Sacituzumab Govitecan Shows Efficacy in HR+, HER2- Breast Cancer

Elizabeth A. Mittendorf, MD, PhD

Rob and Karen Hale Distinguished Chair in Surgical Oncology, Brigham and Women's Hospital

Director, Breast Immuno-Oncology Program

Co-Director, Breast Cancer Clinical Research Program

Dana-Farber Brigham Cancer Center

Professor of Surgery, Harvard Medical School

Boston, MA

Targeted Oncology: How has the role of antibody-drug conjugates (ADCs) evolved in hormone receptor (HR)-positive breast cancer?

ELIZABETH A. MITTENDORF, MD, PHD: We use ADCs in our patients with HER2-positive disease, we use them in our patients with triple-negative disease, and what's the role in our HR-positive patients? This is becoming more defined.

The TROPiCS-02 trial [NCT03901339] was a phase 3 study that looked at sacituzumab govitecan [Trodelvy] in HR-positive, HER2-negative metastatic patients with breast cancer, and it was a 1:1 randomization of sacituzumab versus treatment of physician's choice, capecitabine, vinorelbine, gemcitabine, or eribulin. There were a number of stratification factors, with the primary end point being progression-free survival [PFS].

The data were presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2022, and then subsequently published in the Journal of Clinical Oncology.¹ [Looking at] the baseline characteristics of the 2 groups, sacituzumab versus physician's choice [included] a median age in both groups of approximately 55 to 56 years old. They had comparable performance status, [and] about 95% of patients had visceral metastases at baseline. The median time from initial metastatic diagnosis to randomization was about 4 years, 64% had prior chemotherapy, and then—important for our conversation—the prior CDK4/6 inhibitor use; CDK4/6 was used [for 12 months or fewer in approximately 60% of patients].

The baseline characteristics of the HR [expression]…was of great interest because I'm personally interested in this ER [estrogen receptor]-low space, those with 1% to 10% [expression]. I think genomically and otherwise they're more like our basal-like or triple-negative cancers, but they are ER-positive by definition, so a small percentage of patients had 1% to 10% [ER expression]. One of the points Hope S. Rugo, MD, made when she presented [these data] was, we therefore cannot attribute this to the same effect that we saw in the trials looking at sacituzumab in our patients with triple-negative disease. This is a HR-positive population, with 95% or so being over 10% [ER expression].

What were the outcomes of the TROPiCS-02 trial?

The PFS data were after a median follow-up of 10 months, and the median PFS in the sacituzumab group was 5.5 months, compared with 4 months in the arm of the trial where patients received physician's choice of chemotherapy, with a hazard ratio of 0.66 [favoring sacituzumab], and it's steady now [after] 6, 9, and 12 months.

The forest plot showed if there were any particular subgroups [that stand out], and although I've seen more striking forest plots, in general, it showed that most groups do benefit from sacituzumab. For visceral metastasis, there was a wider CI, and [the upper bound] does cross 1.0. There was a relatively small group of 26 patients who did not have visceral metastasis, so I'm not certain that we can draw conclusions from that.

The OS [overall survival] was presented in their second interim analysis.² This was a secondary end point of the trial, and…the median OS for patients receiving sacituzumab was 14.4 months versus 11.2 months for those receiving chemotherapy. That translated to a 12-month OS rate of 61% compared with 47%, [respectively]. Much like we see with PFS benefit, it was generally consistent across pre-defined subgroups, including patients who had multiple prior lines of chemotherapy in the metastatic setting in patients with visceral metastasis, and patients who had received prior endocrine therapy in the metastatic setting for 6 months or longer.

At the second interim analysis, the objective response rate was 57% for patients receiving sacituzumab versus 38% for those receiving chemotherapy [odds ratio, 1.63; 95% CI, 1.03-2.56; P = .035].^1,2 The data broken down by best overall response showed a majority of patients who were experiencing stable disease [with sacituzumab], and then [a superior] clinical benefit rate [for sacituzumab].

With respect to safety and quality of life, 51% of patients had grade 3 or 4 neutropenia. Fewer than 10% of patients had grade 3 or 4 diarrhea. Overall, the patients in the sacituzumab arm of the trial had improved health-related quality of life when compared with those receiving chemotherapy, and there were no new safety signals from prior presentation of the data.

The data looked at whether or not TROP2 is a biomarker of response, and the answer to that, generally, is that it is not.³

_References:

_{1. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376. doi:10.1200/JCO.22.01002}

_{2. Rugo HS, Bardia A, Marmé F, et al: Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HR+/HER2– metastatic breast cancer. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089}

_{3. Sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC): Efficacy by Trop-2 expression in the TROPiCS-02 study of patients (pts) with HR+/HER2– metastatic breast cancer (mBC). Cancer Res. 2023;83(5_suppl):GS1-11. doi:10.1158/1538-7445.SABCS22-GS1-11}