In a planned final overall survival (OS) analysis from the TROPiCS-02 study conducted in pretreated, endocrine-resistant hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), sacituzumab govitecan demonstrated a statistically significant improvement in OS compared with single-agent chemotherapy. Treatment with sacituzumab govitecan resulted in a 21% relative reduction in risk of death, and the corresponding 3.2 month improvement in median OS compared with chemotherapy. At both the primary analysis and the planned final analysis of this study, the adverse events reported remained consistent with the known safety profile of sacituzumab govitecan.

In this study, Trop-2 expression was observed in 437 patients (95%) patients with evaluable samples. This post-hoc analysis demonstrated that sacituzumab govitecan improves outcomes in patients with HR-positive, HER2-negative MBC compared with treatment of physician’s choice regardless of Trop-2 expression levels. The findings are published by Dr. Hope S Rugo of the Department of Medicine, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center in San Francisco, CA, US, and colleagues on 23 August 2023 in The Lancet.

The authors wrote in the background that there is an unmet clinical need for novel, effective therapies for endocrine-resistant HR-positive, HER2-negative MBC. Sacituzumab govitecan is an antibody–drug conjugate approved in several countries for the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received at least two previous systemic therapies of which at least one for metastatic disease.

The randomised, phase III TROPiCS-02 study evaluated sacituzumab govitecan in patients with endocrine-resistant and chemotherapy-resistant HR-positive, HER2-negative MBC. In the primary analysis, sacituzumab govitecan demonstrated statistically significant improvement in progression-free survival (PFS) compared with single-agent chemotherapy, with a 34% reduction in the risk of disease progression or death and median PFS of 5.5 months versus 4.0 months (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.53–0.83; p = 0.0003). A higher proportion of patients in the sacituzumab govitecan group were alive and were progression free at all landmark timepoints versus those in the chemotherapy group, with three times as many patients being progression free at the 1-year mark (21% versus 7%). Sacituzumab govitecan demonstrated a manageable safety profile consistent with that in previous studies.

At the time of the first prespecified exploratory OS analysis, the median OS was not yet mature (HR 0.84, p = 0.13). In the latest article published in The Lancet, the study team presents results from the final analysis of OS from the TROPiCS-02 study of sacituzumab govitecan versus chemotherapy in patients with HR-positive, HER2-negative MBC, including updated, formally tested response and patient-reported outcomes, efficacy by Trop-2 expression, and safety.

In this randomised, open-label, multicentre, phase III study, which took place in 91 centres across North America and Europe, patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR-positive, HER2-negative locally recurrent inoperable or MBC and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease.

The primary endpoint was PFS, previously reported and not included in this analysis, and secondary endpoints included OS, objective response rate (ORR), and patient-reported outcomes. OS was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry (IHC). In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if OS was significant.

At the data cut-off date of 1 July 2022, a total of 543 of 776 screened patients were randomly assigned between 30 May 2019 and 5 April 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12.5-month of median follow-up, 390 deaths occurred among 543 patients. OS was significantly improved with sacituzumab govitecan versus chemotherapy with median OS of 14.4 months (95% CI 13.0–15.7) versus 11.2 months (95% CI 10.1–12.7) and HR of 0.79 (95% CI 0.65–0.96; p = 0.020).

Survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy, 21% versus 14% (odds ratio 1.63, 95% CI 1.03–2.56; p = 0.035), as was time to deterioration of global health status and quality of life (QoL) with median 4.3 months versus 3.0 months (HR 0.75, 0.61–0.92; p = 0.0059) and fatigue with median 2.2 months versus 1.4 months (HR 0.73, 0.60–0.89; p = 0.0021). The safety profile of sacituzumab govitecan was consistent with previous studies including the TROPiCS-02 primary analysis and the ASCENT study. One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment.

The authors commented that sacituzumab govitecan and trastuzumab deruxtecan have different antibody targets and linkers, and their payloads could be non-cross resistant despite targeting the same enzyme. Resistance mechanisms to antibody–drug conjugates are not well defined but might involve several mechanisms such as downregulation or altered expression of target biomarkers, alterations in lysosomal activity or drug efflux pumps, or alternative signalling pathway activation. Previous post-hoc analyses indicate that sacituzumab govitecan is an effective option for patients with HR-positive, HER2-negative breast cancer regardless of HER2 IHC 0 or HER2-low status. Additional studies to understand resistance mechanisms will help guide therapeutic sequencing strategies for these novel agents and studies are being planned to help understand the efficacy of sequencing various antibody–drug conjugates in the metastatic setting.

The authors concluded that TROPiCS-02 represents the largest study to date specifically done in patients with endocrine-resistant and chemotherapy-resistant HR-positive, HER2-negative MBC who have received previous endocrine and CDK4/6 inhibitor therapy, reflecting current standard of care. This updated efficacy analysis from TROPiCS-02 demonstrated a statistically significant OS benefit for sacituzumab govitecan over chemotherapy, supporting the previously reported PFS data. Combined with delayed deterioration in QoL and a manageable safety profile consistent with previous reports, these efficacy findings indicate that sacituzumab govitecan is an important novel therapy for these patients. An exploratory, descriptive analysis of OS with longer follow-up for this study is planned.

In an accompanied comment Drs. Sibylle Loibl of the German Breast Group, Neu-Isenburg and Centre for Haematology and Oncology Bethanien in Frankfurt, Germany, and Johannes Holtschmidt of the German Breast Group in Forschungs, Germany wrote that although the improvement in OS was statistically significant, whether these results are clinically meaningful remains to be established. This population was heavily pretreated, with 50% of patients having received three or more previous chemotherapy lines for MBC.

Treatment sequencing in MBC is a major issue. The relatively lower benefit was observed for patients who had previously received a CDK4/6 inhibitor for more than 12 months or as a first-line therapy. However, studies are not primarily designed to precisely identify patient subgroups who benefit from the treatment, because they are not powered for these analyses. A heterogeneous treatment context before enrolment, including several lines of therapy between treatment with a CDK4/6 inhibitor and time of randomisation, further hinders interpretation, but does not rule out the effects of possible endocrine sensitivity.

Given the relatively small absolute PFS and OS benefit in TROPiCS-02 and considering the relevant toxicity of sacituzumab govitecan, patients who benefit from sacituzumab govitecan therapy must be identified. Furthermore, a prevalence of the homozygous UGT1A1 mutation close to 10% justifies testing for UGT1A1 to avoid severe neutropenia. To prevent treatment-related deaths, and as sacituzumab govitecan is likely to soon become a treatment option for early breast cancer, testing for UGT1A1 should be considered. In the context of narrow clinical benefit, the reasons why patients discontinued treatment prematurely also need to be addressed. Taxanes or anthracyclines were not offered as treatments of physician’s choice even though at least 16% of all patients had never been treated with an anthracycline, and taxane reinduction might have been a valuable option, too.

The editorialists concluded that the new treatment option of sacituzumab govitecan in heavily pretreated HR-positive, HER2-negative MBC is much appreciated. It is reassuring that patients with early relapse or early failure of CDK4/6 inhibitor therapy appear to benefit most in terms of prolonged survival.

The study was funded by Gilead Sciences. The study was designed through a collaboration of the sponsor and the lead investigators.