Sacituzumab Govitecan Plus Pembro Sustains Benefit Beyond First Progression in PD-L1–Positive mTNBC

First-line sacituzumab govitecan (Trodelvy) plus pembrolizumab (Keytruda) demonstrated sustained long-term benefit beyond initial disease progression in patients with previously untreated PD-L1–positive metastatic triple-negative breast cancer (mTNBC), according to updated data from the phase 3 ASCENT-04/KEYNOTE-D19 study presented at the 2026 ASCO Annual Meeting.¹

The updated analysis focused on progression-free survival 2 (PFS2), the time from randomization to disease progression on the next line of therapy or death from any cause. In the updated analysis, median PFS2 was not reached with sacituzumab govitecan plus pembrolizumab versus 21.0 months with chemotherapy plus pembrolizumab (HR, 0.67; 95% CI, 0.48-0.95), representing a 33% reduction in the risk of a PFS2 event. OS data remained immature at the primary analysis with only 26% maturity as of March 2025, though a trend toward improvement was observed.

The primary analysis of ASCENT-04, previously published in the New England Journal of Medicine, demonstrated that sacituzumab govitecan plus pembrolizumab significantly improved progression-free survival (PFS) by blinded independent central review (BICR) versus chemotherapy plus pembrolizumab (HR, 0.65; 95% CI, 0.51-0.84; P < .001).² Critically, 96 (81%) of 119 patients in the chemotherapy plus pembrolizumab arm who received subsequent therapy went on to receive sacituzumab govitecan, making the PFS2 result particularly meaningful, as it demonstrates sustained benefit even when most control arm patients eventually received the same agent.

Additional efficacy data from the PFS2 analysis showed that at 12 months, event-free probability was 71.9% (95% CI, 64.5-78.0) with sacituzumab govitecan plus pembrolizumab versus 63.7% (95% CI, 51.1-73.9) with chemotherapy plus pembrolizumab. At 24 months, event-free probabilities were 53.0% (95% CI, 44.5-60.8) and 45.6% (95% CI, 35.6-55.1), respectively.

The time to first subsequent therapy (TFST) was also significantly prolonged at 17.3 months with sacituzumab govitecan plus pembrolizumab versus 9.8 months with chemotherapy plus pembrolizumab. Time to second subsequent therapy (TSST) was not reached versus 21.0 months, respectively, further reinforcing the durability of benefit.

At the time of data cutoff, almost twice as many patients in the sacituzumab govitecan plus pembrolizumab group (43%) remained on study treatment compared with the chemotherapy plus pembrolizumab group (23%). Among those who discontinued treatment, 55% in the sacituzumab govitecan plus pembrolizumab arm and 70% in the chemotherapy plus pembrolizumab arm went on to receive second-line or later therapy. In the sacituzumab govitecan plus pembrolizumab arm, the most common subsequent therapy was chemotherapy (88%), while in the chemotherapy plus pembrolizumab arm it was sacituzumab govitecan (81%). Only 4% of patients in the sacituzumab govitecan plus pembrolizumab arm received subsequent sacituzumab govitecan, compared with 81% in the chemotherapy plus pembrolizumab arm.

"In this analysis, PFS2 was improved in the sacituzumab govitecan plus pembrolizumab arm despite a large number of patients in the control arm going on to receive sacituzumab govitecan in the second-line setting. This suggests that the benefit of giving pembrolizumab plus sacituzumab govitecan as first-line therapy over chemotherapy is sustained in the long term, further supporting this combination as a potential new standard of care," said lead study author Kevin Kalinsky, MD, MS, FASCO, of the Winship Cancer Institute of Emory University in Atlanta, Georgia.³

Safety Profile in ASCENT-04

The safety profile of sacituzumab govitecan plus pembrolizumab was consistent with the known profiles of both agents, with no new safety concerns identified. Any treatment-emergent adverse event (TEAE) was reported in more than 99% of patients in both arms. Grade ≥3 TEAEs occurred in 71% of sacituzumab govitecan plus pembrolizumab patients and 70% of chemotherapy plus pembrolizumab patients. Treatment-emergent serious adverse events (SAEs) were reported in 38% versus 31% of patients, respectively, with treatment-related SAEs in 28% versus 19%.

TEAEs leading to treatment discontinuation were notably lower with sacituzumab govitecan plus pembrolizumab (12%) versus chemotherapy plus pembrolizumab (31%). In the chemotherapy plus pembrolizumab arm, the most common TEAEs leading to discontinuation were peripheral neuropathy (5%), pneumonitis (3%), and thrombocytopenia (3%); in the sacituzumab govitecan plus pembrolizumab arm, pneumonitis accounted for 1% of discontinuations. TEAEs leading to dose interruption occurred in 77% and 74% of patients, and dose reduction in 35% and 44%, respectively. TEAEs leading to death occurred in 3% of patients in both arms, with treatment-related fatal events in 3 patients (1%) in the sacituzumab govitecan plus pembrolizumab arm and 1 patient (<1%) in the chemotherapy plus pembrolizumab arm.

ASCENT-04 Study Design and Patient Characteristics

ASCENT-04/KEYNOTE-D19 (NCT05382286) is a global, randomized, open-label, phase 3 trial enrolling 443 patients with previously untreated, locally advanced unresectable or metastatic TNBC that was PD-L1-positive (combined positive score ≥10) and included patients with at least 6 months since treatment in the curative setting.1 Patients were randomized 1:1 to sacituzumab govitecan (10 mg/kg intravenously on days 1 and 8 of 21-day cycles) plus pembrolizumab (200 mg on day 1 of 21-day cycles; maximum 35 cycles; n = 221) or investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) plus pembrolizumab (n = 222). Up to 35% of enrolled patients had de novo metastatic TNBC. The primary endpoint was PFS by BICR per RECIST v1.1; secondary endpoints included OS, objective response rate (ORR), duration of response (DOR), safety, and quality of life. Exploratory endpoints included PFS2, TFST, and TSST. Patients in the chemotherapy plus pembrolizumab arm were offered second-line sacituzumab govitecan monotherapy provided on-study following BICR-verified disease progression, and could also receive sacituzumab govitecan commercially or other subsequent treatments per local practice.

ASCO Expert Perspective on ASCENT-04 Results

"Updated results from ASCENT-04 show that the benefit of sacituzumab govitecan plus pembrolizumab persisted beyond first disease progression with improvement in PFS2 and median time to first subsequent treatment, despite the crossover design of the trial and sacituzumab govitecan being the most commonly used second-line therapy among patients in the chemotherapy plus pembrolizumab arm. These results further support the use of sacituzumab govitecan and pembrolizumab in this patient population and are especially meaningful in a disease where improved outcomes are urgently needed," said Eleonora Teplinsky, MD, head of Breast and Gynecologic Medical Oncology at Valley-Mount Sinai Comprehensive Cancer Care and an ASCO Expert in breast cancer.³

REFERENCES

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

2. Tolaney S, Kalinsky K, Schmid P, et al. Sacituzumab govitecan plus pembrolizumab versus chemotherapy plus pembrolizumab for previously untreated PD-L1-positive metastatic triple-negative breast cancer: ASCENT-04/KEYNOTE-D19. N Engl J Med. 2026;394:354-366. doi:10.1056/NEJMoa2503001

3. American Society of Clinical Oncology. Sacituzumab govitecan helps some patients with PD-L1-positive triple-negative breast cancer live longer without cancer progression. ASCO press release. June 2, 2026. Accessed June 2, 2026. https://tinyurl.com/4ty6s3mf