Already boasting a strong foothold in metastatic triple-negative breast cancer, Gilead Sciences’ Trodelvy has produced positive data that could make the antibody-drug conjugate part of a new front-line standard of care.
In what an American Society of Clinical Oncology (ASCO) expert called practice-changing data, a combination of Trodelvy and Merck & Co.’s Keytruda significantly lowered the risk of progression or death by 35% versus Keytruda and chemotherapy when used as an initial treatment for metastatic triple-negative breast cancer (TNBC) that expresses PD-L1.
Patients who took Trodelvy-Keytruda went a median 11.2 months without progression, versus 7.8 months for chemo-Keytruda, according to results from the phase 3 Ascent-04 trial to be presented at the 2025 ASCO annual meeting.
The readout is practice-changing, Jane Lowe Meisel, M.D., from the Emory University School of Medicine, who’s not involved in the study, said in a press briefing ahead of the official data presentation.
While overall survival data were immature at the March 3, 2025, data cutoff, the trial recorded an early trend in favor of the Trodelvy-Keytruda regimen. The novel combo was linked to a preliminary 11% reduction in the risk of death, as only 26% of deaths needed for a final analysis had happened.
In the control arm, 43% of patients crossed over to receive Trodelvy monotherapy after disease progression, representing 81% of those who received any subsequent treatment following chemo-Keytruda, lead study author Sara Tolaney, M.D., from the Dana-Farber Cancer Institute told reporters at the press conference.
The positive Ascent-4 readout in first-line TNBC builds on Trodelvy’s previous success as the first treatment to have shown a life extension benefit in previously treated TNBC per data from the phase 3 Ascent trial.
Doctors already have “a lot of faith” in Trodelvy in TNBC, Leerink Partners analysts said in a Wednesday note, citing a breast cancer key opinion leader. The TROP2-targeted ADC is the most-prescribed branded therapy in second-line TNBC, Leerink noted.
Following the Ascent-04 win in PD-L1-positive disease, Gilead last week said the Ascent-03 trial comparing Trodelvy with chemo in first-line PD-L1-negative TNBC also demonstrated a “highly statistically significant and clinically meaningful” improvement on progression-free survival (PFS).
About 10% of U.S. breast cancer cases are triple-negative, and about 40% of TNBC expresses PD-L1.
In the original Ascent study, investigators noted numerically better PFS in patients with higher expressions of TROP2. But Trodelvy still performed better than chemo irrespective of TROP2 levels, Tolaney noted. For Ascent-04, the research team will look retrospectively at TROP2 levels and may share those data in the future, she said.
Besides PFS and survival data, Trodelvy-Keytruda’s tumor response rate, at 60%, was marginally higher than chemo-Keytruda’s 53%. But the novel regimen’s duration of response was markedly longer than that from the control arm, at 16.5 months and 9.2 months at median, respectively.
Objective response rate is more important in TNBC than in other breast cancer subtypes, two breast cancer experts told Leerink. Achieving a response is key for these patients, because TNBC comes with a lot of visceral metastases and rapid development of disease, the experts said, as summarized by Leerink.
Three-way TROP2 battle
While Trodelvy is the leading agent in TNBC, competition is creeping up on the first-in-class TROP2 ADC.
Chinese regulators in November approved Kelun-Biotech’s Merck-partnered sacituzumab tirumotecan (sac-TMT) in the same previously treated TNBC indication as Trodelvy’s initial FDA nod.
At ASCO 2025, Kelun trotted out initial results from the phase 2 OptiTROP-Breast05 study for sac-TMT as first-line treatment in TNBC. Among 41 patients enrolled in China, the drug as a single agent recorded a 70.7% objective response rate, lasting for a median 12.2 months. The median PFS was 13.4 months.
In 32 patients with PD-L1-negative disease, the response rate was 71.9%, with a median PFS of 13.1 months.
Kelun has launched a Chinese phase 3 trial for sac-TMT in first-line PD-L1-negative TNBC or in patients with PD-L1-positive tumors following prior PD-1/L1 treatment in early setting.
One of Leerink’s experts highlighted sac-TMT’s “pretty dramatic” response rate, suggesting that it might be a more active agent than Trodelvy. However, the other expert was cautious about whether the phase 2 results can be replicated in a large phase 3 and from a Chinese population to Western patients.
In addition to sac-TMT, AstraZeneca is testing its Daiichi Sankyo-partnered Datroway also in two phase 3 trials. AZ has projected a readout from the Tropion-Breast02 study in PD-L1-negative disease by June and from the Tropion-Breast05 trial in PD-L1-positive tumors in 2026.