Clinical Summary: 

• Design/Population: Exploratory analyses from the phase 3 ASCENT-04 trial evaluated progression-free survival 2 and subsequent treatment outcomes in 443 patients with previously untreated PD-L1–positive metastatic triple-negative breast cancer randomized to sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab.
• Key Outcomes: Sacituzumab govitecan plus pembrolizumab improved PFS2 despite a high rate of crossover to sacituzumab govitecan in the control arm. Benefits were also observed across additional exploratory endpoints, including time to first and second subsequent therapies, with no new safety signals identified.
• Clinical Relevance: These findings provide further evidence that frontline sacituzumab govitecan plus pembrolizumab delivers durable clinical benefit and reinforce its role as a standard-of-care option for PD-L1–positive metastatic triple-negative breast cancer.

Kevin Kalinsky, MD, Winship Cancer Institute at Emory University, Atlanta, Georgia, discusses updated analysis results from the phase 3 ASCENT-04 trial evaluating sacituzumab govitecan plus pembrolizumab in patients with PD-L1–positive metastatic triple-negative breast cancer. The primary analysis previously demonstrated significant improvements in progression-free survival (PFS) compared with chemotherapy plus pembrolizumab, establishing the combination as an important frontline treatment option.

The current analysis focused on PFS2 and subsequent therapy outcomes, addressing questions raised by immature overall survival data and substantial crossover to sacituzumab govitecan in the control arm. Despite these confounding factors, the findings demonstrated continued clinical benefit with frontline sacituzumab govitecan plus pembrolizumab, supporting earlier use of the regimen in this patient population.

Dr Kalinsky presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript: 

Hi, I'm Kevin Kalinsky at Winship Cancer Institute. At ASCO, the primary analysis of ASCENT-04 was reported. That study demonstrated a clinically meaningful and statistically significant improvement for patients with frontline PD-L1–positive triple-negative breast cancer who were randomized to receive the TROP2 antibody-drug conjugate sacituzumab govitecan (SG) plus pembrolizumab compared with chemotherapy plus pembrolizumab. 

The intent of reporting these new data was to look at PFS2, because the overall survival data remain immature. We are still awaiting additional events, and there was also substantial crossover from the control arm, so we felt there would be interest in evaluating PFS2 as an additional measure of clinical benefit.

As a bit of background, ASCENT-04 randomized 443 participants to SG plus pembrolizumab or chemotherapy plus pembrolizumab. The chemotherapy could be either a single-agent taxane or the doublet of gemcitabine plus carboplatin. 

At the time of disease progression, if patients had progression confirmed by blinded independent central review, they were eligible to receive second-line SG through the study. Approximately 80% of participants in the chemotherapy plus pembrolizumab arm ultimately crossed over to receive SG, whereas only a small number of patients, about 15, received SG as standard of care outside the study. 

The primary end point of ASCENT-04 was progression-free survival by blinded independent central review. PFS2, as well as end points such as time to first subsequent therapy and time to second subsequent therapy, were exploratory analyses.

In terms of safety, there were no new safety signals beyond what had already been reported in the primary analysis. For example, when comparing SG plus pembrolizumab with chemotherapy plus pembrolizumab, the rates of grade 3 or higher treatment-emergent adverse events were generally similar between the 2 arms. It's also worth noting that the chemotherapy arm actually had higher rates of treatment-emergent adverse events leading to dose reductions or treatment discontinuation. 

Looking at specific toxicities, rates of all-grade neutropenia were relatively similar between the two treatment arms. As expected, there was a higher rate of diarrhea with SG, whereas the chemotherapy arm had higher rates of anemia, thrombocytopenia, and peripheral neuropathy. 

The data presented at ASCO used the same cutoff date as the primary analysis, March 2025, with approximately 14 months of follow-up. We observed an improvement in progression-free survival 2, which was defined as the time from randomization to progression on the next line of therapy or death, whichever occurred first. Again, this was an exploratory analysis. The stratified hazard ratio was 0.67 in favor of SG plus pembrolizumab, corresponding to a 33% reduction in the risk of a PFS2 event. Importantly, the median PFS2 was not yet reached in the SG plus pembrolizumab arm, whereas it was approximately 21 months in the chemotherapy plus pembrolizumab arm. 

So what are the implications of these data? Despite the very high crossover rate to single-agent SG in the chemotherapy plus pembrolizumab arm, we still observed an improvement in PFS2 favoring frontline SG plus pembrolizumab. Along with the previously reported findings for time to first and subsequent therapies, these results suggest that there is an ongoing clinical benefit for patients who receive SG plus pembrolizumab upfront. For the approximately 40% of patients with PD-L1–positive triple-negative breast cancer who are treated in the frontline setting, the combination of SG plus pembrolizumab remains a standard-of-care option, and these data further support that approach. Thank you.

Source:

Kalinsky K, Schmid P, Azambuja E, et al. Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-04 study of participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs chemotherapy (chemo) plus pembro. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA1000.