Emerging ADC Data and Combination Strategies Are Set to Redefine First-Line TNBC Management

Ongoing research for patients with triple-negative breast cancer (TNBC) is largely driven by the need for improved first-line therapies that can durably extend survival across patient subsets, which data indicate may come in the form of antibody-drug conjugates (ADCs) such as sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), according to Joyce O'Shaughnessy, MD, who added that ADCs also have the potential to be combined with immunotherapy for increased benefit in certain populations.

“We are seeing better cytotoxic agents and better delivery platforms with ADCs,” O'Shaughnessy said in an interview with OncLive^®. “These are exciting times, and it's good to see that the standard of care [SOC] is changing for that first-line metastatic TNBC [mTNBC] population.”

In the interview, O'Shaughnessy discussed ways that data with sacituzumab govitecan may redefine treatment standards for patients with mTNBC based on PD-L1 status, what progression-free survival (PFS) data often indicate about the overall efficacy of mTNBC treatments, and the known safety profiles of ADCs in this setting.

She highlighted the PFS advantage seen with first-line sacituzumab govitecan plus pembrolizumab (Keytruda) vs pembrolizumab plus chemotherapy in patients with PD-L1–positive advanced or metastatic TNBC. Findings from the phase 3 ASCENT-04 trial (NCT05382286) presented at the 2025 ASCO Annual Meeting showed that the median PFS per blinded independent central review (BICR) was 11.2 months (95% CI, 9.3-16.7) in the sacituzumab govitecan arm (n = 221) vs 7.8 months (95% CI, 7.3-9.3) in the chemotherapy arm (n = 222; HR, 0.65; 95% CI, 0.51-0.84; P < .001).¹

Additionally, O’Shaughnessy spotlighted data from the phase 3 TROPION-Breast02 trial (NCT05374512) evaluating Dato-DXd in patients with locally recurrent inoperable or metastatic TNBC who were not eligible for immunotherapy. The findings, presented at the 2025 ESMO Congress, showed that the median PFS by BICR was 10.8 months (95% CI, 8.6-13.0) with Dato-DXd (n = 323) vs 5.6 months (95% CI, 5.0-7.0) with investigator’s choice of chemotherapy (n = 321; HR, 0.57; 95% CI, 0.47-0.69; P < .0001).²

O'Shaughnessy is co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at the Baylor Charles A. Sammons Cancer Center and The US Oncology Network in Dallas, Texas.

OncLive: How do the data from ASCENT-04 shape your current approach to treating patients with advanced TNBC?

O’Shaughnessy: The ASCENT-04 trial showed that the combination of sacituzumab govitecan and pembrolizumab was superior to chemotherapy plus pembrolizumab in that first-line mTNBC setting in patients with breast cancers that were PD-L1 positive. [This trial showed] a clear advance regarding PFS. We await overall survival [OS] data; those are immature.

[However, thus far, we have] a clear signal that this cytotoxic agent—the topoisomerase-1 inhibitor govitecan that's part of the sacituzumab govitecan [compound]—is superior to the taxanes and gemcitabine/carboplatin that we were using with pembrolizumab in the first-line setting. This is great to see. These are non–cross-resistant agents. [If] we have FDA approval and National Comprehensive Cancer Network guideline endorsement, [sacituzumab govitecan plus pembrolizumab will be] the new SOC for those patients.

In the first-line TNBC setting, what are the most pressing unmet needs, and how might emerging data with TROP-2–directed ADCs begin to address those gaps?

In first-line mTNBC, our big limitation is durability of response to therapy and improvement in OS. We [saw] a [data readout] regarding Dato-DXd in the first-line mTNBC setting [in the] TROPION-Breast02 trial. That [trial enrolled] a PD-L1–negative population, [as well as patients who were] PD-L1–positive and not appropriate candidates for a checkpoint inhibitor. [Dato-DXd] was being compared with standard first-line chemotherapy, which is capecitabine, nab-paclitaxel [Abraxane], or paclitaxel.

There was an improvement in OS [with Dato-DXd]. That's important. That's what we want to see and what we need in that mTNBC setting. At ESMO 2025, [we saw data from] a parallel trial with sacituzumab govitecan: the phase 3 ASCENT-03 trial [NCT05382299] in the PD-L1–negative population of patients who were not eligible for pembrolizumab. [ASCENT-03 compared] sacituzumab govitecan vs the same chemotherapy agents [as in TROPION-Breast02 in patients with] first-line mTNBC.

Why has PFS remained a key end point in TNBC clinical trials?

PFS remains an important end point. If there is a large enough delta of improvement in PFS [with an investigational agent] compared with a control, oftentimes in TNBC, that translates into improved OS. Unfortunately, the median OS is only approximately 16 to 18 months in mTNBC.

Sometimes, for example, in the ASCENT-04 trial, patients were given the opportunity to cross over from [the control arm of] pembrolizumab plus chemotherapy at disease progression to receive sacituzumab govitecan. [In total], 81% of patients [who received any subsequent treatment after discontinuing chemotherapy plus pembrolizumab] switched over.¹ Therefore, [most of the overall population in that trial] either received sacituzumab govitecan in the second-line setting, or sacituzumab govitecan in the first-line setting with pembrolizumab. It's unlikely we're going to see an OS advantage in that trial because patients were given that wonderful opportunity to receive sacituzumab govitecan [after progression on the control arm]. That's a trial design issue. That doesn't speak against the ability of the sacituzumab govitecan/pembrolizumab combination to improve OS. With all patients receiving sacituzumab govitecan [as late as the] second-line setting, we're not likely to see an OS advantage [in the investigational arm]. Therefore, that nice PFS advantage in ASCENT-04 is clinically meaningful to us.

With more TROP-2–directed ADCs and immunotherapy combinations being investigated in the TNBC treatment paradigm, how are you approaching AE management?

Regarding the first-line use of TROP-2–directed ADCs and immunotherapy, in ASCENT-04, for example, we did not see additional toxicities from pembrolizumab plus sacituzumab govitecan compared with chemotherapy plus pembrolizumab. That was reassuring. We saw standard toxicities as expected with sacituzumab govitecan. We saw immune-related adverse effects [irAEs] that pembrolizumab brought in, but [there was not a big] difference between the arms, so that's encouraging.

We'll have to wait for [readouts from] additional studies in the first-line settings, such as the phase 3 TROPION-Breast05 trial [NCT06103864], which is still enrolling; that's [investigating] Dato-DXd plus durvalumab vs chemotherapy plus pembrolizumab. Sacituzumab tirumotecan [SKB264/MK-2870] is also being evaluated in the first-line setting in combination with pembrolizumab. We'll have more data forthcoming, but so far, so good. In the phase 1/2 BEGONIA trial [NCT03742102] of Dato-DXd plus durvalumab [in patients with mTNBC], there wasn't anything untoward regarding irAEs or other AEs.

Are there clinical scenarios that might make you hesitant to reintroduce immunotherapy after progression in patients with TNBC?

Regarding rechallenging a patient with an immune checkpoint inhibitor in that first-line metastatic setting, if they had already been treated with pembrolizumab in the curative setting per the phase 3 KEYNOTE-522 trial [NCT03036488] regimen [of pembrolizumab plus chemotherapy], I wouldn't hesitate to do it if they met the eligibility criteria. For example, in ASCENT-04, patients had to have a treatment-free interval [after] the completion of adjuvant or neoadjuvant therapy in the curative setting of at least 6 months. If a patient meets those criteria, I would be comfortable retreating them, because the ASCENT-04 results were excellent, and I would want the patient to have the opportunity to have that benefit. [However], if a patient had a history of having been treated with pembrolizumab in the curative setting and had developed a significant and severe irAE—grade 4 or even serious, grade 3—I might be a bit more hesitant to reintroduce the checkpoint inhibitor.

References

1. 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
2. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.