Sardesai Discusses ADC Selection Based on HR and HER2 Status in mBC

Sagar D. Sardesai, MD (MODERATOR)

Clinical Associate Professor

The Ohio State University College of Medicine

Breast Cancer Medical Oncologist

The Ohio State University Comprehensive Cancer Center – The James

Columbus, OH

EVENT REGION Kentucky, Ohio, West Virginia

PARTICIPANT LIST: Baidehi Maiti, MD | Seema Misbah, MD | Megan Kruse, MD | Michael Nemunaitis, MD | Shyamal Bastola, MD

Maiti: I think I have definitely changed my practice, and I [would use] sacituzumab for [those] patients. I think the overall survival improvement is modest, but it still gives an option for these heavily pretreated patients. [In terms of the] toxicity, generally I think cytopenias are very pronounced. I have tried using G-CSF [granulocyte colony-stimulating factor] for primary prophylaxis if insurance approves it. If not [I use] dose reduction and secondary prophylaxis, but I think it gives a reasonable option to our patients.

Sardesai: Thank you for making that point on G-CSF.

Misbah: I agree with Dr Maiti. I also agree with using it earlier on after endocrine therapy because of the cytopenias, because these patients are already heavily treated with endocrine therapies, but a lot of them have maintained their [blood cell] counts. But I’ve used sacituzumab in later lines, and it’s much more difficult because of the cytopenias.

SardesaiI: I agree, and…the ASCENT-07 trial [NCT05840211] has nearly completed its accrual. That is the frontlinesacituzumab trial in comparison with TPC [treatment of physician’s choice]. I think we’re going to see positive results based on moving it into earlier lines and [see] better tolerability in that population that’s not as heavily pretreated.

In the TROPiCS-02 data, the number of grade 3 treatment-emergent adverse events [TEAEs] was quite high for sacituzumab and quite high for TPC.1 The rate of treatment discontinuations was about the same in both groups [6% vs 4%, respectively, as was the rate of] dose reductions [34% vs 33%, respectively]. Overall, it’s very similar in terms of the number of treatment discontinuations, dose delays, and dose reductions. There were 2 deaths in the sacituzumab arm, and the treatment-related deaths were less than 1% [n = 1]. There were no new safety signals for sacituzumab.

The most common TEAEs we see are neutropenia—half of the patients experienced grade 3 [or higher] neutropenia—and grade 3 diarrhea in 10% and a smattering of others [Table 1¹].

DISCUSSION QUESTIONS

• Please share your perspectives and experiences with the safety profile of sacituzumab govitecan.
• What supportive care do you offer your patients?

Sardesai: We heard the point about G-CSF. Dr Kruse, can you comment on how your institution follows practice for G-CSF use? Is it primary prophylaxis or secondary prophylaxis? Is it filgrastim [Neupogen] or long-acting G-CSF for sacituzumab?

Kruse: I think it’s highly variable, and it’s a point that we’ve struggled with a lot because we often tried to at least get it approved for primary prophylaxis, even if we don’t use it, so we have an approval ready to go. The worst-case scenario is your patient comes in on day 8 and they have marginal counts. You might be able to treat them, but you know they’re going to be cytopenic, and you don’t yet have the pegfilgrastim [Neulasta], or whatever you want to use, approved. We have tried to do more preventive approval, if not preventive use.

I thought that I would consistently have more trouble on day 8, but I sometimes get surprised and have trouble with neutropenia on day 1 of the subsequent cycle. If it’s day 8 neutropenia, I think you’re much more successful with short-acting growth factor. Of course, if it’s day 1, you can get away with the pegylated forms. I have a lot more trouble with approval and administration of short-acting growth factor, since it can be hard to get it for home use and patients often can’t come multiple days to the infusion center. It’s become a logistics issue, and I’ve done a lot of dose reduction to try to get at this if I can’t get growth factor approved, which seems to be safe, and patients are still responding. But I think it’s case by case, because the kinetics of the neutropenia are different for every patient, and the insurance plans are so highly variable.

Sardesai: Toxicities [in patients with triple-negative breast cancer in ASCENT; NCT02574455] were no different [from TROPiCS-02].² I think it’s the same [rate of] neutropenia in about half the patients; if you look at grade 3 and grade 4, it’s [34%] of patients, and then 10% of patients had grade 3 diarrhea.

The outcomes by age…are clinically relevant, given the toxicities of diarrhea and cytopenias. One might be concerned about either the starting dose of sacituzumab or how the population would do with older adults, but I think the benefit is maintained.³ The toxicities were very similar to what we’ve been seeing in those in the intent-to-treat population, and there were no treatment-related deaths in this population as well [Table 2³]. It’s a good point to note that older adults also receive benefit from this therapy, much like our younger patients.

Sardesai: Is there a particular reason you would select trastuzumab deruxtecan (T-DXd; Enhertu) over sacituzumab for this patient with metastases to the bone and liver?

Misbah: I think trastuzumab deruxtecan is very well tolerated with fewer AEs than sacituzumab, so I would use it prior.

Sardesai: I think the flexibility of giving it every 3 weeks vs [giving sacituzumab on] day 1 and 8 [of a 21-day cycle] does that.

Misbah: That helps too, but [I think] it is better tolerated overall.

Sardesai: [In terms of TEAEs] for T-DXd, nausea is the most common, but there were very few grade 3 events, only 5%.⁴ Transaminases increase of grade 3 or 4 [occurred in] 4%. Neutropenia of grade 3 [or higher occurred in] 14%. I think that we’ve [all] been using this drug now for quite some time, so we’re quite familiar with expected toxicities.

[For] AEs of special interest, they’ve been collected rigorously in multiple of these T-DXd trials. For DESTINY-Breast-04 [NCT03734029] there were 4 grade 5 events related to treatment-related pneumonitis, so 1% [of] patients…experienced death from interstitial lung disease [ILD] related to their T-DXd compared with none on the TPC arm.⁵ The majority of these ILDs were grade 1 and grade 2. This just speaks to the importance of rigorous monitoring of these patients, either with a high-resolution CT scan or clinical assessment. I typically tend to get high-resolution CT scans…of their chest every 8 to 10 weeks, and in those [patients] who are asymptomatic but still show signs of ILD, whether it’s focal or diffuse, we typically tend to hold the drug; for those who are symptomatic, there’s no question [about holding the drug]. I think most of us would hold and start steroids. But the empiric use of steroids is equally important, and what has been stressed in multiple conferences and meetings is identifying these toxicities early and intervening with steroids, which helps patients in terms of going on to their next line of therapy or resuming T-DXd once the toxicity resolves.

Nemunaitis: Have you been able to continue it if they’re asymptomatic and just saw findings on the CT scan, or are you done [giving T-DXd] even if they have no symptoms?

Sardesai: In my experience, if they’re asymptomatic, and it was grade 1, then I hold the drug and then resume once the toxicity resolves, which can usually take about 6 to 8 weeks. If there is that kind of time for the patient to wait, then I would resume. If there’s not that kind of time for the patient, then we switch. For those with grade 2, I do not rechallenge with T-DXd again.

Kruse: Do you usually start steroids right when you start a drug hold, or do you just hold the drug, see if they improve, and then go with steroids if they don’t?

Sardesai: In my practice, for grade 1 asymptomatic [events], I hold the drug, but for those who are symptomatic, I start steroids.

DISCUSSION QUESTIONS

• How do you weigh the data from ASCENT and DESTINY-Breast04 with respect to patients with HR–, HER2 IHC 1+ metastatic breast cancer (mBC)?
• What do you consider to be the ideal therapeutic sequence for PD-L1–negative, germline BRCA1/2 wild-type, HR–, HER2 IHC 1+ mBC?

Sardesai: What made you feel like you would choose this over sacituzumab for this patient, going back to why the majority of us said T-DXd in this triple-negative cohort?

Kruse: For me, it’s the overall survival trend. We don’t see drugs like this very frequently. In reality, patients are going to get both antibody-drug conjugates [ADCs], because we have limited options. Even though it’s a small population in DESTINY-Breast04, those curves are impressive, and with the tolerability and the schedule… you can’t beat it for quality of life. We know sacituzumab is effective in later-line settings, albeit we don’t know about giving it after an ADC. It gives me some comfort using sacituzumab a little later.

Sardesai: What do you consider to be the ideal therapeutic sequence for PD-L1–negative, BRCA1 or BRCA2 wild-type [disease]? These patients are probably going to see both ADCs, but…how do you do it? Do you sequence one right after the other? Do you sandwich a chemotherapy in between these ADCs?

Kruse: I don’t know the best way to do it. I have been going back-to-back. I had some interest in sandwiching a therapy in between, but there was a poster at the American Society of Clinical Oncology Annual Meeting where they looked at a small population of patients who had a sandwich therapy of cytotoxic chemotherapy.⁶ This was from the group at the University of California, San Francisco, that has put out almost all the sequencing data we have on ADCs, and they didn’t see any difference in ADC response with an intervening therapy. It’s hard to believe that any of the standard-of-care therapies are going to be better than either of the ADCs, so I just go back-to-back.

Misbah: I agree with [sequencing] back-to-back, and the reason is what you just said with those data, but also that I don’t like using sacituzumab before T-DXd. But then if you wait too long to use sacituzumab, then it’s not effective because it becomes more toxic, and there are more issues with cytopenias, especially after a chemotherapy.

Sardesai: [I agree], since the cytopenia is following chemotherapy. I think the majority of us…would consider T-DXd for HER2 ultralow as well.

Bastola: I personally don’t have a lot of these patients. It’s a rare disease, but I tend to treat with sacituzumab before T-DXd based on…I feel it has more data, and sometimes I feel like, is there going to be enough time if somebody already has liver metastases and they [experience progression], and are they able to get another treatment? Because of those reasons, I have been sequencing sacituzumab first, and then I probably would be open to using T-DXd for HER2 ultralow because we don’t have a lot of other options. So if somebody’s gotten sacituzumab, and then I’m figuring out what else I can use, it is a very well-tolerated drug, so I probably would consider trying it after.

Sardesai: I do the same, Dr Bastola. I think I was one of the few people who answered sacituzumab. I have stuck to sacituzumab, but this discussion was helpful. I may look at T-DXd differently as well. I agree that it’s more flexible, and for some patients better tolerated.

Does your preferred approach with respect to use of sequencing of ADCs and chemotherapy differ for patients who are HR positive? I think we agreed that if it’s HER2 IHC 1+, then we would all favor T-DXd, especially if it’s HR positive; I think that’s where the data [favor it] over sacituzumab for those patients.

REFERENCES:

1. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/ JCO.2023.41.16_suppl.1003

2. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

3. Kalinsky K, Oliveira M, Traina TA, et al. Outcomes in patients (pts) aged≥65 years in the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2021;39(suppl 15):1011. doi:10.1200/JCO.2021.39.15_suppl.1011

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5. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

6. Huppert LA, Mahtanai RL, Fisch SC, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): updated data and subgroup analyses by age, sites of disease, and use of intervening therapies. J Clin Oncol. 2024;42(suppl 16):1083. doi:10.1200/JCO.2024.42.16_suppl.1083