Considering Sacituzumab in HR+, HER2- Breast Cancer After Progression

Laura Huppert, MD

Assistant Professor, Medicine

University of California, San Francisco School of Medicine

San Francisco, CA

CASE SUMMARY

• A 52-year-old postmenopausal women with a history of T2N0M0 estrogen receptor-positive/progesterone receptor-negative, HER2 immunohistochemistry (IHC) 0 breast cancer.
• Received lumpectomy and sentinel lymph node biopsy; 21-gene recurrence score: 27
• She completed adjuvant docetaxel and cyclophosphamide followed by 5 years of letrozole.
• Eight months after completion of letrozole, she presented with persistent low-back pain and fatigue that restricted exercise.

Follow-Up Diagnostic Tests

• ECOG performance status: 0
• Complete blood count and comprehensive metabolic panel: hemoglobin 9.8 g/dL, all other indices within normal limits
• Fluorodeoxyglucose F 18 ([18F] FDG) PET/CT scan: fluorodeoxyglucose-avid radiotracer uptake detected in L4-L5 vertebrae and right pubic bone
• Biopsy of L4 bone lesion: malignant cytokeratin positive cells consistent with breast adenocarcinoma; hormone receptor (HR)-positive, HER2 IHC 0
• Molecular profile showed no alterations in ESR1, PIK3CA, PTEN, AKT, or pathogenic germline BRCA1/2 mutations​

Treatment and Progression

• First-line therapy with fulvestrant plus ribociclib was initiated and well tolerated.
  • Initial response noted on imaging at 3 months​.
• Fourteen months after starting first-line therapy:​
  • Evidence of progressive disease (PD), with new areas of bone involvement in T-spine, left ribs, and L2​
  • Circulating tumor DNA showed no actionable alterations, including ESR1 mutation.
• She then received exemestane plus everolimus for 6 months​.
• Radiographic evidence showed PD with numerous new bony metastases.
• Capecitabine was initiated, which was well tolerated

After 9 Months of Capecitabine​

• CT of chest/abdomen/pelvis and bone scan: 2 liver lesions, 1.8 cm and 2.4 cm; persistent bony metastases consistent with PD; lung lesions too small to characterize, but in setting of other findings concerning for metastatic disease​

Follow-Up Diagnostic Tests​

• ECOG performance status: 1​
• Laboratory profile: within normal limits

Targeted Oncology: What is the history of antibody-drug conjugates (ADCs) in breast cancer?

Laura Huppert, MD: Trastuzumab emtansine [TDM-1; Kadcyla] for breast cancer was first approved back in 2013, and then it was approved in the adjuvant setting in 2019. Trastuzumab deruxtecan [T-DXd; Enhertu] was also approved in 2019. Then in 2020, we got sacituzumab govitecan [Trodelvy] for a triple-negative breast cancer. In 2022, T-DXd expanded indication in HER2-positive and HER2-low breast cancer. Then sacituzumab for patients with HR-positive, HER2 negative disease was approved in 2023.

Now there's an explosion at ADCs in clinical trials and development, so a lot more to come. The next approval [was] datopotamab deruxtecan this year for HR-positive, based on the TROPION-Breast01 data. Then they'll probably expand the T-DXd indication for the HER2-ultralow population, which hasn't been formally done yet, but I think a lot is in the pipeline.

CASE UPDATE

• Sacituzumab govitecan was initiated.
• Best response of partial response observed, with further symptomatic improvement.
• Patient maintained an absolute neutrophil count of 3,900/μL and white blood cell count of 7,800/μL​.
• Follow-up [18F] FDG PET/CT scan: resolution of FDG-avidity in vertebral and pelvic bones

What was the background and design for sacituzumab in patients such as this one?

The TROPiCS-02 clinical trial [NCT03901339] looked at patients with metastatic or locally recurrent, inoperable HR-positive, HER2-negative breast cancer. They had to have had at least 1 line of endocrine therapy, taxane, and CDK4/6 inhibitor. These are heavily pretreated patients, so at least 2, but no more than 4 lines of chemotherapy for metastatic disease and have measurable disease. Investigators randomly assigned patients 1:1 to sacituzumab govitecan vs treatment of physician's choice [TPC] with a primary end point of progression-free survival [PFS], and then overall survival [OS] was a secondary end point.^1,2

Please discuss the efficacy seen on the TROPiCS-02 study.

At a median follow-up of 12.8 months, the median PFS differed by 1.5 months [HR, 0.65; 95% CI, 0.53-0.81; P = .0001]. Some people said this was underwhelming, but what I find more compelling about this is the 12-month PFS rate [sacituzumab, 21.7% vs TPC, 8.4%] and the 18-month PFS rate [sacituzumab, 14.4% vs TPC, 4.7%]. These are heavily pretreated patients, and some patients dropped off no matter what, and so they weren't going to respond either way, but if they responded to sacituzumab, they were 3 times as likely to be on sacituzumab at 12 months than TPC. I think that's the more compelling thing. For some of these patients, neither will work, but if it does work, they are going to hopefully be on it longer.

In terms of OS, it did have a benefit as well: 14.4 months vs 11.2 months, [HR, 0.79; 95% CI, 0.65-0.96; P = .020], so a 3-month difference in OS.

In a subgroup analysis looking by TROP2 expression, the key takeaway is it doesn't matter. We don't check TROP2; regardless of the level of TROP2 expression, sacituzumab seems to work in this setting. There was no difference by PFS and OS. Also by HER2 IHC status—you wouldn't expect that it would matter, it's a TROP2-directed ADC—but they checked whether it mattered and regardless of whether they were IHC 0 or HER2 low, patients responded to sacituzumab.

What was the toxicity seen in these patients with HR-positive, HER2-negative breast cancer?

There were no new safety signals at the updated analysis. We think about neutropenia and diarrhea as being the most problematic, and I think fatigue being the third, but grade 3 or greater events occurred in 74% of patients given sacituzumab vs 60% with TPC, but few led to dose [reductions]…. Any-grade neutropenia was 71% but 52% had grade 3 or greater. The use of growth factor is extremely helpful.

_References:

_{1. 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}

_{2. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X}