Sacituzumab govitecan confers OS benefit for HR+/HER2– metastatic breast cancer

In the second interim overall survival (OS) analysis of the phase III TROPiCS-02 study, sacituzumab govitecan (SG) – a first-in-class Trop-2*-directed antibody-drug conjugate approved for triple-negative metastatic breast cancer (mBC) with ≥2 prior therapies (≥1 in the metastatic setting) – conferred an OS benefit for pretreated HR+/HER2– mBC, compared with treatment of physician’s choice (TPC**).

Treatment for HR+/HER2– mBC is endocrine-based therapy (ET), followed by single-agent chemotherapy (CT). For ET-resistant disease, the standard of care is sequential single-agent CT. However, it is associated with low response rates, poor disease control, impaired quality of life (QoL), and increased toxicity. [Ann Oncol 2021;32:1475-1495; J Clin Oncol 2021;39:3959-3977; Clin Breast Cancer 2022;22:223-234; Eur J Cancer 2019;112:57-65]

“[Women] with ET-resistant HR+/HER2– mBC [thus have] limited treatment options,” said study presenter Dr Hope Rugo from the University of California – San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, US, at ESMO 2022. “[In the current analysis,] SG demonstrated a statistically significant and clinically meaningful improvement in OS in [this patient setting].”

Compared with the TPC arm, the SG arm had a longer OS and a 21-percent reduction in the risk of death (median 14.4 vs 11.2 months; stratified hazard ratio [HR], 0.79; p_{stratified log rank}=0.02). “[H]aving met statistical significance, no further formal statistical testing of OS will occur,” Hugo noted.

The OS benefit with SG vs TPC was generally consistent across predefined subgroups, including patients with ≥3 prior CT regimens in the metastatic setting (HR, 0.75; p=0.034), visceral metastases (HR, 0.76; p=0.007), and those who have had prior ET in the metastatic setting for ≥6 months (HR, 0.79; p=0.030). [ESMO 2022, abstract LBA76]

There were also significant improvements in overall response rate (21 percent vs 14 percent; odds ratio [OR], 1.63; p=0.035) and clinical benefit rate (34 percent vs 22 percent; OR, 1.8; p=0.003), with prolonged duration of response (median 8.1 vs 5.6 months) with SG vs TPC.

QoL Improvements were also seen with SG vs TPC, as reflected by the significant extensions in time-to-deterioration of Global Health Status/QoL (median 4.3 vs 3.0 months; stratified HR, 0.75; p_{stratified log rank}=0.006) and fatigue (median 2.2 vs 1.4 months; stratified HR, 0.73; p_{stratified log rank}=0.002).

Despite the higher rate of grade ≥3 treatment-emergent adverse events (TEAEs; 74 percent vs 60 percent) and TEAEs leading to death (n=6 vs 0) with SG vs TPC, the overall safety profile of SG was generally consistent with those that have been previously reported. [N Engl J Med 2021;384:1529-1541; Ann Oncol 2020;31:1709-1718; J Clin Oncol 2022;doi:10.1200/JCO.22.01002] There were no new safety signals identified after further follow-up.

A novel therapy for HR+/HER2– mBC?

This study evaluated 543 women (median age 56 years, 3 percent Asian) with metastatic or locally recurrent inoperable HR+/HER2− BC that progressed after at least one ET, taxane, and CDK4/6 inhibitor in any setting, and 2–4 prior lines of CT. They were randomized 1:1 to receive SG 10 mg/kg IV (days 1 and 8, every 21 days) or TPC until progressive disease or unacceptable toxicity.

“The statistically significant and clinically meaningful benefit of SG over TPC from [the current analysis] supports the use of SG as a novel therapy for patients with pretreated HR+/HER2– mBC,” Hugo concluded.

The current findings boost its recently reported significant progression-free survival benefit with SG vs TPC in this subgroup of patients, as well as a manageable safety profile that aligns with that seen in other SG trials. [J Clin Oncol 2022;doi:10.1200/JCO.22.01002; N Engl J Med 2021;384:1529-1541]