ADCs Demonstrate Superiority Vs Chemotherapy in Recurrent Breast Cancer

Reshma Mahtani, DO

Chief of Breast Medical Oncology

Baptist Health Wellness and Medical Complex

Miami Cancer Institute

Baptist Health South Florida

Plantation, FL

Targeted Oncology: For patients with hormone receptor (HR)-positive, HER2-negative or HER2-low breast cancer, what do you use in later lines of therapy?

Reshma Mahtani, DO: For patients in the second line who have HR-positive, HER2-low disease, the recommendation is for trastuzumab deruxtecan [Enhertu; T-DXd]. In patients who are not a candidate for T-DXd, the National Comprehensive Cancer Network guidelines indicate that sacituzumab govitecan [Trodelvy] is the preferred therapy.¹

Please discuss the trial data behind sacituzumab govitecan in this population.

The phase 3 TROPiCS-02 study [NCT03901339] looked at patients who had HR-positive, HER2-negative—negative here means immunohistochemistry [IHC] 0 as well as HER2-low, including both of those groups—patients who had at least 1 prior endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting. Recognize here the [lines of prior] chemotherapy these patients had were a much heavier line of prior treatment as compared with Destiny-Breast04 [NCT03734029], where the majority of those patients had 1 to 2 prior lines of therapy. Here, patients had at least 2, but no more than 4 lines of chemotherapy, and this was in the metastatic setting.

The randomization here was to the antibody-drug conjugate [ADC] sacituzumab govitecan, which targets Trop-2, vs treatment of physician's choice [TPC]. What we saw was very clinically meaningful improvements.

At first glance, the magnitude of benefit doesn't seem to be as much as some of the data with T-DXd, but recognize that you can't compare these populations, because these are patients who are much more heavily pretreated, and recall that no single-agent chemotherapy in this setting has shown a survival benefit. There was an HR of 0.65 [95% CI, 0.53-0.81] for progression-free survival [PFS], and the 6-, 12-, and 18-month PFS probability rates all favor sacituzumab govitecan over TPC.²

What did subgroup analyses show in the TROPiCS-02 trial?

The approximately 3-month overall survival advantage is a high bar to reach in this group of heavily pretreated patients. [Looking at] TROPiCS-02’s efficacy by Trop-2 expression level, we see that there was no impact of Trop-2 expression on efficacy, and this was looked at various cut points. This tells us that we don't have to test for Trop-2. It's ubiquitously expressed, and there was efficacy regardless of the H score, which is a measure of Trop-2 expression.²

Similarly, we saw the efficacy broken down by HER2 IHC status. For those who are wondering why this analysis was done, because this drug targets Trop-2, not HER2, the thinking here is, is there something unique about the biology of HER2-low disease where this drug may not be as effective? Of course, we have the other drug, T-DXd, for HER2-low [disease], so there was interest in looking at this subset specifically. Sacituzumab govitecan improved overall survival vs TPC in HER2-low, as well as HER2 IHC 0 subgroups.

The [overall] response rate was 21% compared with 14% in the TPC arm [odds ratio, 1.66; 95% CI, 1.06-2.61; P = .027]. We saw a very reasonable clinical benefit rate, and that includes partial, overall, and complete response, and stable disease for at least 6 months. The median duration of response was 8.1 months with sacituzumab govitecan [vs 5.6 with TPC]. To put this in perspective, these patients, as you think back to patients in the past who had been on 2, 3, or 4 lines of chemotherapy, to get an agent that has a response that lasts for about 8 months in this late-line setting is extremely clinically meaningful.

As we are all now starting to use this drug more frequently, we know the toxicity profile is largely consistent with gastrointestinal issues and neutropenia, hematologic issues, some cramping, and abdominal discomfort. We saw rates of treatment discontinuation [of 6% with sacituzumab govitecan vs 4% with TPC] and dose delays [of 66% vs 44%, respectively].

What newer ADCs are coming down the pipeline for patients with HR-positive, HER2-low breast cancer?

Datopotamab deruxtecan is the next ADC that is hopefully going to get approved. It's a Trop-2–directed ADC, but the payload is deruxtecan, just like T-DXd. We've seen promising antitumor activity in a manageable safety profile in pretreated patients. What we heard at the European Society for Medical Oncology [Congress] in 2023 was the TROPION-Breast01 study [NCT05104866]. These were patients with HR-positive, HER2-negative disease that was either 0, 1+, or 2+ and fluorescence in situ hybridization negative. They had 1 to 2 prior lines of chemotherapy, and experienced progression on endocrine therapy. It was datopotamab deruxtecan vs investigator’s choice.³

Median PFS was about 6.9 months as compared with 4.9 months with investigators’ choice chemotherapy [HR, 0.63; 95% CI, 0.52-0.76]. Overall survival at this early time point was not [mature]. We saw overall responses at 36.4% compared with 22.9% and some dose reductions were needed.

In terms of safety, the main issue with this drug tends to be some issues with dry eye, and we saw stomatitis with the drug. Ocular events are described [in the report]; most were dry eye. One patient discontinued treatment in the datopotamab deruxtecan group. We also saw oral mucositis and stomatitis that has led to discontinuation.

How do you think about sequencing these therapies?

As we get these ADCs, we're going to struggle with how to sequence them and how to handle all of these different data sets. But it’s good news for our patients that newer drugs are coming. We have 3 ADCs: trastuzumab emtansine [Kadcyla], T-DXd, and sacituzumab. [Then there are] the data on datopotamab deruxtecan. But even beyond that, there are more therapies coming, so sequencing questions and target and payload issues are going to be very important as we try to figure out how to optimally sequence these drugs.

REFERENCES:

1. Clinical Practice Guidelines in Oncology. NCCN. Breast cancer; version 4.2024. Accessed August 20, 2024. https://tinyurl.com/y6e5ffne

2. 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

3. Bardia A, Jhaveri K, Im SA, et al. LBA11 Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Primary results from the randomised phase III TROPION-Breast01 trial. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015