Significant progression-free survival benefit with sacituzumab govitecan in patients with HR+/HER2- advanced breast cancer

After the positive results with sacituzumab govitecan (SG) in a phase I/II study, the randomised phase III TROPiCS-02 study aimed to evaluate SG for heavily pre-treated patients with HR+/HER2- metastatic disease who have received endocrine therapy, a CDK4/6 inhibitor, and prior chemotherapy. In this patient population with limited treatment options, SG demonstrated a manageable safety profile and a statistically significant, clinically meaningful PFS benefit over single-agent chemotherapy.

Sequential endocrine therapy (ET) combined with targeted agents is the recommended option for metastatic HR+/HER2- breast cancer. For ET resistant disease, sequential singe-agent chemotherapy is the standard of care, although it is associated with declining response rates, disease control and quality of life, and increased toxicity. With limited chemotherapy options available in later lines, a high unmet medical need remains. Sacituzumab govitecan (SG) is an anti–Trop-2 antibody-drug conjugate approved for metastatic triple-negative breast cancer with at least two prior therapies (≥1 for metastatic breast cancer [MBC]). In the single-arm phase I/II IMMU-132-01 study (N= 54), SG showed encouraging clinical activity in patients with previously treated metastatic HR+/HER2- breast cancer. TROPiCS-02 is a phase III randomised study evaluating SG therapy for heavily pre-treated patients with HR+/HER2- metastatic disease, who have received ET, a CDK4/6 inhibitor and prior chemotherapy.

Study Design

Adults with locally determined HR+/HER2-, unresectable, locally advanced or MBC, ECOG performance status of 0 or 1, and 2-4 prior chemotherapy regimens for MBC were eligible. One prior therapy for MBC was allowed if disease progressed within twelve months after (neo)adjuvant therapy. Patients had to have received ≥1 prior taxane, CDK4/6 inhibitor, and endocrine therapy in any setting. Patients were randomised in a 1:1 ratio to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) per RECIST v1.1 by blinded independent central review.

Results

At the data cut-off on January 3, 2022, 272 vs. 271 patients were randomised to receive SG vs. treatment of physician’s choice (TPC), respectively. Patient characteristics in the SG and TPC arms were similar (3 median prior chemotherapy regimens for MBC [range, 0-8 in the SG arm], 95% had visceral metastases, 86% had prior endocrine therapy for MBC for ≥6 months, 60% and 38% received prior CDK4/6 inhibitors for ≤12 and > 12 months, respectively).

After a median follow up of 10.2 months, SG demonstrated a statistically significant improvement in PFS compared to standard chemotherapy with a 34% reduction in the risk of disease progression or death (median PFS 5.5 vs. 4.0 months, HR [95%CI]: 0.66 [0.53-0.83]; p= 0.0003). PFS rates at all landmark timepoints (6, 9 and 12 months) were 46.1% vs. 30.3%, 32.5% vs. 17.3% and 21.3% vs. 7.1%, respectively. The PFS benefit for SG vs. TPC was consistent across predefined subgroups, including patients with at least three prior chemotherapy regimens in the metastatic setting, visceral metastases or age ≥65 years. In addition, SG vs. standard chemotherapy showed a non-significant trend for improvement in OS (median OS 13.9 vs. 12.3 months, HR: 0.84; p= 0.14) in the first of three planned OS analyses, with follow-up ongoing. The objective response rate (21% vs. 14%; p= 0.03) and clinical benefit rate (34% vs. 22%, p= 0.002) were higher with sacituzumab govitecan vs. standard therapy and the median duration of response was 7.4 vs. 5.6 months, respectively.

Overall, 74% of patients treated with sacituzumab govitecan and 60% of patients treated with standard chemotherapy experienced grade ≥3 treatment-emergent adverse events (TEAEs), including low white blood cell counts (51% vs. 38%) and diarrhoea (9% vs. 1%). TEAEs leading to discontinuation were low (6% vs. 4%). There was one treatment-related death in the SG arm; none in the standard chemotherapy arm. Furthermore, there were no events of interstitial lung disease in the SG arm (vs. 1% in the TPC arm) and no TRAEs of cardiac failure or left ventricular dysfunction in either arm. Finally, SG also demonstrated an overall health-related quality of life (QoL) benefit over TPC, with delayed deterioration in fatigue and global health status/QoL scales in EORTC QLQ-C30.

Conclusion

Sacituzumab govitecan demonstrated a significant improvement in clinical benefit and a manageable safety profile compared with standard chemotherapy in patients with heavily pre-treated, endocrine-resistant HR+/HER2- advanced breast cancer and should be considered a potential treatment option in this patient population.

Reference

Rugo HS, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. Presented at ASCO 2022; abstract LBA1001.