ASCENT-04 Data Yields Longer PFS2 in Previously Untreated Metastatic TNBC

Results from the phase 3 ASCENT-04 trial (NCT05382286) showed first-line sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) incurred a longer progression-free survival (PFS) after next line of treatment (PFS2) compared with chemotherapy plus pembrolizumab for patients with previously untreated, PD-L1–positive locally advanced unresectable or metastatic triple-negative (mTNBC).

The results, which were presented during the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that at a median follow-up of 14.0 months (range, 0.1-28.6), the median PFS2 was not reached (NR; 95% CI, NR-NR) in the sacituzumab govitecan/pembrolizumab arm (n = 221) vs 21.0 months (95% CI, 16.0-NR) in the chemotherapy/pembrolizumab arm (n = 222), translating to a 33% reduction in the risk of a PFS2 event (stratified HR, 0.67; 95% CI, 0.48-0.95). The benefit emerged despite a high rate of crossover, as 96 of 119 patients (81%) in the chemotherapy/pembrolizumab arm who went on to receive subsequent therapy received sacituzumab govitecan in any later line.

“PFS2 was improved in those randomly assigned to sacituzumab govitecan plus pembrolizumab compared with chemotherapy plus pembrolizumab, despite the high crossover rate of about 80%, indicating a sustained long-term benefit beyond first progression,” lead study author Kevin Kalinsky, MD, MS, FASCO, said in a presentation of the data.

Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology, and director of the Glenn Family Breast Center at Winship Cancer Institute, of Emory University School of Medicine, in Atlanta, Georgia.

How was the ASCENT-04 trial designed?

ASCENT-04/KEYNOTE-D19 randomly assigned 443 patients 1:1 to receive sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab at 200 mg on day 1 of each 21-day cycle, or physician’s choice of chemotherapy in the form single-agent paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin, plus pembrolizumab.

Eligible patients had previously untreated, locally advanced, unresectable or metastatic TNBC with PD-L1–positive disease defined as a combined positive score of 10 or higher and were at least 6 months removed from treatment in the curative setting. Prior exposure to anti–PD-(L)1 therapy was permitted. Treatment continued until blinded independent central review (BICR)–verified progression or unacceptable toxicity.

Control-arm patients with BICR-verified progression were offered second-line sacituzumab govitecan monotherapy through the study, although they could opt to receive it commercially as local standard of care.

PFS by BICR was the primary end point; sacituzumab govitecan plus pembrolizumab previously demonstrated a median PFS of 11.2 months (95% CI, 9.3-16.7) vs 7.8 months (95% CI, 7.3-9.3) with chemotherapy plus pembrolizumab (stratified HR, 0.65; 95% CI, 0.51-0.84; P < .001).² The 6-month PFS rate in the sacituzumab govitecan arm was 71.6% (95% CI, 64.9%-77.3%) vs 63.2% (95% CI, 56.2%-69.4%) in the chemotherapy arm; the 12-month PFS rates were 48.3% (95% CI, 40.6%-55.6%) and 32.9% (95% CI, 26.0%-40.0%). Sacituzumab govitecan–based regimens have also shown a consistent first-line PFS benefit across biomarker-defined subgroups in advanced TNBC.^3,4 Biomarker subgroup data from ASCENT-04 and ASCENT-03 (NCT05382299) were also reported at this year’s meeting.

PFS2, time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) served as exploratory end points.¹ This post hoc analysis used the primary analysis data cutoff date of March 3, 2025. PFS2 was defined as the time from randomization to first documented progression on next-line therapy per investigator assessment, or death from any cause, whichever occurred first.

“PFS2 can be used to measure long-term clinical benefit when overall survival data are immature and is particularly valuable when overall survival is confounded by crossover,” Kalinsky noted.

What did the PFS2 and subsequent-therapy analyses show in PD-L1+ mTNBC?

PFS2 events occurred in 55 patients in the sacituzumab govitecan arm vs 83 patients in the chemotherapy arm. The PFS2 event-free probability was 71.9% (95% CI, 64.5-78.0) vs 53.0% (95% CI, 44.5%-60.8%) at 18 months and 63.7% (95% CI, 51.1-73.9) vs 45.6% (95% CI, 35.6%-55.1%) at 24 months for the respective arms.

The median TFST was 17.3 months (95% CI, 12.7-NR) with sacituzumab govitecan plus pembrolizumab vs 9.8 months (95% CI, 8.7-10.9) with chemotherapy plus pembrolizumab (stratified HR, 0.59; 95% CI, 0.46-0.76), and the median TSST was NR (95% CI, 22.9-NR) vs 21.0 months (95% CI, 16.6-NR; stratified HR, 0.82; 95% CI, 0.59-1.14).

At the data cutoff, 43% of patients in the sacituzumab govitecan arm remained on study treatment vs 23% of those in the chemotherapy arm. Among patients who discontinued first-line treatment, 55% in the sacituzumab govitecan arm and 70% in the chemotherapy arm received a second-line or later therapy. A subsequent antibody-drug conjugate (ADC) was received by 19% of the sacituzumab govitecan arm vs 82% of the chemotherapy arm, and subsequent sacituzumab govitecan specifically was received by 4% vs 81% of patients, respectively.

In the second line, most patients in the sacituzumab govitecan arm received chemotherapy (33%), whereas 77% of patients in the chemotherapy arm received sacituzumab govitecan. Moreover, 14% vs 17% of patients in the respective arms went on to receive third-line therapy.

“Time to first and second subsequent therapies demonstrate that participants receiving frontline sacituzumab govitecan and pembrolizumab experience a longer initial disease control and delayed need for the initiation of subsequent therapy,” Kalinsky said.

What did the safety analysis show with sacituzumab govitecan plus pembrolizumab?

The adverse effects (AEs) observed were consistent with the known profiles of both agents, with no new safety signals observed, Kalinsky noted.

Grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 71% of patients in the sacituzumab govitecan arm vs 70% of those in the chemotherapy arm. TEAEs leading to treatment discontinuation were less frequent with the ADC-based combination (12%) than with chemotherapy plus pembrolizumab (31%), as were TEAEs leading to dose reduction (35% vs 44%). Treatment-emergent serious AEs occurred in 38% vs 31% of patients, respectively, and TEAEs leading to death occurred in 3% of patients in each arm (treatment related in 1% vs < 1%).

The most common all grade AEs reported in the sacituzumab govitecan and chemotherapy arms, respectively, included neutropenia (63% vs 59%), fatigue (58% vs 56%), nausea (68% vs 38%), diarrhea (70% vs 29%), anemia (37% vs 51%), alopecia (52% vs 32%), constipation (41% vs 35%), increased alanine aminotransferase level (20% vs 30%), vomiting (29% vs 14%), headache (25% vs 17%), increased aspartate aminotransferase level (16% vs 25%), rash (21% vs 20%), leukopenia (19% vs 21%), thrombocytopenia (5% vs 29%), and peripheral neuropathy (7% vs 21%).

What are the implications for first-line treatment of PD-L1+ mTNBC?

“These results support the use of the combination of sacituzumab govitecan and pembrolizumab as a new frontline standard of care for patients with PD-L1–positive advanced triple-negative disease,” Kalinsky concluded.

Disclosures: Kalinsky reported consulting or advisory roles with Mersana, AstraZeneca, Bicycle Therapeutics, BioTheranostics, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, Menarini Silicon Biosystems, Merck, Novartis, Pfizer, ProteinQure, Puma Biotechnology, Regor, and Relay Therapeutics; institutional research funding from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen; and employment and stock ownership held by an immediate family member with ADC Therapeutics and EQRx.

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. Abstract LBA1000.
2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959
3. Barrios C, Hurvitz SA, Tolaney SM, et al. ASCENT-03: Efficacy by biomarker subgroup with sacituzumab govitecan (SG) vs chemotherapy (chemo) in participants (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are not candidates for PD-(L)1 inhibitors (PD-[L]1i). J Clin Oncol. 2026;44(suppl 16):1014. doi:10.1200/JCO.2026.44.16_suppl.1014
4. Tolaney SM, Schmid P, de Azambuja E, et al. ASCENT-04: Analysis of efficacy by biomarker subgroups with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2026;44(suppl 16):1013. doi:10.1200/JCO.2026.44.16_suppl.1013