In a virtual roundtable titled “ADCs in the Frontline: Evolving Approaches in Metastatic TNBC,” Claudine Isaacs, MD, professor of medicine and associate director of Clinical Research at the Lombardi Comprehensive Cancer Center at Georgetown University, led community and academic oncologists through first-line antibody-drug conjugate (ADC) data in metastatic triple-negative breast cancer (TNBC), with a focus on the efficacy and safety of sacituzumab govitecan-hziy (Trodelvy).

Participants included Arielle Heeke, MD, clinical associate professor in the Department of Hematology and Oncology at Wake Forest University School of Medicine; Neelam Desai, MD, breast medical oncologist and Atrium Health; Ashley Sumrall, MD, section chief of neuro-oncology at Atrium Health Levine Cancer and as a clinical associate professor at Wake Forest University School of Medicine; Walid El Ayass, MD, medical oncologist of Luminis Health Anne Arundel Medical Center; Arun Bhandari, MD, Teaching Faculty of Internal Medicine Residency Program at Anne Arundel Medical Center - a part of Luminis Health; Louay Hanna, MD, medical oncologist of Carolina Oncology Specialists; Nitin Verma, MD, medical oncologist of Kaiser Permanente Mid-Atlantic; Margaret Howard, MD, MSc, medical associate professor in the Department of Medicine of Duke Cancer Institute; and Jun Sun, MD, medical oncologist of Maryland Oncology Hematology.

The panel weighed the phase 3 ASCENT-04 trial (NCT05382286) and phase 3 ASCENT-03 trial (NCT05382299) against the phase 3 TROPION-Breast02 trial (NCT05374512), debated what crossover means for overall survival (OS), and compared approaches to neutropenia and diarrhea.

ASCENT-04: Sacituzumab Govitecan Plus Pembrolizumab in PD-L1-Positive Disease

Isaacs: ASCENT-04 is the first-line study of sacituzumab govitecan in PD-L1-positive triple-negative disease. One of the important things to know about the series of ASCENT trials in the first-line setting is that they allowed the patients who were on the chemotherapy plus pembrolizumab, so on the standard-of-care arm, to cross over to second-line SG once it was verified that they had disease progression, and the sacituzumab govitecan was provided to them. The median PFS was 11.2 vs 7.8 months. The survival data were not yet mature at the time of primary analysis. But 81% of the patients who were in the standard-of-care arm who went on to receive subsequent treatment received sacituzumab govitecan.

That translated to about a 35% reduction in risk of disease progression or death. It was highly statistically significant. The 6-month PFS rate is 72% vs 63%, and at 12 months, it’s 48% vs 33%. Clearly, [this is] an effective therapy in this setting. For the vast majority of the subsets, everything favored sacituzumab govitecan plus pembrolizumab vs chemotherapy plus pembrolizumab. [Investigators] also looked at whether there was a benefit based on TROP2 levels, whether there was a tumor-related BRCA mutation, and the different HER2 subgroups. PFS2 was improved with sacituzumab govitecan plus pembrolizumab vs chemotherapy plus pembrolizumab. The median PFS2 was not yet reached in the sacituzumab govitecan group vs 21 months in the women who received standard of care as their first line, and 24-month PFS2 rates were 64% vs about 45%. If you look at the duration of response, it was far more prolonged in the group of women who received sacituzumab govitecan; it was 16.5 months vs 9.2 months.

Bhandari: As you showed, sacituzumab govitecan plus pembrolizumab is what I use. We have experience using sacituzumab govitecan in other tumor types also. It’s well tolerated, we know how to use it, and we know how to manage the toxicity.

El Ayass: At this point, after the data, Dr Isaacs, I’m using this as my primary line of treatment in patients who are eligible. The data are clear. ADCs have out-benefited conventional chemotherapy in all trials so far. Having these data plus what we know, again, as Dr Bhandari mentioned, we’re now very comfortable dealing with sacituzumab govitecan as well as other ADCs and managing their possible treatment-related toxicity, which is overall acceptable. That’s what I’m doing at this point. Hopefully we will find data for the other ADC with immunotherapy, so we have 2 options instead of 1 in the first line.

Isaacs: Let’s talk about the more challenging space. What if you have somebody who progresses very quickly after completing, or while on, their neoadjuvant therapy? What are you thinking if progression occurs within 6 months of prior immunotherapy? How are you approaching those patients?

El Ayass: This is, again, [an area where] we don’t have solid data. We can still argue whether we want to continue immunotherapy, depending on whether the patients were able to tolerate it in the neoadjuvant part, or after they completed the 1 year of the adjuvant [therapy] part, if they had no issues with it. I would be a little bit hesitant to continue the immunotherapy in the first-line metastatic setting within 6 months of completing the adjuvant immunotherapy. I would be a little bit hesitant. I’ll discuss it with the patient. I don’t have clear data to present to them, but I would prefer to do just sacituzumab govitecan or datopotamab deruxtecan-dlnk [Datroway] in this setting.

Heeke: I was struggling with the distinction: Are we talking about 6 months from completion of their chemotherapy vs 6 months from completion of their adjuvant [pembrolizumab]? Because I don’t think there were many of those patients ultimately in ASCENT who had done the phase 3 KEYNOTE-522 trial [NCT03036488].

Isaacs: There were very few who had done the KEYNOTE [regimen], so you’re absolutely right that we have no data from this. There was only a handful. It was less than 10% who had gotten prior pembrolizumab in the early-stage setting before relapse. You’re right that we don’t even have those data to tell us how this regimen would fare in somebody who had disease progression having received prior pembrolizumab, even with a much longer disease-free interval.

ASCENT-03, Crossover, and the Overall Survival Question

Isaacs: [ASCENT-03 is] to be commended, because when we look at these trials, it’s so not the norm to do this, but it’s what we’re trying to figure out as clinicians: If we have an active drug, when should we use it? You can see the curves separate quite early and remain separated. The hazard ratio was 0.62, statistically significant. If you look at the 6-month PFS rate and these landmark analyses, [it was] 65% vs 53%, and 41% vs 24% [at 12 months], showing that in the PD-L1-negative [population], the ADC outperforms standard chemotherapy. [Investigators] looked at it across all TROP2 levels, again suggesting that it’s not by amount of TROP2; it’s not that if you have TROP2-low [disease], [patients are] not going to benefit from it. If they had a tumor BRCA mutation, or across all HER2 subgroups, the benefit was similar. The thing that was improved was the duration of response; it’s about 12.2 months vs 7.2 months.

Isaacs: Now let’s talk about the ASCENT-03 trial, which was a first-line trial as well, but this is in PD-L1-negative disease or in individuals who are not candidates for PD-L1 inhibitors. Eligible patients were able to cross over and were provided with sacituzumab govitecan following BICR-verified disease progression. For median PFS, the delta was just under 3 months, so 9.7 vs 6.9 months. The median OS is 21.5 months vs 20.2 months. It was not different, but the data are not mature. Despite the fact that most patients in the control group did get sacituzumab next, there was a benefit for the patients who got sacituzumab govitecan in the first-line setting. That was true in ASCENT-03, so in the PD-L1-negative population, and in ASCENT-04 in the PD-L1-positive population. What do you think about this crossover?

El Ayass: The crossover at this point is an ethical thing, because there’s a drug that is outperforming. From an ethical perspective, allowing crossover gives more of a chance to the other group of patients who were randomly assigned to the control arm. Now, showing that clear difference in PFS2, and again, the superiority of the group having sacituzumab govitecan over the control arm, at this point it plays a good surrogate for an OS benefit if the crossover was not allowed. I would favor that. I would tell the patient that this has already shown benefit in patients who were on the conventional arm and then were given that drug. It boosts my confidence in the drug.

Sun: I would think that the PFS2 represents a group that benefited from sacituzumab govitecan. How do we tease out which subgroup benefits is the question I don’t think we have answered right now. I don’t think all triple-negative breast cancer is the same. I do think that there are subtypes. There’s a way to tease out which subtype potentially responds to sacituzumab, so we can pick the patients better. This is an all-comer trial, so I don’t think we have any information on that. We treat everybody to see who would benefit. At the end of the day, more work needs to be done.

Weighing Sacituzumab Govitecan Against Datopotamab Deruxtecan

Isaacs: Let’s move on and talk about Dato-DXd, the TROPION-Breast02 study. Patients who relapsed within a year of completing curative-intent therapy were eligible, but it was capped at 20% of the population. In this trial, crossover was not provided. That does impact things. If we look at OS here, you can see that the data were mature and were statistically significant. In the control arm, only about 40% went on to receive any ADC. In the first-line setting, then, how are people making decisions in the PD-L1-negative population, where we have 2 drugs that are approved? I would assume you’re going to use Dato-DXd based on the reasons that you explained earlier. Is that correct?

Hanna: Correct, because you have a high response rate. The subgroup analysis was a small number, but the patients who benefited the most from Dato-DXd, it feels to me, were those with brain metastases too. Those did so well, and I know those are a very small group. if I have a patient with PD-L1-negative disease, I’m going with Dato-DXd.

El Ayass: In my practice, I’m giving both options to the patient, not favoring one over the other. First of all, because I don’t think we can do this cross-trial comparison, and the inclusion of crossover will make a big difference. I will not try to tell the patient that here we have an OS benefit and here we don’t have an OS benefit, because I guess that crossover plays a big role in the OS data analysis. Now, Dato-DXd is [administered] every 3 weeks, whereas sacituzumab govitecan is days 1 and 8 every 3 weeks. That by itself, from a practical perspective, might be easier for the patients. Again, the cost is a trade-off with the potential [adverse] effects; both have different [adverse] effects. I present all this to the patients, give them the option, and take into consideration how far the patient lives from the infusion center. I present both options to the patient and take it from there.

Heeke: I was going to add, if a patient is a candidate for T-DXd in a later line, I might lean on sacituzumab govitecan a little bit more. Otherwise, I agree with all the sentiments.

Isaacs: We’ll be seeing more data on ADC post ADC at [the San Antonio Breast Cancer Symposium]. There are small series where people have looked back within their experiences, or a couple of institutions’ experiences, and shown that most do much better with first line than second line, but there are the occasional patients who do better with one drug vs the other. [The phase 2] TBCRC 064 [trial (NCT06533826)] is studying that directly in both hormone receptor-positive and triple-negative HER2-low patients, so we may start seeing at least some prospective data from that. It is another one of those difficult situations.

It’s important to think about where trials were done, and I’m sure this goes way beyond breast cancer as well. If we have an active drug that we know is active in the second-line setting, and we want to be thinking about moving it up to first line, there’s no question that all of us want to use one of these drugs, whatever it is. It’s an ADC; we don’t have to argue which ADC. If you’re going to move up a drug that you’ve shown efficacy for in a later line, I think it’s important to provide [it to patients on the control arm], both from an ethical perspective and also to inform us and our patients what the best sequencing should be.

Safety: Neutropenia, Diarrhea, and Prophylaxis

Sun: Our office participated in the registration trial of sacituzumab, so we have a little bit more of a preference for sacituzumab govitecan. We have Dato-DXd as well. For sacituzumab govitecan, cytopenia is a major issue, especially for some populations. Sometimes, for the patients who are older or more frail patients, I do sacituzumab govitecan every 2 weeks with growth factor after each dose, and in my experience, that seems to be a well-tolerated regimen. There is a way you can modify the schedule to make things easier. Dato-DXd toxicity is unique and can be very difficult. Quality of life matters. Sacituzumab govitecan is much better tolerated than Dato-DXd, in my experience. I do think that’s a big factor in the selection of the regimen.

Isaacs: Somebody said it’s like Dato-DXd is the child of T-DXd and sacituzumab govitecan. It has the TROP2 target but the DXd payload. With sacituzumab govitecan, you can see that the main toxicities are the diarrhea and the neutropenia. With Dato-DXd, nausea was a little bit lower, at 45%. Alopecia was at 41%. Then you’ve got those 2 unique toxicities with Dato-DXd that can be mitigated, but I have to say, [they require] somebody who’s rather compliant: stomatitis, at 57%, and dry eye, at 24%. Myelosuppression is more of an issue with sacituzumab govitecan, as we all know.

If we look at the most common grade 3 or greater toxicities, you can see that with sacituzumab govitecan it’s the neutropenia. Diarrhea can be grade 3 in about 10% of patients. Primary prophylaxis is recommended for all patients who have risk factors for febrile neutropenia. For us, if we’re doing liquid biopsies, we’re getting the UGT1A1 genotyping with it. [PRIMED] was a small trial, but it looked at giving growth factor support with short-acting white blood cell growth factor for 2 days after day 1 and day 8. [Patients received] it on day 3 and day 4, and then also on day 10 and day 11. Patients [received] loperamide [Imodium] for the first 2 cycles. You can see how the rate of neutropenia is lower using those 2 days after day 1 and day 8. I have to say, I have moved to this routinely, I’ve started it at the get-go with my patients now, and I haven’t had any issues with insurance approval. Dose reductions were far less using this [strategy], and AEs leading to treatment interruptions were also significantly reduced.

Desai: For those who have given Dato-DXd and had eye toxicity, what do you do? Have you found that reducing the dose helps? Or at what level, if it's just dry eyes, I know they have to see the ophthalmologist every so often, but at what level do you do something and what is it that you do?

Hanna: We get the recommendation from the ophthalmologist. I don't go much into the details because the expert is managing that. If I get the report that there is a serious issue, I will follow [up].

Desai: And [the ophthalmologists] would know what drops and such to use, but I guess you just follow the prescribing information in terms of dose modification and holding, which is reasonable. In my experience, I found that the moment I started adding growth factor support to SG, I really didn’t have too much trouble with neutropenia, and all I did was just add day 9. In terms of the diarrhea, it’s just being proactive. If they have that UGT1A1 [variant], giving an up-front dose reduction is what’s worked for me very well, and I haven’t had too much trouble with sacituzumab govitecan.

Isaacs: Using those 2 days [of growth factor support] after each cycle made a big difference for me in terms of helping to manage the neutropenia. There are clear dose reductions; I think Nitin put them in the chat. [Thank you] for how to manage the ocular toxicities. I’ve had 1 patient who said, “I’m not wearing my contacts,” so that was an easy discussion. I do think that patient choice comes in because [the toxicity profile] is very different. As we all know, some patients tolerate something better than you think they will and others don’t. That’s something we can always go to.

Sun: One question, Dr Isaacs: Some patients are heterozygous for UGT1A1, and I struggle with those patients. I don’t know what to do.

Isaacs: They’re coming up, aren’t they? We’re seeing them now all the time. I’ve had a couple of those patients, and they’ve been a bit on the older side, and I have dose reduced them at the get-go. I figure for the first cycle, let’s see how they do, and then go from there. We all struggle with what to do in that setting. Many of the drugs that we use have been developed to the maximum tolerated dose, not necessarily to the minimum effective dose. I feel very comfortable in the metastatic setting doing that. I don’t do that off the bat for all my patients, but if I have an older patient or somebody who is a heterozygote, I’d definitely go down to 7.5 [mg/kg].

Verma, MD: It’s like your DPYD intermediate metabolizers, right? You just don’t know how they’re going to do with 5-FU. At least from what I’ve read, the majority of the risk is with homozygotes.

Isaacs: My 2 heterozygotes were older patients too, so I don’t see a reason to risk it on the first [cycle], but I think that Nitin is correct on that.

Key Takeaways

Two first-line indications: Sacituzumab govitecan is FDA approved with pembrolizumab for metastatic TNBC with PD-L1 CPS of 10 or higher (ASCENT-04) and as monotherapy for patients who are not candidates for PD-1/PD-L1 inhibitors (ASCENT-03), making it the only ADC approved in combination with immunotherapy in this setting.

Consistent PFS benefit: Both ASCENT trials improved PFS vs chemotherapy, with longer duration of response and improved PFS2 even though most control-arm patients went on to receive sacituzumab govitecan. OS data remain immature, and panelists differed on whether PFS2 can serve as a surrogate for OS.

Trial design shapes comparisons: The ASCENT trials provided sacituzumab govitecan to control-arm patients at progression; TROPION-Breast02 did not provide crossover and reported a significant OS benefit with Dato-DXd. Panelists cautioned against cross-trial comparisons, and Dr Isaacs called on sponsors to offer active drugs to control-arm patients.

Selecting a regimen: PD-L1 status, disease-free interval (the ASCENT trials excluded relapse within 6 months), dosing schedule, plans for later T-DXd, distance from the infusion center, and patient preference all factored into the choice. Several panelists use sacituzumab govitecan plus pembrolizumab as their standard for eligible PD-L1-positive disease.

Manageable toxicity: Neutropenia and diarrhea are the main toxicities with sacituzumab govitecan. Panelists reported success with prophylactic growth factor support, proactive loperamide, and UGT1A1 genotyping with up-front dose reduction for poor metabolizers or select older or heterozygous patients. Some preferred its tolerability and monitoring requirements over the ocular and oral care needed with Dato-DXd.

References

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