TROPiCS-02 Data Presented at SABCS 2023: Implications for the HR+ Breast Cancer Treatment Paradigm

The Oncology Brothers—Rahul Gosain, MD, of the University of Rochester, and Rohit Gosain, MD, of the UPMC Hillman Cancer Center—talk with Paolo Tarantino, MD, of the Dana-Farber Cancer Institute, about the TROPiCS-02 study presented at SABCS. The study compared sacituzumab govitecan versus physician’s choice in patients with HR+/HER2‒ metastatic breast cancer. The study included a subgroup analysis of outcomes based on patient age, including those aged ≥65 years and older.

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Dr. Rahul Gosain: Just about two weeks ago, more than 1,500 abstracts were presented at 2023 San Antonio Breast Cancer Symposium. Today, we’re going to focus on a particular data set around sacituzumab govitecan. For this, we’re joined by none other than Dr. Paolo Tarantino, a medical oncologist from Dana-Farber. Paolo, thank you so much for joining us, and it was so good to see you in person in Texas.

Dr. Tarantino: Hello Rahul and Rohit. So nice to meet you, and to be here with you to review the many news that have been presented in the last year, especially at San Antonio, in the field of hormone receptor-positive breast cancer, and especially sacituzumab. Always a pleasure to meet you, to e-meet you, and even better to meet you in person. It was really nice at San Antonio.

Dr. Rohit Gosain: I definitely missed out on quite a bit of fun there, but I’m glad Rahul was able to attend it live, and I was able to keep myself up-to-date with the social media. Welcome Paolo. Before getting started on the most recent update, here is the current landscape, or where we stand in the hormone receptor-positive space, which is rapidly changing. We recently saw an approval of capivasertib, based on the CAPItello study, and also elacestrant earlier this year. However, when looking at the endocrine-resistant patient population, sacituzumab, which is approved in endocrine-resistant, which is a TROP-2 antibody-drug conjugate (ADC), which was rather approved in February 2023, based off of the TROPiCS-02 study. Paolo, can you please briefly touch upon the study design of TROPiCS-02?

Dr. Tarantino: Yeah, first of all, I would like to say that it’s quite impressive to see 3 new drugs approved for metastatic breast cancer in the last year. It just speaks to the fact that we are moving so fast in this area, especially hormone receptor-positive/HER2-negative, that is the most common subtype of breast cancer. Of course, we had many drugs approved in the past for HER2-positive breast cancer, some also for triple-negative. But up to 70% of all of our patients have hormone receptor-positive/HER2-negative disease. It’s important to focus, of course, on every subtype, but remember this distribution and to remember, as you mentioned, that there’s many options for patients with endocrine-sensitive disease when we have many biologic treatments, CDK4/6 inhibitors, PI3K inhibitors, AKT inhibitors, PARP inhibitors. But once the disease becomes endocrine-refractory, and we move to the chemotherapy setting, for a long time we only had chemotherapy. Recently, we realized that we could deliver chemotherapy in a better way, in a more selective way, and in a more active way through antibody-drug conjugates, and we had seen two approvals.

One is trastuzumab deruxtecan for patients with HER2-low disease. More recently this year, as you mentioned, sacituzumab govitecan. That is basically a Trop-2 targeted antibody-drug conjugates delivering a topoisomerase inhibitor, SN-38, that is the active metabolite of irinotecan. Although irinotecan had been tested in the past for hormone receptor-positive disease, it was not as effective as sacituzumab has proven to be.

Sacituzumab was already approved for triple-negative breast cancer based on the ASCENT trial, and now the TROPiCS-02 really was meant to validate the activity of this drug, not only for triple-negative, but also hormone receptor-positive disease. This was a phase 3 trial for patients with hormone receptor-positive/HER2-negative metastatic breast cancer that received prior treatment with at least one line of endocrine therapy, a taxane, a CDK4/6 inhibitors, and receipt of two to four lines of chemotherapy for metastatic disease. The overall population had a median of three prior lines of chemotherapy, so a highly pretreated setting.

Patients were randomized 1:1 to either sacituzumab govitecan, at the standard dose and schedule, utilized also for triple-negative disease, or treatment of physician choice. Basically, single-agent chemotherapy, with the primary endpoint being progression-free survival (PFS), secondary endpoint, overall survival objective response rate, and safety. There were several post-hoc analyses of which the last one is based on age, that was presented at the San Antonio [Breast Cancer Symposium], and the main analysis were age, more or less than 65 years old, or also 75 years old.

Dr. Rahul Gosain: Thank you so much for covering that. I want to emphasize a few things here, again. This was indeed a very heavily pretreated patient population. Despite that, this drug got approved because of PFS, and it also showed overall survival benefit here. You started to chit-chat about the current update; the subset analyses is what we’re looking at based on age. Paolo, diving right into it, what did this most recent update show?

Dr. Tarantino: We already knew that there was both a significant improvement in PFS and overall survival with the sacituzumab govitecan, with about a 3.2-month delta in overall survival with sacituzumab compared to chemotherapy. But of course, it’s important to understand if there is any differential benefit depending on the age of the patients, especially because we know that we are seeing a more and more onco-geriatric population in our clinic, I think it’s important to understand the value of our drugs for these patients.

I think it was very reassuring to see that the benefit of sacituzumab govitecan was really preserved, maintained both in patients younger and older than 65 years old, and also of 75 years old, although the population starts becoming very small beyond 75 years old. In terms of PFS, the hazard ratio for progression-free survival was 0.69 before 65 years old and 0.59 for more than 65 years old.

The same in overall survival, there was a very consistent benefit with about a hazard ratio of 0.8 for less or more than 65 years old. Actually, if you look at the medians, it seems like there was a slightly prolonged benefit in patients older than 65; that it’s very interesting, and just speaks to the fact that this drug is highly effective, both for patients that are younger and older than this age. Duration of response was longer with sacituzumab across age subgroups, and objective response rate was improved also in all the subgroups, apart from the patients with more than 75 years old, but we know once again this was a very small cohort of patients.

Interestingly, grade 3 or higher adverse events were slightly more common in patients with 75 years old or more. We know that in this sub-analysis, also, patients that were older had more comorbidities and were more likely to have a higher performance status. This may also have impacted the safety results. I think it’s also important to note that it was more common to see discontinuation of sacituzumab govitecan in patients that were older than 65 years old. But in general, quality of life seem to be prolonged irrespective of the age. Once again, speaking to the fact that sacituzumab govitecan is an approved and valid treatment option for patients, both younger and older than 65 years old, both prolonging progression-free survival and overall survival and improving quality of life.

Dr. Rohit Gosain: Thanks, Paolo. This is extremely important, PFS and OS, certainly, we have been monitoring these patients for these primary and secondary endpoints, but the important thing is this is a heavily pretreated patient population who derived benefit from quality of life aspect as well. So that’s extremely important. Paolo, you mentioned 3 drug approvals that came across in the hormone receptor-positive space. It’s certainly and exciting time, but with the recent approvals, now what? Sequencing certainly remains a mystery. We are starting to see more and more real-world data come through on this, but again, time will tell how to truly sequence them. From your standpoint, any key takeaways on sequencing ADCs from the San Antonio Breast Cancer Symposium?

Dr. Tarantino: That’s a great point, because we’re seeing more and more data, specifically with Topo-1 ADCs. We know that two of them are approved, sacituzumab govitecan and trastuzumab deruxtecan, as I mentioned. Now we’ve seen, recently this year, also promising data with datopotamab deruxtecan, a third Trop-1 ADC, which may be potentially approved next year. The question, of course, comes to mind, will 3 Trop-1 ADCs be effective one after the other? I think some lessons from the past tell us that they may be effective. For instance, we know that we can utilize eribulin after taxanes, and although they have a similar mechanism of action, they can be both effective one after the other, and the same happens with ADCs.

We know that T-DM1 has prolonged overall survival in patients pretreated with taxanes, and both agents have got microtubule inhibitors. In this case, I think, as you mentioned in a moment, we need to rely on real-world data. The real-world data we’ve seen, it is quite confusing, just because it’s including patients that have received one ADC after the other, but also patients that have received many intervening treatments. The second ADC in most of these experiences, in the experience by UCSF, in the one by MGH, in other French experience, in most of the cases, the second ADC was less effective than the first one, in terms of PFS, and sometimes in response rate. But it’s hard to dissect if this is related to the more pretreated setting, or because they share the mechanism of action.

I do believe that, for the moment, since we have 2 drugs that have shown improvement in PFS and OS over chemotherapy in phase 3 trials, we are supposed to utilize both of them in clinical practice. I do believe that utilizing a different agent in between, what is being called the “sandwich” strategy is not a crazy idea. For instance, utilizing a microtubule inhibitor in between 2 Trop-1 ADCs can be an effective strategy to wait before utilizing a similar agent. But I would utilize both of them. Of course, if datopotamab deruxtecan is approved, it’ll be more challenging.

In the future, we will get better data, in 2 different ways. Through registries, and there is a TBCRC registry of many centers in the US, that are collecting prospective data on ADC after ADC. Then, also, prospective clinical trials. For instance, we recently launched a clinical trial with sacituzumab after T-DXd in HER2-positive disease. The SATEEN trial that I worked on, here at Dana-Farber. Also, my colleague Ana Garrido-Castro, MD, here at Dana-Farber, developed a concept called Trade-DXd. That is the first randomized trial testing T-DXd after datopotamab deruxtecan, or the opposite sequence, which will provide, in the next few years, some prospective data.

For the moment, once again, we rely on the data that has been presented and published, on some real-world data, and I invite everybody to collect this real-world data. We are doing that at Dana-Farber, and I think it’s precious to understand how to utilize these drugs in the best possible way.

Dr. Rahul Gosain: Paolo, I think it’s important to bring something up. The opinion around how to sequence is continuously changing. You brought up that sandwich approach. That theoretically makes sense, but again, once we have real-world data, or prospective data, we all will quickly adapt to this. I want the listeners to understand that this is a very rapidly evolving field, and this is a moving target. I could tell you that, “Yeah, maybe I do use back-to-back two ADCs.” Whereas here, Paolo, what you’re saying is maybe the sandwich approach is right. We don’t have enough data to completely commit to one or the other, and that’s the reason why knowing all this is so important.

Dr. Tarantino: I totally agree, and I think this may change already next year, because we know that there’s trials trying and developing T-DXd and sacituzumab in early lines, in patients right after failure of endocrine treatment, instead of utilizing the first line of chemotherapy. These patients are randomized to chemotherapy or T-DXd, which is the DESTINY Breast-06 trial. But also, though, with sacituzumab, there is a similar trial in the first line. Everything is moving fast, it’s a moving target, as you mentioned. We need to adapt to this, and the best way is discussing, if possible, attending the conferences, of course. Also, thanks to your help, trying to stay updated, and understanding how the knowledge is evolving in the field.

Dr. Rahul Gosain: Paolo, one thing, as a community oncologist, what should we do today? Coming back to that algorithm, or the data in hand, given the data from TROPiCS-02, and you brought up the ASCENT trial, right now, do you use sacituzumab before T-DXd in triple-negative breast cancer and vice versa in hormone receptor-positive patients?

Dr. Tarantino: That’s a great question. I believe that both agents should be offered and discussed with patients in the second line, because they clearly differ in terms of side effect profile. That can help also the patient choose the treatment that is more fit to her preference or his preference. But I believe that there is more evidence for sacituzumab govitecan. I do believe that if a patient progresses with triple-negative disease, metastatic disease, progresses to first-line chemotherapy without immunotherapy, the drug that has been developed in a phase 3 trial, and has got more data in support, is sacituzumab govitecan. But if disease is also HER2-low, I do believe that it’s important to discuss every option with the patients. If the patient is BRCA mutated, of course, PARP inhibitors are also an important option.

Dr. Rahul Gosain: Absolutely.

Dr. Rohit Gosain: Thanks, Paolo. That is so important to stress that. Collective decision-making should be the key. Telling the patient about the side effect profile from either of those treatment options is extremely important. As oncologists, it is extremely important for us to get comfortable with managing these side effects, as the field is changing by the minute. Paolo, I know when it comes to sacituzumab, we have been battling concerns of diarrhea and neutropenia. How are you tackling this in your clinic?

Dr. Tarantino: In general, there’s a lot of discussion, if there’s a need of prophylactic utilization of anti-diarrhetic or even in growth factors. In general, in my practice, I don’t do that, and I introduce these agents, both growth factors or loperamide for diarrhea, in case you have these issues, mostly because there are some patients that tolerate the drug very well and do not need any prophylaxis.

But I do believe it’s important, at the first visit, before initiating the agent, to discuss it with the patient, to have the patient have available loperamide in case of diarrhea, and also growth factors in case they’re needed. Since the drug is given on day 1 and day 8, it’s important to remember that if you need to use growth factors, you have to use short-acting growth factors after day 1. You can utilize Neulasta long-acting growth factor after day 8.

I do hope that in the future there is some development of concepts to escalate progressively the dose of sacituzumab. This helped a lot with the drugs like neratinib, that had a lot of diarrhea. In the controlled trial, escalating the dose of the drug helped a lot. I think, also, with sacituzumab, this may help. There is no concept yet that has been developed, to my knowledge, but I think this potentially, as a research practice, could help to understand which patients can receive the full dose, and which patients, instead, may need a lower dose of the drug. That sometimes helps to mitigating the side effects.

Dr. Rohit Gosain: Especially, we have been seeing, more and more from the breast cancer space, for example ribociclib or other drugs, where we have been utilizing lower doses, while the efficacy is not being affected majorly. We’ll see how the real-world data looks like, and of course the trials are going to unwrap that as well. Paolo, thank you so much for covering all this. ADCs are here to stay, and sacituzumab is an approved option with OS benefit for breast cancer patients in the hormone receptor-positive space. This update continues to reiterate this as part of our standard of care, but we have to be very mindful about the toxicity profile, especially when we are dealing with the elderly population. Again, Paolo, thank you so much for joining us.

Dr. Tarantino: Rohit, Rahul, thank you so much for sharing this discussion. Always a pleasure to meet you, and thank you everybody for attending this presentation.