential in ovarian cancer and potential for improvement in NSCLC, as well as a new ADC platform.
