Survival and Safety Outcomes Factor into Use of Sacituzumab Govitecan in HR+ Breast Cancer

Mark Pegram, MD

Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology

Stanford University School of Medicine

Associate Director of Clinical Research

Stanford Comprehensive Cancer Institute

Stanford, CA

Targeted Oncology: Could you describe the TROPiCS-02 trial (NCT03901339) that led to the approval of sacituzumab govitecan (Trodelvy) in patients with hormone receptor–positive, HER2-negative breast cancer?

MARK PEGRAM, MD: [Concerning] the TROPicS-02 clinical trial design, it was a phase 3 study in patients with metastatic hormone receptor–positive disease who had received at least 1 endocrine therapy, a taxane and CDK4/6 inhibition in any setting. If you had somebody on adjuvant CDK4/6 inhibitor in the modern era, or they received neoadjuvant or adjuvant taxane, that all counted for eligibility in this trial. [Patients on the trial] had received least 2 but not more than 4 lines of chemotherapy for metastatic disease in the patient population in this trial, and must have had measurable disease by RECIST. They [received] treatment with sacituzumab govitecan at 10 mg/kg IV on day 1 and 8 on a 21-day cycle, or treatment of physician’s choice with capecitabine, vinorelbine, gemcitabine, or eribulin. The primary end point was progression-free survival [PFS] by a blinded independent committee review.¹

What are the key efficacy outcomes observed in this trial?

[Looking at] topline data for the primary end point of PFS: there was a statistically significant improvement in PFS favoring patients who were randomly assigned to sacituzumab govitecan as compared with chemotherapy.² The HR is 0.65 [95% CI, 0.53-0.81; nominal P = .0001], so [these are] impressive results for this agent. Overall survival [OS] also favored [sacituzumab govitecan with] an HR of 0.79 [95% CI, 0.65-0.95, P = .0133]. So, there was a survival benefit over chemotherapy for an antibody-drug conjugate [ADC] targeting TROP2 with a topoisomerase-I inhibitor payload.

These [PFS and OS] data were updated at the 2023 American Society of Clinical Oncology Annual Meeting.² The responses were more modest, 21% [with sacituzumab govitecan vs 14% with chemotherapy]. But in the clinic, we all make treatment decisions on clinical benefit rate, that is responders plus stable disease, hopefully long term. The clinical benefit rate in this paper was [defined as] responders plus disease stability for at least 6 months or more. That is a more respectable fraction, over a third of the patients had that and that was statistically significantly better than chemotherapy control in this trial [34% vs 22%, odds ratio 1.80; 95% CI, 1.23-2.63; P = .0025]. Duration of response was approximately 8 months compared with less than 6 months for chemotherapy.²

What should physicians know about the tolerability and management of sacituzumab govitecan in this patient population?

You have to be mindful of adverse events [AEs] with sacituzumab govitecan because it does have some chemotherapy-like AEs.² It does cause cytopenias, not dissimilar from chemotherapy. It also is moderately emetogenic, so you need to use antiemetics routinely as a premedication for this agent. It can cause diarrhea, which is also in the prescribing information, so be mindful of that and dose modify or [use] comedication accordingly. There can also be alopecia, [which occurred] in half the patients, some fatigue [was seen] in almost one-third, anorexia [in 21%], and aspartate aminotransferase elevation in [approximately] 10%. It's not like trastuzumab emtansine [T-DM1; Kadcyla], and it doesn’t cause thrombocytopenia like T-DM1 does either, or as much transaminase elevation, but T-DM1 is a pretty easy ADC to use. It was the first one that we all got used to using back in the day. [Sacituzumab govitecan] was a little bit more challenging in terms of safety signals, but if you control these, it can be extremely well tolerated.

Focusing on the AEs of grade 3 or higher, we see about half the patients have neutropenia. Hardly anybody had grade 3 thrombocytopenia, only 1 patient out of 268, so that's distinctly unusual. There was some [grade 3 or 4] diarrhea in approximately 10% [of patients]. There was a bit of upper gastrointestinal toxicity, but only [grade 3 or higher in] 1%. Abdominal pain is also a feature in the prescribing information. I don't know the mechanism of that, but it seems to be consistent, but it's seen a small fraction of patients.

Treatment-emergent AEs led to treatment discontinuation [of sacituzumab govitecan] in only 6%, [which is] impressive. Dose delay is more common [with this therapy, as seen in 66% of patients]. Approximately one-third of patients needed a dose reduction. I also find that I use growth factor quite a bit with this agent. I usually give pegfilgrastim [Neulasta] after day 8 and if someone is neutropenic from a prior cycle, or had a delay from a prior cycle, that usually takes care of it. I've seen fatigue and [used] dose modification for that, [as well].

_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. 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}