First-line treatment with the antibody drug conjugate sacituzumab govitecan-hziy plus pembrolizumab led to a longer progression-free survival after next line of treatment—ie, progression-free survival-2 (PFS2)—than chemotherapy plus pembrolizumab in patients with previously untreated, PD-L1–positive advanced triple-negative breast cancer, according to an exploratory post hoc analysis of the phase III ASCENT-04/KEYNOTE-D19 trial¹ presented at the 2026 ASCO Annual Meeting by Kevin Kalinsky, MD, MS, FASCO, Professor and Director in the Division of Medical Oncology and Co-Director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University School of Medicine, Atlanta.

Kevin Kalinsky, MD, MS, FASCO

At a median follow-up of 14.0 months, median PFS2 was not reached in the sacituzumab govitecan/pembrolizumab arm and was 21.0 months in the chemotherapy/pembrolizumab arm, translating to a 33% reduction in the risk of a PFS2 event with a confidence interval (CI) that did not cross one (hazard ratio [HR], 0.67; 95% CI, 0.48-0.95). The benefit emerged despite a high crossover rate (81%) in the control arm, many of whom went on to receive subsequent sacituzumab.

“PFS2 was improved in those randomly assigned to sacituzumab govitecan plus pembrolizumab compared with chemotherapy plus pembrolizumab, despite the high crossover rate, indicating a sustained long-term benefit beyond first progression,” Dr. Kalinsky said, adding that this regimen also yielded longer median time to second subsequent treatment. “These results support the use of the combination of sacituzumab govitecan and pembrolizumab as a new front-line standard of care for patients with PD-L1–positive advanced triple-negative disease,” Dr. Kalinsky said.

About ASCENT-04

ASCENT-04/KEYNOTE-D19 enrolled 443 patients with previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1), defined as a combined positive score ≥ 10. Prior exposure to anti–PD-(L)1 therapy was permitted. Patients were randomized to receive sacituzumab govitecan or physician’s choice of chemotherapy in the form single-agent paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin, plus pembrolizumab. Upon progression, control-arm patients were offered second-line sacituzumab govitecan monotherapy through the study, or to receive it commercially as local standard of care.

As previously reported, the primary endpoint—progression-free survival by blinded independent review—was significantly improved in the sacituzumab arm, with a median of 11.2 months, vs 7.8 months in the control arm (HR, 0.65; P < .001).²At 12 months, progression-free survival rates were 48.3% vs 32.9%, respectively. Benefits were consistent across biomarker-defined subgroups.

New Exploratory Analysis

PFS2 was defined as the time from randomization to first documented progression on next-line therapy per investigator assessment, or death from any cause. PFS2 events occurred in 55 patients in the sacituzumab govitecan arm vs 83 patients in the chemotherapy arm, with a PFS2 event-free rate of 71.9% vs 53.0% at 18 months and 63.7% vs 45.6% at 24 months for the respective arms. Dr. Kalinsky noted that the duration of response, reflected by the PFS2, might be attributed to the robust immunogenic cell death that can be achieved by combining an antibody-drug conjugate with immunotherapy.

To “help contextualize PFS2,” the findings on subsequent therapy are important, he said. Time to first subsequent therapy and time to second subsequent therapy served as additional exploratory end points. The median time to first subsequent treatment was 17.3 vs 9.8 months, respectively (HR, 0.59; 95% CI, 0.46–0.76), and the median time to second subsequent therapy was not reached vs 21.0 months (HR, 0.82; 95% CI, 0.59–1.14), Dr. Kalinsky reported.

The adverse effects observed were consistent with the known profiles of both agents, with no new safety signals observed.

Subsequent Treatment Findings

At data cutoff, 43% of patients in the sacituzumab govitecan arm remained on first-line treatment vs 23% in the chemotherapy arm. After discontinuing first-line therapy, 55% in the sacituzumab arm and 70% in the chemotherapy arm received a second-line or later drug, which was an antibody-drug conjugate in 19% of the sacituzumab arm vs 82% of the chemotherapy arm; subsequent sacituzumab govitecan, specifically, was received by 4% vs 81% of patients, respectively. As a second line of treatment, 33% in the sacituzumab arm received chemotherapy, 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.

The data on time to first and second subsequent therapies indicate, Dr. Kalinsky said, “that participants receiving front-line sacituzumab govitecan and pembrolizumab experience a longer initial disease control and delayed need for the initiation of subsequent therapy.” 

DISCLOSURE: Dr. 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, et al: 2026 ASCO Annual Meeting. Abstract LBA1000. Presented June 2, 2026.

2. Tolaney SM, de Azambuja E, et al: N Engl J Med 394:354-366, 2026.

EXPERT POINT OF VIEW

The invited discussant of the ASCENT-04 exploratory analysis was Meredith M. Regan, ScD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, does not support the growing use of progression-free survival-2 (PFS2) as a trial endpoint when the trial is designed to answer whether an experimental first-line therapy is superior to standard first-line therapy. “PFS2 is not a meaningful measure of clinical benefit in this context,” she said.

Meredith M. Regan, ScD

“PFS2 is a dubious outcome measure, with a really unclear endpoint definition,” said Dr. Regan, a biostatistician. “In such trials, comparison of PFS2 does not inform whether experimental therapy should be used in the first line or later lines. Neither do the subsequent therapy endpoints, but they do at least have clear definitions, and I do feel that these can provide insightful summaries of the patient’s experience across lines of therapy.”

Dr. Regan pointed out that the U.S. Food and Drug Administration (FDA) guidance on oncology endpoints does not mention PFS2 and generally does not use it for its benefit-to-risk assessment in such clinical trials, based on a variety of concerns.²

“There’s total lack of clarity of what we mean by PFS2 to the whole construct of the outcome measure,” she said. “What really are we trying to capture? Does PFS2 answer whether there is an advantage to using an experimental treatment in the first line vs second line? And can we consider it a surrogate for overall survival?”

Her answer to both these questions was no. As ASCENT-04 was designed, with its primary objective and all its heterogeneity, she said, the PFS2 endpoint does not isolate the efficacy effects attributable to the experimental therapy and thus does not align with the question of sequencing therapy. And there is inadequate evidence that PFS2 is a surrogate for overall survival in metastatic breast cancer, Dr. Regan indicated.

Dr. Regan was hopeful, however, that PFS2 could become a more useful endpoint if researchers would collaborate to eliminate the current heterogeneity and arrive at a uniform definition, common setting for its use, and reliable way to measure it. “We have all these trials with individual patient data that we can share and put together to look at definitions and implementation,” she noted. 

DISCLOSURE: Dr. Regan had personal financial disclosures for Bristol-Myers Squibb, Merck, AstraZeneca, Roche, Tersea, and Tolmar.

REFERENCES

1. Kalinsky K, et al. Progression-free survival after next line of treatment and subsequent therapies in the ASCENT-04 study of participants with previously untreated PD-L1+ metastatic triple-negative breast cancer treated with sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab. 2026 ASCO Annual Meeting. Abstract LBA1000. Presented June 2, 2026.

2. Fiero MH, Shah M, Amiri-Kordestani L: Is progression-free survival 2 ready for prime time in US Food and Drug Administration regulatory decision making? J Clin Oncol 44:1865-1868, 2026.