Trials Demonstrate First-Line Role of Sacituzumab in Metastatic TNBC

The antibody-drug conjugate sacituzumab govitecan (Trodelvy) has emerged as an option for treating patients with metastatic triple-negative breast cancer (mTNBC). In a virtual Case-Based Roundtable event for oncologists in Tennessee, moderator Sara Nunnery, MD, MSCI, and participants discussed their impressions of the trial results supporting its use for PD-L1–positive mTNBC, as well as the emerging data in the PD-L1–negative space in the first line of therapy. They considered when chemotherapy plus pembrolizumab (Keytruda) could still be used and how factors such as time to response, site of metastasis, and disease burden affect outcomes of treatment.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• What are your reactions to the ASCENT-04 clinical trial (NCT05382286) data? ​
• What do you view as the pros and cons of using conventional chemotherapy vs sacituzumab govitecan in combination with pembrolizumab for mTNBC? ​
• Approximately what proportion of your patients with disease progression on first-line therapy for mTNBC go on to receive a second line of therapy?

Sara Nunnery, MD, MSCI: What proportion of your patients with disease progression on first-line therapy go on to the second line or third line? Do you feel like most patients make it to the second line in your practice, or are you seeing different outcomes?

Ibrahim N. Nakhoul, MD: Most of them do.

Susanna Awoyode, MD: [In terms of] what patients to opt for pembrolizumab/chemotherapy over sacituzumab/pembrolizumab, if the patient’s coming in with a huge burden of disease, I might want to do chemotherapy with pembrolizumab in that patient, because it might give me a better response and a faster response than sacituzumab.

Nunnery: It may be helpful to see some time to response data. I think that’s always valuable to see. It’s a good point.

DISCUSSION QUESTIONS

• Which efficacy end points are most meaningful to you in the second line?
• What other factors influence your decision making? ​

Nunnery: What efficacy end points are most meaningful to you in the second line? I think we all agree that progression-free survival [PFS] is very meaningful. In terms of other factors that influence your decision making, Dr Awoyode made a great point about how time to response can be helpful as another data point. Any other factors that sway you when evaluating all this new data?

David Chism, MD: Some of the studies are going to look specifically at the sites of disease, whether they have central nervous system or liver [metastasis], in terms of looking at the efficacy….

Nunnery: Yes, they did, and we do have a breakdown that’s available to see.¹ But to your point, most of these studies do not allow active brain metastases, so that’s definitely still a big area of unmet need. How would you change your sequencing if a patient had a germline BRCA mutation? If sacituzumab/pembrolizumab were approved in the first line, how would you sequence PARP inhibitors?

Revathi Kollipara, MD: I haven’t been in this situation, but I think it would depend on symptom burden. I probably wouldn’t do sacituzumab/pembrolizumab if they had a large disease burden.

Nunnery: Good points. What will you do if the patient had received pembrolizumab in the neoadjuvant setting? Is there any particular cutoff that is in your mind for when you would rechallenge with pembrolizumab?

Wei Lin, MD: In the study, it was 6 months. I think that I would follow that minimum of 6 months. Otherwise, you would consider them a non-responder.

Nunnery: That’s very reasonable. And what if the patient was not eligible for the PD-L1 inhibitor? What is your first-line treatment for those patients?

Nakhoul: [I would use] capecitabine.

Michael Hemphill, MD: Are there any smaller trials looking at capecitabine and immunotherapy? Are there any negative trials that you know of?

Nunnery: It’s a great question. I don’t know of any trials with capecitabine. It’s all been intravenous chemotherapy.

DISCUSSION QUESTION

• What are your impressions of the phase 3 ASCENT-03 trial (NCT05382299) for patients with previously untreated metastatic TNBC?

Nunnery: The ASCENT-03 study was looking at using first-line sacituzumab vs chemotherapy for PD-L1–negative mTNBC. This include patients who were PD-L1 negative or PD-L1 positive who were not eligible to receive PD-L1 therapy, and then again, they’re using the same cutoffs as de novo stage IV disease, or those patients who have completed treatment 6 months or more after a curative intent chemotherapy. Patients were randomly assigned between sacituzumab and physician’s choice chemotherapy. We had a press release back in May that this trial was positive.² It met its primary end point of improving PFS, and we will see the full data presented at ESMO in October. [Editor’s note: sacituzumab resulted in a 38% reduction in risk of progression or death]. Potentially, we’ll be having sacituzumab move to the first line for all our patients with mTNBC.

Hemphill: Was this compared with single-agent chemotherapy?

Nunnery: They do have gemcitabine plus carboplatin as one of the potential options, along with nab-paclitaxel or paclitaxel. After discussion of this case, would you change any of your recommendations for this patient?

Nakhoul: If the options include sacituzumab plus pembrolizumab, then yes, probably.… If it’s approved, we will probably try that [in the first line].

Hemphill: I remember when I first started, 10% was a cut off for either estrogen receptor [ER] or progesterone receptor [PR]. That has dropped to 1%, which I assume is to capture a subset that might benefit from aromatase inhibitor therapy years ago. Now it’s almost flipped on its head, because you have some of these 3% and 5% [expressors] where the tumor by biology seems to be triple negative. I have concerns about trying to get that approved on immunotherapy. We have a big enough group that we will be able to do it, but still, what if this comes up in the real world?

Nunnery: It very likely will. I still feel like there’s a lot of variability in some of these newer trials that we’ve been opening. They have shifted away to allowing those patients with ER less than 10% or PR less than 10%, so I think a lot more of them are moving to include those patients, because in reality, we all treat them as triple negative, so it’s not helpful when they’re all excluded. But a lot of these trials still stick to that true ER negative, less than 1%, PR less than 1%.

Nakhoul: Do you have a hard time getting pembrolizumab for an ER-low tumor?

Nunnery: I’ve done a lot of [pembrolizumab] for them.… I can’t think of any issues I’ve had recently with it.

Awoyode: I haven’t had any problems getting it approved for my patients who’ve been ER-low or PR-low.

Nunnery: OK, good to hear.

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DISCLOSURES: There were no known relevant disclosures.

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. ASCENT-03: Trodelvy® demonstrates highly statistically significant & clinically meaningful improvement in progression free survival in patients with first-line metastatic triple-negative breast cancer who are not candidates for checkpoint inhibitors. News release. Gilead Sciences, Inc. May 23, 2025. Accessed May 27, 2025. https://tinyurl.com/37yv34pe