Sacituzumab Govitecan With/Without Pembrolizumab Aims to Fill Gap in Treatment-Naive TNBC

In light of the established efficacy of sacituzumab govitecan-hziy (Trodelvy) in patients with pretreated triple-negative breast cancer (TNBC), there has been interest in moving the agent into the frontline setting, both as monotherapy and a combination component, in order to expand options for patients who may not eligible for immunotherapy, according to Sara M. Tolaney, MD, MPH.

“One of our biggest challenges is that patients with metastatic TNBC unfortunately have very high-risk cancers, and [their] survival is quite short,” Tolaney explained in an interview with OncLive^®. “We see that a lot of patients can’t get from their first-line treatment to their second line of therapy, either because of deterioration in health or death. So, it’s critical that we try to give our most effective treatments up front. We have had sacituzumab govitecan available for patients with pretreated metastatic TNBC, based on [data from] the [phase 3] ASCENT trial [NCT02574455], which showed that sacituzumab govitecan improved both progression free survival [PFS] and overall survival [OS], but we wanted to see if we could move [the agent] into the first-line setting.”

Tolaney is the chief in the Division of Breast Oncology and the associate director of the Susan F. Smith Center for Women’s Cancers, as well as a senior physician at Dana-Farber Cancer Institute, in Boston, Massachusetts. She is also an associate professor of medicine at Harvard Medical School in Boston.

In April 2021, the FDA approved sacituzumab govitecan for the treatment of patients with unresectable locally advanced or metastatic TNBC who have previously received 2 or more systemic therapies, at least 1 of them for metastatic disease.¹ The agent previously received accelerated approval in April 2020 for the treatment of patients with metastatic TNBC who had received at least 2 prior therapies for metastatic disease. The full approval was supported by data from ASCENT, which demonstrated that patients who received sacituzumab govitecan achieved a median PFS of 4.8 months (95% CI, 4.1-5.8) vs 1.7 months (95% CI, 1.5-2.5) among those who received chemotherapy (HR, 0.43; 95% CI, 0.35 -0.54; P < .0001). The median OS values were 11.8 months (95% CI, 10.5-13.8) and 6.9 months (95% CI, 5.9-7.6) respectively (HR, 0.51; 95% CI, 0.41-0.62; P < .0001).

What were the updated data from ASCENT-03?

Sacituzumab govitecan monotherapy was examined for the treatment of patients with previously untreated advanced TNBC who were not candidates to receive PD-(L)1 inhibitors in the phase 3 ASCENT-03 trial (NCT05382299).² Patients were randomly assigned 1:1 to receive sacituzumab govitecan or chemotherapy. The primary end point was PFS per blinded independent central review (BICR); secondary end points included OS, overall response rate (ORR), duration of response (DOR), and safety.

Primary findings from ASCENT-03 presented during the 2025 ESMO Congress revealed that the median PFS per BICR in the sacituzumab govitecan arm (n = 279) was 9.7 months (95% CI, 8.1-11.1) compared with 6.9 months (95% CI, 5.6-8.2) in the chemotherapy arm (n = 279; stratified HR, 0.62; 95% CI, 0.50-0.77; P < .0001). The respective 6-month PFS rates were 65% (95% CI, 59%-71%) and 53% (95% CI, 47%-59%). The 12-month PFS rates were 41% (95% CI, 34%-47%) and 24% (95% CI, 19%-30%), respectively.

Although OS data were not mature at the time of the presentation, there was a numerical benefit seen with sacituzumab govitecan vs chemotherapy (stratified HR, 0.98; 95% CI, 0.75-1.30). The respective ORRs were 48% (95% CI, 42%-54%) and 46% (95% CI, 40%-52%). The median DOR values were 12.2 months (95% CI, 9.7-13.8) and 7.2 months (95% CI, 5.7-8.4), respectively.

“We saw that the sacituzumab govitecan arm did significantly better than the chemotherapy arm [in terms of] PFS,” Tolaney said. “The OS data are still immature, so they were presented descriptively. We did see that the [time to second progression] was substantially longer in the sacituzumab govitecan arm vs the chemotherapy arm, which is reassuring, suggesting that the patients [who received] sacituzumab govitecan continue to do well even beyond that first line of treatment.”

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in the investigational (n = 275) and control (n = 276) arms at respective rates of 99% and 97%. Grade 3 or higher TEAEs (66% vs 62%), as well as TEAEs leading to treatment discontinuation (4% vs 12%), interruption (66% vs 62%), reduction (37% vs 45%), and death (3% vs < 1%), occurred in both arms.

What were the updated data from ASCENT-04?

Sacituzumab govitecan is being evaluated in combination with pembrolizumab (Keytruda) for the treatment of patients with previously untreated, PD-L1–positive advanced or metastatic TNBC in the phase 3 ASCENT-04/KEYNOTE-D19 trial (NCT05382286).³ Patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab or pembrolizumab plus chemotherapy. The primary end point was PFS by BICR; secondary end points included OS, ORR, DOR, and safety.

Primary results from ASCENT-04 presented during the 2025 ASCO Annual Meeting showed that patients in the sacituzumab govitecan arm (n = 221) achieved a median PFS per BICR of 11.2 months (95% CI, 9.3-16.7) compared with 7.8 months (95% CI, 7.3-9.3) in the chemotherapy arm (n = 222; stratified HR, 0.65; 95% CI, 0.51-0.84; P < .001). The 6-month PFS rates were 72% (95% CI, 65%-77%) and 63% (95% CI, 56%-69%), respectively. The respective 12-month PFS rates were 48% (95% CI, 41%-56%) and 33% (95% CI, 26%-40%).

The ORR in the investigational arm was 60% (95% CI, 52.9%-63.3%) vs 53% (95% CI, 46.4%-59.9%) in the chemotherapy arm (stratified OR, 1.3; 95% CI, 0.9-1.9). The respective complete response rates were 13% and 8%. The median DOR in the sacituzumab govitecan arm was 16.5 months (95% CI, 12.7-19.5) compared with 9.2 months (95% CI, 7.6-11.3) in the chemotherapy arm.

“[Patients who received] sacituzumab govitecan plus pembrolizumab fared better compared with [those who received] standard chemotherapy plus pembrolizumab,” Kevin Kalinsky, MD, MS, FASCO, said in an interview with OncLive.

Kalinsky is the Louisa and Rand Glenn Family Chair in Breast Cancer Research and the director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, as well as director and professor in the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine, both in Atlanta, Georgia.

Moreover, data from a safety analysis from ASCENT-04 presented during the 2025 San Antonio Breast Cancer Symposium showed that sacituzumab govitecan in combination with pembrolizumab displayed a favorable benefit/risk profile compared with chemotherapy plus pembrolizumab in patients with previously untreated metastatic TNBC and PD-L1 expression.⁴ Any-grade TEAEs were observed at rates of over 99% in both arms. The exposure-adjusted incidence rates (EAIRs) of TEAEs that lead to dose reduction (EAIR difference, –0.31; 95% CI, –0.56 to –0.08) or treatment discontinuation (EAIR difference, –0.38; 95% CI, –0.53 to –0.25) favored the investigational arm. Rates of anemia (EAIR difference, –0.59; 95% CI, –0.86 to –0.33), thrombocytopenia (EAIR difference, –0.44; 95% CI, –0.58 to –0.31), pneumonitis (EAIR difference, –0.08; 95% CI, –0.15 to –0.02), and peripheral neuropathy (EAIR difference, –0.26; 95% CI –0.39 to –0.15) also favored the sacituzumab govitecan arm.

“Ultimately, these data continue to show that for patients who have PD-L1–positive tumors, there’s an improvement in PFS, [and] there are nuances in terms of the differences in toxicities that we can see between the 2 arms,” Kalinsky said. “But this is a feasible as well as clinically meaningful difference in terms of how long patients can respond to the treatment, which has led to sacituzumab govitecan plus pembrolizumab becoming a standard of care for patients with PD-L1–positive tumors.”

References

1. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Update April 8, 2021. Accessed January 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-sacituzumab-govitecan-triple-negative-breast-cancer
2. Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Ann Oncol. 2025;36(suppl 2):S1680-S1681. doi:10.1016/j.annonc.2025.09.030
3. 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
4. Kalinsky K, Schmid P, de Azambuja E, et al. Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro for previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract PS5-02-28.