Sacituzumab Govitecan/Pembrolizumab Backed as New SOC in PD-L1+ TNBC

Sacituzumab govitecan plus pembrolizumab reduced the risk of death by 35% vs chemotherapy plus pembrolizumab.

Combining sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) yielded significantly higher progression-free survival (PFS) vs chemotherapy plus pembrolizumab for patients with PD-L1–positive, advanced or metastatic, triple-negative breast cancer (TNBC), per primary findings from the phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286) presented ahead of the 2025 ASCO Annual Meeting in a press briefing.

At a data cutoff date of March 3, 2025, sacituzumab govitecan plus pembrolizumab (n = 221) led to a median PFS of 11.2 months (95% CI, 9.3-16.7) by blinded independent central review (BICR) vs 7.8 months (95% CI, 7.3-9.3) with chemotherapy plus pembrolizumab (n = 222), translating to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.51-0.84; P < .001). The 6- and 12-month PFS rates in the sacituzumab govitecan arm were 72% (95% CI, 65%-77%) and 48% (95% CI, 41%-56%), respectively; in the chemotherapy arm, these respective rates were 63% (95% CI, 56%-69%) and 33% (95% CI, 26%-40%).

“Results from ASCENT-04/KEYNOTE-D19 support the use of sacituzumab govitecan plus pembrolizumab as a potential new standard of care for patients with previously untreated, PD-L1–positive, locally advanced unresectable or metastatic TNBC,” Sara M. Tolaney, MD, MPH, chief of the division of Breast Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts, said in the briefing. She is also an associate professor of medicine at Harvard Medical School.

Unmet Needs Paving the Path to ASCENT-04

Data from previous studies showed that median PFS achieved with chemotherapy with immune checkpoint inhibition ranges from 7.5 months to 9.7 months in patients with PD-L1–positive metastatic TNBC; however, most patients will experience progressive disease and approximately half of those treatment for metastatic TNBC in the first line do not go on to receive second-line treatment.

Trial Design: Eligibility, Treatment, Objectives

The global, randomized, phase 3 study enrolled patients with treatment-naive, locally advanced unresectable or metastatic TNBC who had PD-L1 positivity defined as a combined positive score (CPS) of at least 10 per the 22C3 assay. At least 6 months must have passed since treatment in the curative setting, where prior anti–PD-(L)1 inhibition was permitted.

Participants (n = 443) were randomly assigned 1:1 to receive 10 mg/kg of intravenous sacituzumab govitecan on days 1 and 8 and 200 mg of pembrolizumab on day 1 of 21-day treatment cycles (n = 221) vs pembrolizumab at the same dose and schedule plus chemotherapy in the form of 90 mg/m² of paclitaxel or 100 mg/m² of nab-paclitaxel (Abraxane) on days 1, 8, and 15 of 28-day cycles or 1000 mg/m² of gemcitabine plus area under the curve 2 of carboplatin on days 1 and 8 of 21-day cycles (n = 222). Treatment continued until progressive disease and intolerable toxicity. All patients who experienced disease progression by BICR were permitted to cross over to receive single-agent sacituzumab govitecan in the second line.

Stratification factors comprised region (US/Canada/Western Europe vs the rest of the world), previous exposure to PD-(L)1 inhibition (yes vs no), and curative treatment-free interval (de novo TNBC vs recurrence within 6 to 12 months from treatment completion in the curative setting vs recurrence longer than 12 months from completion of treatment in the curative setting).

The primary end point of the study was PFS by BICR, and secondary end points included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by BICR, safety, and quality of life.

All patients were female and had a PD-L1 CPS of 10 or higher. Most patients were White (sacituzumab govitecan arm, 63%; chemotherapy arm, 63%), from the rest of the world (62%; 62%), and had an ECOG performance status of 0 (71%; 69%). Regarding curative treatment-free interval, most patients were recurrent in over 12 months (48%; 48%), followed by de novo (34%; 34%), and recurrent within 6 to 12 months (18%; 18%). Metastatic sites included lymph nodes (72%; 69%), lung (50%; 43%), other (37%; 32%), bone (28%; 20%), liver (25%; 26%), and brain (4%; 3%).

The chemotherapy selected before randomization in the sacituzumab arm was taxane for 52% of patients and gemcitabine/carboplatin for 48% of patients; in the chemotherapy arm, these respective rates were 51% and 49%. Four percent of patients in the antibody-drug conjugate (ADC) arm vs 5% of those in the chemotherapy arm had prior exposure to PD-(L)1 inhibition.

Additional Efficacy Revelations

Although OS data were immature at the time of the report, with a maturity rate of only 26%, a positive improvement was observed for the sacituzumab govitecan plus pembrolizumab arm vs chemotherapy plus pembrolizumab arm—despite a high crossover rate. Specifically, 43% of those on the chemotherapy arm crossed over to receive the ADC as a single agent in the second line, which accounted for 81% of those who were subsequently given treatment after chemotherapy/pembrolizumab was discontinued.

The median OS was not reached (NR) in the sacituzumab arm (95% CI, 25.6-NR), and it was also NR in the chemotherapy arm (95% CI, NR-NR); 53 and 61 events were reported in the arms, respectively. The hazard ratio for OS was 0.89 (95% CI, 0.62-1.29).

Sacituzumab plus pembrolizumab induced an ORR of 60% (95% CI, 52.9%-66.3%) vs 53% (95% CI, 46.4%-59.9%) with chemotherapy plus pembrolizumab (stratified odds ratio, 1.3; 95% CI, 0.9-1.9). In the ADC arm, 13% of patients achieved a complete response (CR) and 47% had a partial response (PR); 32% had stable disease (SD), 4% progressed, and 5% were not response evaluable. In the chemotherapy arm, the CR and PR rates were 8% and 45%, respectively; 32% of patients had SD, 12% experienced disease progression, and 4% were not evaluable.

The median time to response in the sacituzumab arm was 1.9 months (range, 1.0-9.3); it was also 1.9 months (range, 1.1-11.4) in the chemotherapy arm. Notably, the median DOR was 16.5 months (95% CI, 12.7-19.5) in the ADC arm and 9.2 months (95% CI, 7.6-11.3) in the chemotherapy arm.

Safety Spotlight

Any-grade treatment-emergent adverse effects (TEAEs) occurred in over 99% of those in the sacituzumab and chemotherapy arms; these effects were grade 3 or higher for 71% and 70% of patients, respectively. Treatment-emergent serious AEs (SAEs) were experienced by 38% of those who received the ADC vs 31% of those given chemotherapy; 28% and 19% of cases, respectively, were treatment related.

In the sacituzumab plus pembrolizumab arm, TEAEs led to dose reductions or interruptions in 35% and 77% of patients, respectively; TEAEs led to treatment discontinuation for 12% of patients and proved fatal for 3% of patients. Three of the 7 TEAEs that led to death were determined to be related to treatment. In the chemotherapy plus pembrolizumab arm, TEAEs led to dose reductions and interruptions for 44% and 74% of patients, respectively; TEAEs led to discontinuation for 31% of patients. TEAEs led to death for 3% of those in this arm; 1 of these cases was related to treatment.

“Overall, the safety profile of sacituzumab govitecan plus pembrolizumab was consistent with the known safety profiles of each drug,” Tolaney said. “The rate of SAEs was higher in the sacituzumab govitecan plus pembrolizumab group compared with the chemotherapy plus pembrolizumab group; however, the rate of TEAEs leading to dose reduction or treatment discontinuation was lower.”

Topline Takeaway

Jane L. Meisel, MD, professor in the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory University School of Medicine in Georgia, commented on the significance of the findings.

“I do think this is really such potentially practice-changing data. We've seen in previous studies how sacituzumab govitecan works so well for patients with metastatic TNBC later on in their treatment. And now, to see this combined with pembrolizumab and compared with chemotherapy plus pembrolizumab with such both statistically and clinically meaningful benefits for patients, I think it really does change the game for this subgroup,” she said. “This is very exciting, and I look forward to seeing this potentially make its way into clinical practice. I think the nice thing too, is that as clinicians, many of us have used both of these agents—sacituzumab govitecan and pembrolizumab—quite a bit, and so the fact that there were no additional toxicities seen [beyond what we have] seen before, will help people get used to using this and feel comfortable with it once it makes its way into the clinic.”

Reference

Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109