How Sacituzumab Govitecan Is Reshaping First-Line Metastatic TNBC Care Following Updates to the NCCN Guideline

The National Comprehensive Cancer Network (NCCN) has granted sacituzumab govitecan (Trodelvy; Gilead) a Category 1 preferred designation for first-line treatment of metastatic triple-negative breast cancer (TNBC), marking a pivotal shift toward antibody-drug conjugates (ADCs) in this historically challenging setting. In this interview with Pharmacy Times, Jordan Hill, PharmD, BCOP, discusses the evidence behind the update, its implications for biomarker testing, how it changes real-world workflows, and what new data from ASCENT-03 and ASCENT-04 mean for patient care and shared decision-making.

Q:Sacituzumab govitecan was just added to the National Comprehensive Cancer Network (NCCN) Guidelines as a Category 1 preferred first-line treatment option for metastatic triple-negative breast cancer (TNBC)—and notably, this designation applies regardless of programmed death-ligand 1 (PD-L1) status in patients with no germline BRCA1/2 pathogenic variant. Can you walk us through what that Category 1 designation actually means in terms of the strength of evidence behind it, and why this particular update is significant?

Jordan Hill, PharmD, BCOP: Of course. In general, Category 1 just means there is high-level evidence, such as a phase 3 randomized trial. In addition to the level of evidence, it also means that there was uniform NCCN consensus, which they define as at least 85% support from the panel. It is not always the easiest to get that Category 1 recommendation from NCCN. This is a very exciting update, for sure, and particularly important because it really dramatically shifts the treatment paradigm in the metastatic triple-negative space away from traditional chemotherapy to antibody-drug conjugates in the first-line setting, which I think is really exciting for patients and providers.

Q:What does this shift mean for how we think about biomarker testing upfront—specifically, does PD-L1 status still matter in this new treatment landscape, and how should clinicians interpret these biomarker results when making first-line decisions?

Hill: Yeah, yes. That is a really important point to consider. I think in all of breast cancer, biomarker testing is extremely important. In this specific setting, in the metastatic triple-negative breast cancer space, there has not been much of a change to practice with this update as far as what biomarkers we are getting. Previously, both BRCA mutations as well as PD-L1 status dictated first-line treatment decisions, and that is still the case here. Even though the cytotoxic agent that is being chosen, whether that be with or without pembrolizumab (Keytruda; Merck), may change from chemotherapy to an antibody-drug conjugate, the biomarkers have not really changed in the information that we need to be able to make those first-line decisions.

Q:The guideline update hinges on biomarker-driven decision-making. How does this guideline change the upfront biomarker testing conversation, and what role do pharmacists play in making sure the right tests are ordered before treatment selection?

Hill: Absolutely. I really think that pharmacists have an integral role in ensuring that the necessary biomarker testing is not only occurring but also occurring as quickly as possible. In this setting, with metastatic triple-negative breast cancer, we really want to make sure that our initiation of treatment is as timely as possible. As soon as metastatic disease is even a concern, whether it is even back on final pathology, the conversation about biomarker testing—what needs tested, how we are going to send it—should be immediately started.

Because pharmacists are so integrated into the clinics, it is a really important and essential role for us to play in making sure that timeliness can occur. I know there are all sorts of background complicating factors like insurance and authorizations, but making sure those discussions around what biomarkers we need done and how quickly we can start that process really needs to happen as soon as possible.

Q:What does guideline-concordant care look like in practice for a patient newly diagnosed with first-line metastatic TNBC today? Walk us through the clinical decision tree a pharmacist would use and where you see the most common gaps between what the guideline recommends and what actually happens at the bedside.

Hill: For me, the decision tree really starts with the germline BRCA testing. Frequently, patients have already had this done. It is in the guidelines for early-stage triple-negative patients to receive this testing. If you have a patient who is a recurrence from an early-stage triple-negative breast cancer, a lot of times they will have already had this testing done. That is usually the first place I start.

There is obviously the scenario where they are de novo metastatic and this is all new, and we still have to get that testing. But that is usually the place that I start: have they already had this testing done, and what is the result? If a patient does have a germline BRCA mutation, we can start the process of initiating a PARP inhibitor without really having to wait for PD-L1 status. But that is not the majority of patients.

For people who are BRCA wild-type, next is determining that PD-L1 status. That does have a little bit of a delay while waiting for those results. Once those results are available, if they are BRCA wild-type and PD-L1 negative, then we can start the process for sacituzumab govitecan as a single agent. If they are BRCA wild-type and PD-L1 positive, then we would want to initiate sacituzumab govitecan with pembrolizumab.

Some gaps arise around somatic BRCA mutations. Every clinician may not do the exact same thing in that scenario. Some people may still treat with a PARP inhibitor first. But technically, what is in the guidelines is that germline BRCA is Category 1, and somatic is an option in certain circumstances in Category 2. That may not always be the same from provider to provider.

Additionally, when to start sacituzumab govitecan can vary. Now that sacituzumab govitecan is Category 1 preferred regardless of PD-L1 status, do you go ahead and get that agent started and then add pembrolizumab when the PD-L1 result comes back? Or is the thought more that you want to make sure you are starting immunotherapy when disease burden is highest, so even if they come back PD-L1 positive, you would ideally want to start it all at the same time? That is typically my preference. But delays in this very aggressive setting are problematic, so it may not always be the same in every patient scenario.

Q:From your own experience, have you seen guideline-concordant care implemented at your institution since this update? What barriers have you encountered, and what has worked well?

Hill: Yes. At least in my experience, the guideline-concordant care has been implemented pretty quickly and easily. I think the biggest challenge is the delay in waiting for those PD-L1 results. That is not specific to the recent update—that was the same before—but it is definitely one of the challenges. In an ideal setting, my preference would be to put in a sacituzumab govitecan with pembrolizumab treatment plan in the patient’s electronic medical record (EMR), get all of the background steps of insurance approval done, and then, as soon as the result comes back, go ahead with both agents. Or, if PD-L1 is negative, pull off the pembrolizumab and proceed with the single agent. But insurances do not like that. They want the PD-L1 result before approving any component.

So what ends up happening is: you wait for the result, then you put in the treatment plan, then you wait for the insurance to approve it. It is 2 delays. The logistics of getting treatment started quickly in this population—where you really do not want delays—is probably the biggest challenge.

Q:We’re now seeing important data from ASCENT-03 and ASCENT-04 in advanced or metastatic TNBC, particularly regarding efficacy signals and comparative performance against current standards. From your perspective, what are the most clinically meaningful findings, and how might these results shift sequencing or address gaps?

Hill: The obvious excitement is the significant improvement in progression-free survival. Historically, this has not been a patient population with a lot of effective lines of therapy. The longer we can stay on first-line therapy, the better.

In addition, the duration of response is very important. There was a very significant improvement in duration of response for those who did have an initial response to sacituzumab govitecan. Instead of the difference in progression-free survival being three to three and a half months in ASCENT-03 and ASCENT-04, it is five to seven months different in duration of response. Anecdotally, that is what you see in practice. The people who respond have very long responses.

For me, that is the most exciting part. They are on their first-line treatment for over a year in those trials, and that is a dramatic shift from what we have seen previously. I have been working in the breast oncology space a little over 10 years now, and that definitely was not always the case.

Outside of efficacy, tolerability is also meaningful. The side effects with antibody-drug conjugates are very different from traditional chemotherapy. Traditionally, patients would receive indefinite taxanes, which almost certainly cause dose-limiting peripheral neuropathy. Sacituzumab govitecan does have side effects, but they are sometimes more able to be prevented and easier to manage than peripheral neuropathy, which can severely impact quality of life.

There will always be gaps. We do not know the efficacy of a second-line antibody-drug conjugate after sacituzumab govitecan in the first line. That is a data-free zone. Lots of centers are looking at that, but we do not have large randomized trials to guide us.

Q:This guideline update created a meaningful shift in how TNBC is treated in the first-line setting. How should this update reshape the way oncology pharmacists approach shared decision-making with patients?

Hill: I honestly find this change in practice to be pretty meaningful for patients. Their first-line treatment prior to this often was a taxane, frequently given weekly. Even though the visits are not that much less with sacituzumab govitecan, it is a little bit less with the day 1/day 8 every-21-day schedule, and they at least get that third week off. That can be very important, especially if they are still working.

The side effect profile with sacituzumab govitecan includes a high probability of neutropenia and diarrhea, but I do find these toxicities easier to prevent and manage than peripheral neuropathy. At our institution, we use primary prophylactic granulocyte colony-stimulating factor (G-CSF) in almost all sacituzumab govitecan patients, which makes a big difference in neutropenia rates. We are typically able to prevent and manage diarrhea as well.

There are additional considerations. Even mild diarrhea may impact their daily functioning, so scheduling treatment on certain days may help. Another important aspect is pharmacogenomics. Many institutions are using commercial next-generation sequencing (NGS) tests that include pharmacogenomics, so we know someone’s UGT1A1*01 status. We do not have recommendations to lower the dose if someone is a poor metabolizer, but we do know they are more likely to experience side effects.

I think that is a good place for a shared decision-making conversation: either start at full dose and reduce if needed, or start with a preemptive dose reduction. Letting the patient choose is very reasonable.

Q:How do these factors shape the shared decision-making conversation, and how do you ensure the patient’s voice is meaningfully incorporated alongside the clinical data?

Hill: I think that is an essential role for pharmacists. I find commonly that patients are more comfortable discussing dose reductions with their clinical pharmacist than with their treating oncologist. Their concerns may only be communicated to us, even if they also saw their provider that day. It is important for us to make sure their concerns are heard and to be part of the decision-making—what options we have, what we can try, and what works best for the patient without impacting outcomes.