Two-drug combo rises to the challenge as 1L Tx for mTNBC

In the primary analysis of the ASCENT-04/KEYNOTE-D19 study, a combination regimen comprising sacituzumab govitecan (SG) and pembrolizumab delivers significant progression-free survival (PFS) benefit in women with previously untreated PD-L1+ advanced triple-negative breast cancer (TNBC).

“ASCENT-04 is the first randomized phase III study to evaluate the efficacy and safety of an antibody drug conjugate (ADC) combined with an immune checkpoint inhibitor (ICI) for the first-line (1L) treatment of patients with PD-L1+ metastatic TNBC (mTNBC),” said Dr Sara Tolaney from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, US, during her presentation at ASCO 2025.

After a median follow-up of 14 months, there was a statistically significant and clinically meaningful improvement in the primary endpoint of PFS by blinded independent central review (BICR) with SG plus pembrolizumab vs chemo plus pembrolizumab (median 11.2 vs 7.8 months; hazard ratio [HR], 0.65; p<0.001). This translates to a 35-percent reduction in the risk of disease progression or death. [ASCO 2025, abstract LBA109]

“The Kaplan-Meier curves started to separate early and continued to widen over time, with benefits seen across key landmark timepoints,” said Tolaney. Nearly half of the patients on the investigational combo were free of progression or death at 12 months compared with only a third of those in the chemo arm.

The PFS by BICR aligned with that observed by investigator assessment (median 11.3 vs 8.3 months; HR, 0.67; p=0.002).

The benefit with SG plus pembrolizumab was seen across key prespecified subgroups, except for women who had prior ICI therapy. “I would, however, interpret this with caution, as there were only 20 patients in this subgroup, leading to very wide confidence intervals and making it difficult to draw any definitive conclusions,” Tolaney noted.

The overall survival (OS) data were immature (26 percent maturity rate). Nonetheless, there was an early positive trend in favour of the experimental combo vs the chemo and pembrolizumab regimen (HR, 0.89). Of note, 81 percent of patients who received any subsequent treatment after discontinuation of chemo plus pembrolizumab were given SG.

Objective response rate was higher with SG plus pembrolizumab vs chemo plus pembrolizumab (60 percent vs 53 percent; stratified odds ratio, 1.3), as was complete response rate (13 percent vs 8 percent). Importantly, median duration of response was markedly longer with the former vs the latter regimen (16.5 vs 9.2 months).

Despite the longer median duration of treatment with the investigational vs chemo-based combo (~9 vs ~6 months), the proportions of grade 3/4 adverse events (AEs) were similar between arms (71 percent vs 70 percent). There were more treatment-related serious treatment-emergent AEs (TEAEs) tied to SG plus pembrolizumab than its comparator (28 percent vs 19 percent), but fewer TEAEs leading to treatment discontinuation (12 percent vs 31 percent) and dose reductions (35 percent vs 44 percent). Importantly, treatment-related TEAEs leading to death were low (1 percent in each arm).

The most common grade ≥3 toxicities associated with SG plus pembrolizumab treatment include neutropenia (43 percent), diarrhoea (10 percent), and fatigue (8 percent). Overall, the AEs observed were consistent with the known individual toxicity profiles of the agents utilized, suggesting no additive toxicities.

Looking at AEs of special interest, the 10-percent incidence of grade ≥3 diarrhoea with the investigational regimen aligns with those reported in prior trials on SG. There was no increase in the rate of immune-related toxicities with the experimental regimen.

“[Taken together,] these data support the use of SG plus pembrolizumab as a potential new 1L standard of care for patients with previously untreated PD-L1+ mTNBC,” said Tolaney.

A critical unmet need

TNBC is an aggressive BC subtype comprising ~15 percent of cases, Tolaney noted. About 40 percent of TNBCs are PD-L1+. The previously reported median PFS with chemo plus ICI for PD-L1+ mTNBC in the 1L setting ranges from 7 to 9 months. Unfortunately, about half of patients who initiate therapy for mTNBC are not able to go on to receive second-line (2L) treatment due to deterioration in health, disease progression, or death, Tolaney said.

“[Hence,] there is an unmet need for better treatments in the 1L setting for patients with PD-L1+ mTNBC,” said Tolaney.

Discussant Dr Sonya Reid from the Vanderbilt Cancer Center, Nashville, Tennessee, US, echoed Tolaney’s sentiments. “Despite significant therapeutic advancements in BC, TNBC remains the most significant unmet clinical need in breast oncology. In the real world, 34 percent of patients die before receiving 2L therapies. We really need to think about getting better drugs upfront for our patients.”

Combining ADCs and ICIs

SG is the only TROP-2-directed ADC that has previously shown improvements in both PFS and OS compared with chemo in pretreated triple-negative disease. It is currently approved as a second- and later-line treatment alternative for mTNBC and pretreated HR+/HER2- mBC in several countries, noted Tolaney. “There has been much interest in trying to combine ADCs with ICIs given robust preclinical and clinical data for this combination.”

In ASCENT-04, 443 women (median age 54 years) were randomized 1:1 to receive IV SG 10 mg/kg (days 1 and 8) plus pembrolizumab 200 mg (day 1) or physician’s choice of chemo plus pembrolizumab in 21-day cycles. Chemo options include paclitaxel 90 mg/m², nabpaclitaxel 100 mg/m², or gemcitabine 1,000 mg/m² plus carboplatin AUC 2 (GC). Those in the chemo arm may cross over to 2L SG.

Thirty-four percent of participants had de novo disease, 18 percent had recurrence within 6–12 months, and 48 percent had recurred >12 months from completion of systemic therapy in the early disease setting. The primary metastasis sites were the lymph nodes (70 percent), followed by the lung (46 percent), liver (25 percent), and bone (24 percent).

About half of the patients in the chemo arm received taxanes; the other half received GC. Five percent of patients had received a prior ICI in the early disease setting.

Earlier utilization of SG

“ASCENT-04 supports the potential for earlier utilization of SG in combination with pembrolizumab in the 1L treatment of PD-L1+ mTNBC,” Reid noted. “However, [we may] need to put that into context of where we are right now, when we are seeing an increase in the use of (neo)adjuvant pembrolizumab for patients with curative intent.”

“[We also] need to think about the OS data to understand whether the earlier use of SG translates to an OS advantage,” Reid continued. She recommended further investigation to ascertain the safety and efficacy of ADC sequencing.