August 29, 2023

Courtney Flaherty

Sara M. Tolaney, MD, MPH, highlights updated survival and safety data seen with sacituzumab govitecan in patients with hormone receptor–positive, HER2-negative breast cancer; underscores how Trop-2 and HER2 testing is not necessarily needed for this agent in this population at this time; and shares how ongoing efforts are exploring the utilization of this agent earlier in the treatment course.

Sara M. Tolaney, MD, MPH

Findings from the final survival analysis of the phase 3 TROPiCS-02 trial (NCT03901339) confirm the survival advantage provided with sacituzumab govitecan (Trodelvy) vs single-agent chemotherapy in patients with hormone receptor–positive, HER2-negative breast cancer,1 and solidifies its role as a new standard of care (SOC) in this population, according to Sara M. Tolaney, MD, MPH.

As previously reported, TROPiCS-02 met its primary end point of improved progression-free survival (PFS; HR, 0.66) with sacituzumab govitecan (n = 272) vs chemotherapy (n = 271), and showed a substantial improvement in overall survival (OS; HR, 0.79) and overall response rate (ORR; odds ratio, 1.63). Based on these findings, in February 2023, the FDA approved sacituzumab govitecan for use in patients with unresectable locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer who progressed on endocrine therapy and 2 or more systemic therapies in the metastatic setting.¹

Data presented at the 2023 ASCO Annual Meeting showed that with a median follow-up of 12.8 months, sacituzumab govitecan resulted in a median PFS of 5.5 months (95% CI, 4.2-6.9) vs 4.0 months (95% CI, 3.0-4.4) with chemotherapy, translating to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.53-0.81; P = .0001). Moreover, the median OS was 14.5 months (95% CI, 13.0-16.0) in the investigative arm vs 11.2 months (95% CI, 10.2-12.6) in the control arm (HR, 0.79; 95% CI, 0.65-0.95; P = .0133). Notably, the survival benefit with sacituzumab govitecan was observed regardless of TROP-2 expression and HER2 immunohistochemistry (IHC) score.

“[Sacituzumab govitecan provides] another treatment option that isn’t just improving PFS but is extending how long people live. It’s an important [development] for our patients,” said Tolaney, who is the chief of the Division of Breast Oncology at Susan F. Smith Center for Women’s Cancers, the associate director of the Susan F. Smith Center for Women’s Cancers, a senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

In an interview with OncLive®, Tolaney highlighted updated survival and safety data seen with sacituzumab govitecan in patients with hormone receptor–positive, HER2-negative breast cancer; underscored how Trop-2 and HER2 testing is not necessarily needed for this agent in this population at this time; and shared how ongoing efforts are exploring the utilization of this agent earlier in the treatment course.

OncLive: Please provide some background of the TROPiCS-02 study. What are the previously reported findings from the first and second interim analyses?

Tolaney: TROPiCS-02 is a phase 3 study comparing sacituzumab govitecan, the Trop-2–directed antibody-drug conjugate [ADC,] with physician’s choice of chemotherapy in pretreated [patients with] metastatic hormone receptor–positive breast cancer.

We’ve previously seen data from this study. At the time of the primary analysis, we saw that the primary objective of the trial was met, as [treatment with] sacituzumab govitecan led to a significant improvement in PFS. At the time of the second interim analysis, we saw that the study met its OS end point. Sacituzumab govitecan led to a significant improvement in OS, with a 3.2-month delta between the 2 arms and a HR of 0.79. [The agent also resulted in] a significant improvement in the ORR.

What updated data were presented at the 2023 ASCO Annual Meeting?

[At the meeting,] we presented the final OS analysis. This analysis was done when we had 13 months of follow-up. We re-looked at the survival outcomes and showed that sacituzumab govitecan continued to [provide] a significant benefit in PFS [over chemotherapy], going from 4 months to 5.5 months. [The agent] also continued to show a significant improvement in OS, going from 11.2 months to 14.5 months.

We also looked at an updated analysis that looked at the associations of Trop-2 expression and HER2 IHC scores with survival outcomes. We found that irrespective of Trop-2 expression or HER2 IHC score, sacituzumab govitecan always [performed] better than chemotherapy. It didn’t matter if [a patient was] Trop-2 low or high, or HER2 low or HER2 zero; sacituzumab govitecan still [performed] better than standard chemotherapy. Overall, these data reinforce what we knew: sacituzumab govitecan, with extended follow-up of about 13 months, is leading to improvements in both PFS and OS.

[The agent] also led to improvements in ORR and duration of response [DOR]. Again, the benefits [observed with the ADC] were irrespective of Trop-2 [expression] or HER2 IHC score and were pretty consistent across predefined subgroups. [Therefore, sacituzumab govitecan] should be a standard therapeutic option for patients with pretreated hormone receptor–positive breast cancer.

Were any of these efficacy findings surprising or unexpected?

One of the questions that has come up is: Shouldn’t it matter how much expression of the target there is for an ADC to work? It seems a little strange to just say, “Hey, you’re delivering an ADC that’s targeting Trop-2, but you don’t need to test whether Trop-2 is present for the drug to work.” It speaks to the fact that we don’t completely understand how ADCs work. If you look at sacituzumab govitecan and you break down the degree of Trop-2 expression, you can see that as Trop-2 expression goes up, the absolute PFS for sacituzumab govitecan goes up. [In other words,] if Trop-2 expression gets stronger, PFS does seem to be better. But even at the lowest level of Trop-2 expression, sacituzumab govitecan is still [performing] better than chemotherapy. Because it’s always [performing] better than standard chemotherapy no matter what the expression level is, we’re saying [we] don’t need to test for [Trop-2 expression].

This analysis re-examined Trop-2 expression with longer follow-up time for PFS and OS and continued to confirm [the drug’s efficacy.] In the future, as we get a little fancier and have lots of ADCs available, I do wonder whether we [can reach a point where] we do start looking at quantitative levels of the target to help us understand and predict what the right order of ADCs is. [However], we’re a bit far away from that at this point in time. Right now, these data confirm that we don’t need to be doing Trop-2 testing.

Were any new safety signals revealed with extended follow-up? More broadly speaking, what adverse effects (AEs) associated with sacituzumab govitecan should your colleagues be aware of?

We did look at toxicity with extended follow-up, and no new safety signals emerged; this is reassuring. There are the known toxicities of sacituzumab govitecan. [One of] the most prevalent AEs to keep in mind [is] neutropenia. In fact, 52% of patients had grade 3/4 neutropenia in TROPiCS-02, and about half of the patients ended up using growth factor support in the study. Clearly, it is important to monitor for neutropenia in these patients and to utilize growth factor support if needed.

The other thing to keep in mind is that sacituzumab govitecan does cause diarrhea. However, this is mostly low-grade diarrhea, so most patients can just use loperamide as needed and do great. Their diarrhea is typically nicely controlled with that strategy. The other thing to warn patients about is that sacituzumab govitecan does cause alopecia. Uniformly, patients who have hair when they’re starting the drug will usually go bald with the drug. That is an important thing to discuss with patients.

What is the clinical significance of this research, and how do these findings support the continued investigation of sacituzumab govitecan in other areas in the breast cancer realm?

TROPiCS-02 reinforces that sacituzumab govitecan works in [patients with] pretreated disease; [those in the study] had received 2 to 4 prior lines of chemotherapy, with a median of 3 lines of chemotherapy. It begs the question: Couldn’t we just use the drug a bit earlier? Why did we have to use it in such a pretreated group of patients? There is an ongoing [phase 3] study looking at this question.

ASCENT-07 [NCT05840211] is taking patients who have metastatic hormone receptor–positive disease who progressed through their endocrine therapy and are ready to move on to chemotherapy. They will be randomly assigned to receive sacituzumab govitecan in the first-line setting or standard chemotherapy of physician’s choice. This study is now enrolling and will help assess the performance of sacituzumab govitecan earlier on in the course of treatment for [patients with] metastatic hormone receptor–positive disease.

There are also [ongoing phase 3] studies looking at sacituzumab govitecan in the first-line treatment of metastatic triple-negative breast cancer [TNBC]: ASCENT-03 [NCT05382299] and ASCENT-04 [NCT05382286]. There’s even a study looking at sacituzumab govitecan in people with early disease. Patients, for example, with TNBC who received preoperative therapy and have residual disease, will get randomized to sacituzumab govitecan with pembrolizumab [Keytruda] or capecitabine and pembrolizumab. All these studies are suggesting that sacituzumab govitecan does work well, and we need to figure out how to get it to patients earlier on in their course of treatment.

What is your take-home message?

It’s nice to see that ADCs are [performing] better than standard chemotherapy. We’ve struggled a bit because response rates to single-agent chemotherapy in [patients with] pretreated metastatic breast cancer are unfortunately low. We really do need to do better for our patients. It’s been a great year to see at least 2 ADCs become available for [patients with] metastatic hormone receptor–positive breast cancer.

What other presentations at the 2023 ASCO Annual Meeting did you find particularly interesting in the breast cancer space?

For breast cancer, one of the exciting presentations was of the [phase 3] NATALEE trial [NCT03701334], which looked looked at adjuvant ribociclib [Kisqali] in patients with intermediate- and high-risk, early-stage hormone receptor–positive breast cancer. These patients were randomly assigned to get endocrine therapy or endocrine therapy with 3 years of ribociclib. We already have a CDK4/6 inhibitor approved in patients with early-stage hormone receptor–positive breast cancer, abemaciclib [Verzenio]. That [agent is] approved to be used in high-risk disease. The distinction here, and the reason this trial is interesting, is that it’s not just including the high-risk patients [specified in the] indication for abemaciclib. It is broadening that indication by adding in the intermediate-risk patients who were not included, for example, in [the phase 3] monarchE trial [NCT03155997]. It allowed [patients with] node-negative [disease] into the trial, as well. The study did meet its primary end point, but it did show that adding ribociclib to endocrine therapy did lead to an improvement in invasive disease-free survival. In essence, it reduced the risk of recurrence by about 25%, with an absolute difference of about 3% between the 2 arms.

The challenge is that the trial was giving ribociclib [to patients] for 3 years, which is a long time. We’re used to giving abemaciclib [to patients] for 2 years. That has cost and toxicity implications. The other problem is that the data [were reported] a bit early. Their follow-up time is a little under 30 months, and only 20% of patients on the trial had gotten through all 3 years of their ribociclib treatment. That means that most people are still on treatment. It always raises the question of, what’s going to happen as you follow people longer? Is the benefit going to get wider? Is it going to continue to improve outcomes? Or is the benefit going to start to diminish over time because you stopped the drug? Because ribociclib is a cell cycle inhibitor, some people wonder whether you will stop seeing the benefits in patients if you take the brakes off of the cell cycle.

We saw with abemaciclib that the benefit continued and, in fact, widened over time. Here, a lot of people would argue that they want to see what happens over time. [Still,] I think the data are very exciting and encouraging and suggest that ribociclib can be a very nice treatment option for some of our intermediate- and high-risk patients.

Reference

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