Dr Tolaney on the Efficacy of First-Line Sacituzumab Govitecan in Advanced IO-Ineligible TNBC

“We did see that the [time to second progression] is substantially longer in the sacituzumab arm compared [with] the chemotherapy arm, which is really reassuring, suggesting that those patients getting sacituzumab govitecan continue to do well, even beyond that first line of treatment.”

Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, reviewed the efficacy data and clinical implications of the phase 3 ASCENT-03 trial (NCT05382299), which evaluated sacituzumab govitecan-hziy in the first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who were ineligible for immunotherapy.

 was a randomized study comparing sacituzumab govitecan with chemotherapy of physician’s choice, which included paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin. Patients randomly assigned to the chemotherapy arm were offered sacituzumab govitecan at the time of confirmed progression, allowing for planned crossover.

The primary end point was progression-free survival (PFS) assessed by blinded independent central review. Tolaney noted that sacituzumab govitecan demonstrated a statistically significant improvement in PFS compared with chemotherapy, with a median PFS of 9.7 months (95% CI, 8.1-11.1) with sacituzumab govitecan vs 6.9 months (95% CI, 5.6-8.2) with chemotherapy (HR, 0.62; 95% CI, 0.50-0.77; 

 < .001). She emphasized that achieving this magnitude of PFS benefit in first-line TNBC, an aggressive subtype with historically limited frontline options, is clinically meaningful.

PFS rates at fixed time points also favored sacituzumab govitecan. At 6 months, the PFS rate was 65% (95% CI, 59%-71%) with sacituzumab govitecan vs 53% (95% CI, 47%-59%) with chemotherapy. At 12 months, PFS rates were 41% (95% CI, 34%-47%) and 24% (95% CI, 19%-30%), respectively.

Overall survival (OS) data remained immature at the time of data readout during the 

. Early OS results appeared similar between arms, likely influenced by the crossover design, in which patients progressing on chemotherapy subsequently received sacituzumab govitecan. Tolaney indicated that longer follow-up will be needed to determine whether OS differences emerge once survival curves mature.

ASCENT-03 also evaluated time to second progression (PFS2), defined as the time from randomization to progression on the next line of therapy. PFS2 was substantially longer for patients treated with sacituzumab govitecan (HR, 0.70; 95% CI, 0.55-0.90), suggesting that early use of the antibody-drug conjugate may provide sustained disease control extending beyond first-line treatment.

Tolaney concluded that ASCENT-03 establishes sacituzumab govitecan as an effective first-line option for patients with advanced TNBC who are not eligible for immunotherapy, and mature OS data will further clarify the long-term impact of incorporating sacituzumab govitecan earlier in the treatment sequence.

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Sara Tolaney, MD, MPH, discusses the clinical implications of sacituzumab govitecan in the first-line treatment of advanced triple-negative breast cancer.

Dr Tolaney on Implications of Data for Sacituzumab Govitecan in First-line Advanced TNBC

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 

. “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

 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; 

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 

, 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; 

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.

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

: 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.

 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.

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

. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109

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.

Articles

Joyce O'Shaughnessy, MD, discusses ways that data with sacituzumab govitecan and Dato-DXd may shift treatment standards for patients with mTNBC.

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

Treatment with sacituzumab govitecan-hziy (Trodelvy) led to a 38% reduction in the risk of disease progression or death vs chemotherapy in patients with previously untreated, locally advanced unresectable, or metastatic triple-negative breast cancer (TNBC) who were ineligible for PD-1/PD-L1 inhibitors, according to findings from the phase 3 ASCENT-03 trial (NCT05382299) presented at the 

“This data might support a potential new standard, potential good option for patients with triple-negative breast cancer when they develop metastasis and are unable to receive immune checkpoint inhibitors,” Javier C. Cortés, MD, PhD, head of the International Breast Cancer Centre in Barcelona, Spain, said during a presentation of the data.

How did sacituzumab govitecan perform against chemotherapy in mTNBC?

Among patients treated with sacituzumab govitecan, median PFS by blinded independent central review (BICR) was 9.7 months (95% CI, 8.1-11.1) compared with 6.9 months (95% CI, 5.6-8.2) with chemotherapy (HR, 0.62; 95% CI, 0.50-0.77; 

 <.001). Further, PFS rates were superior with sacituzumab govitecan compared with chemotherapy at 6 months (65% [95% CI, 59%-71%] vs 53% [95% CI, 47%-59%], respectively) and 12 months (41% [95% CI, 34%-47%] vs 24% [95% CI, 19%-30%)].

When assessed by the investigators, PFS in the sacituzumab govitecan arm was 9.6 months (95% CI, 8.3-10.6), compared with 6.8 months with chemotherapy (95% CI, 5.6-7.2; HR, 0.64; 95% CI, 0.52-0.79). The 6- and 12-month PFS rates with sacituzumab govitecan were 65% (95% CI, 59%-70%) and 52% (95% CI, 46%-58%), respectively, compared with 38% (95% CI, 32%-44%) and 22% (95% CI, 17%-27%) with chemotherapy.

PFS benefit was observed across all patient subgroups, including by age, ECOG PS, geographic region, disease state, PD-L1 status, and chemo selection prior to randomization.

In addition, the objective response rate (ORR) with sacituzumab govitecan was 48% (95% CI, 42%-54%) compared with 46% (95% CI, 40%-52%) for those received chemotherapy (stratified odds ratio [OR], 1.1; 95% CI, 0.8-1.6). In the sacituzumab govitecan and chemotherapy arms, respectively, 20 patients (7%) and 15 patients (5%) experienced a complete response, 115 (41%) and 112 (40%) had a partial response, 113 (41%) and 101 (36%) had stable disease, and 14 (5%) and 36 (13%) developed progressive disease.

“Objective response rates were similar in both treatment groups; however, duration of response was substantially longer with sacituzumab govitecan vs chemo,” Cortés noted. Median DOR was 12.2 months (95% CI, 9.7-13.8) with sacituzumab govitecan compared with 7.2 months for chemotherapy (95% CI, 5.7-8.4).

Time to response by BICR was 1.6 months in both the sacituzumab govitecan (95% CI, 0.7-16.7) and chemotherapy (95% CI, 0.9-6.8) groups.

Overall survival (OS) data was not mature at the time of the presentation; however, Cortés acknowledged that, of the 179 patients who initiated subsequent treatment after chemotherapy, 147 (82%) received sacituzumab govitecan.

At the time of the presentation, median OS was 21.5 months (95% CI, 17.7-not reached [NR]) and 20.2 months (95% CI, 18.2-NR), respectively (HR, 0.98; 95% CI, 0.75-1.30).

Median PFS2 was 18.2 months (95% CI, 15.9-NR) and 14.0 months (12.5-17.4) with sacituzumab govitecan and chemotherapy, respectively (HR, 0.70; 95% CI, 0.55-0.90).

What are the adverse events (AEs) associated with sacituzumab govitecan?

The median duration of treatment with sacituzumab govitecan was 8.3 months (range, <0.1-28.7).

Treatment-emergent AEs (TEAEs) occurred in 99% and 97% of patients in the sacituzumab govitecan and chemotherapy arms, respectively, with grade 3 or higher events occurring in 66% and 62%, with 61% and 53% being treatment related.

In total, 71 serious TEAEs occurred in the sacituzumab govitecan arm, 46 of which were treatment related. TEAEs let to treatment discontinuation in 10 patients, while 181 and 101 patients experienced dose interruptions and reductions, respectively. There were 7 TEAEs leading to death with sacituzumab govitecan. Cortés noted that the majority were due to infections, including 5 infections that were secondary to neutropenia. None of the 5 patients, who each had risk factors for febrile neutropenia, received prophylaxis with G-CSF

The most common grade 3 or higher AEs included neutropenia (43%), diarrhea (9%), and leukopenia (7%). The incidence of AEs that led to discontinuation of sacituzumab govitecan or chemotherapy was 4% and 12%, respectively.

What are the unmet needs in advanced TNBC?

“Chemotherapy for many years, has been the mainstay of treatment for metastatic triple-negative breast cancer compared to other subtypes, and the absolute improvements in median overall survival have been relatively modest over time,” Ana C. Garrido-Castro, MD, medical oncologist, Dana-Farber Cancer Institute and assistant professor of medicine, Harvard Medical School, in Boston, said during an invited discussion of the presentation.

“…And the sobering truth is that across studies in the US and Europe, approximately 25% to 30% of patients diagnosed with metastatic TNBC are no longer alive at 6 months from their metastatic diagnosis, and 6 months is just about the median PFS of first-line chemotherapy. So, if there is a new drug that is able to significantly improve PFS with an acceptable toxicity profile, this should be sufficient to change the current standard of care in the first-line setting.”

According to Cortés, most patients with previously untreated metastatic TNBC are not candidates to receive treatment with a PD-(L)1 inhibitor. Further, about half of the patients treated in the first line do not go on to receive a second line of therapy. “Unfortunately, the great majority of our patients will experience progressive disease, and we need to treat them with subsequent lines of therapies,” he added. “There is an urgent need for improved therapeutic options in earlier lines of therapy to delay progression and time to next line of treatment.”

Sacituzumab govitecan is approved to treat metastatic TNBC in the second-line setting and beyond, as well as for the treatment of patients with pre-treated HR-positive/HER2-negative metastatic breast cancer globally.

The investigators conducted the international, phase 3, open-label, randomized trial of sacituzumab govitecan in patients with previously untreated, locally advanced, unresectable or metastatic TNBC who are not candidates for immune checkpoint therapy.

In the trial, investigators randomized patients 1:1 to receive either 10 mg/kg IV sacituzumab govitecan on days 1 and 8 of 21-day cycles (n = 279) or one of the following chemotherapy regimens (n = 279): 90 mg/m

 nab-paclitaxel on days 1, 8, and 15 of 28-day cycles, or 1000 mg/m

 gemcitabine plus carboplatin AUC2 on days 1 and 8 of 21-day cycles.

Treatment was continued until BICR-verified progression or unacceptable toxicity. Eligible patients were offered to cross over to receive second-line sacituzumab govitecan following BICR-verified disease progression.

Patients were eligible for the trial if they were not candidates for PD-(L)1 inhibitors and were 6 months or less since treatment in the curative setting. Previously treated, stable central nervous system metastases were allowed.

“Knowing that sacituzumab govitecan crossover could impact their final OS results and complicate, potentially, their path towards regulatory approval, the study team should be applauded,” Garrido-Castro commented. “In my opinion, inclusion of crossover should be considered for therapies with known overall survival advantage, particularly in those patient populations with poor prognosis, though we and regulatory agencies must be thoughtful then of how to interpret the results and the impact of crossover.”

PFS, assessed by BICR, served as the primary end point of the study. Secondary end points included OS, ORR, DOR, time to response (TTR) by BICR, safety, and quality of life.

In the sacituzumab govitecan and chemotherapy arms, median age was 56 (range, 22-84) and 54 years (range, 23-86), respectively; and the majority were White (64% each), had an ECOG PS of 0 (66% vs 67%), were PD-L1 negative (99% each), had lung metastases (59% vs 61%), and received prior neoadjuvant therapies (66% vs 68%). Further, 48% of patients in each arm experienced recurrence after 12 months or more following curative treatment

Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: A randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin Germany. Abstract LBA20.

Cortés J, Punie K, Barrios C, et al. Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. 

Sacituzumab govitecan-hziy demonstrated a 38% reduction in disease progression or death risk compared to chemotherapy in patients with advanced triple-negative breast cancer (TNBC) ineligible for PD-1/PD-L1 inhibitors. The phase 3 ASCENT-03 trial showed improved progression-free survival (PFS) and duration of response with sacituzumab govitecan. Although objective response rates were similar, sacituzumab govitecan had a longer median duration of response. Adverse events were common, with neutropenia being the most frequent. The trial underscores the need for better first-line therapies in TNBC, given the limited survival benefits of existing treatments.

Sacituzumab govitecan reduced the risk for disease progression or death by 38% vs chemotherapy in previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer.

Measuring the Effect of Experimental Approaches in Metastatic TNBC | Supplements and Featured Publications

Dr Tolaney on Implications of Data for Sacituzumab Govitecan in First-line Advanced TNBC

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

Sacituzumab Govitecan Reduces Risk of Progression or Death by 38% in PD-1/PD-L1–Ineligible TNBC