Sacituzumab Govitecan Demonstrates Significant Improvement in Survival in Heavily Pretreated, Locally Recurrent Inoperable, or Metastatic HR-positive, HER2-negative Breast Cancer

In a global, randomised, phase III study conducted in patients with heavily pretreated, locally recurrent inoperable, or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer, a Trop-2–directed antibody drug conjugate, sacituzumab govitecan demonstrated significant improvement in progression-free survival (PFS) over chemotherapy with a 34% reduction in risk of disease progression or death and a higher proportion of patients who are alive and progression-free at all landmark time points with non-overlapping confidence intervals [CIs] compared with chemotherapy. Primary results of the TROPiCS-02 study 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 26 August 2022 in the Journal of Clinical Oncology.

The authors wrote in the study background that endocrine therapy combined with CDK4/6 inhibitor has extended overall survival (OS) for metastatic HR-positive, HER2-negative breast cancer to over 5 years in the first-line setting and combinations with PI3K or mTOR inhibitors offer benefit in subsequent treatment lines, but endocrine resistance eventually develops. Sequential single-agent chemotherapy is the next treatment option but is associated with declining response rates and disease control and increased toxicity.

Sacituzumab govitecan is a first-in-class antibody-drug conjugate with an SN-38 payload targeting Trop-2, an epithelial antigen expressed in solid tumours, especially in HR-positive, HER-negative and triple negative breast cancers and linked to tumour progression and poor prognosis. Internalisation of Trop-2–bound sacituzumab govitecan delivers SN-38 into the tumour cell through hydrolysis of the linker. Because SN-38 is a membrane-permeable free molecule released in the tumour microenvironment, it may elicit antitumour effects in adjacent non–Trop-2-expressing tumour cells.

Sacituzumab govitecan received full authorisation from the US Food and Drug Administration and European Medicines Agency for patients with metastatic triple-negative breast cancer who had received at least two prior chemotherapies of which at least one for metastatic disease and has accelerated approval for locally advanced or metastatic urothelial cancer. In the phase I/II IMMU-132-01 basket study, sacituzumab govitecan showed encouraging activity and safety in 54 patients with HR-positive, HER2-negative metastatic breast cancer who progressed on at least one line of endocrine therapy and at least one prior chemotherapy in the metastatic setting.

In TROPiCS-02, global, randomised, phase III study, sacituzumab govitecan was compared with physician’s choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR-positive, HER2-negative locally recurrent inoperable or metastatic breast cancer. The primary endpoint was PFS by blinded independent central review (BICR). Patients were randomly assigned to receive sacituzumab govitecan (272 patients) or chemotherapy (271 patients). The median age was 56 years, 95% had visceral metastases, and 99% had a prior CDK4/6 inhibitor, with 3 median lines of chemotherapy for advanced disease.

Primary endpoint was met with a 34% reduction in risk of progression or death (hazard ratio [HR] 0.66, 95% CI 0.53 to 0.83; p = 0.0003). The median PFS was 5.5 months (95% CI 4.2 to 7.0) with sacizuzumab govitecan and 4.0 months (95% CI 3.1 to 4.4) with chemotherapy. The PFS at 6 and 12 months was 46% (95% CI 39 to 53) versus 30% (95% CI 24 to 37) and 21% (95% CI 15 to 28) versus 7% (95% CI 3 to 14).

Benefit with sacituzumab govitecan was seen across most of the prespecified subgroups, including patients who received at least 3 prior chemotherapies for metastatic disease, had visceral metastases, and were age 65 years or older. Overall, results are consistent with those from the HR-positive, HER2-negative cohort of the phase I/II IMMU-132-01 basket study.

Median OS in first planned interim analysis was not yet mature (HR 0.84; p = 0.14). Additional preplanned follow-up will provide more clarity into the survival benefit of sacituzumab govitecan in this patient population.

Key grade ≥ 3 treatment-related adverse events were neutropenia (51% in case of sacituzumab govitecan versus 38% in case of chemotherapy) and diarrhoea (9% in case of sacituzumab govitecan versus 1% in case of chemotherapy).

The authors commented that the phase III DESTINY-Breast04 study recently compared the antibody drug conjugate trastuzumab deruxtecan with chemotherapy of physician’s choice in a patient population that partially overlaps with those enrolled in TROPiCS-02. Trastuzumab deruxtecan significantly improved both PFS and OS in patients with HR-positive, HER2-low metastatic breast cancer. But, there are important differences in the study populations that limit comparisons; DESTINY-Breast04 only included patients with HER2-low less heavily pretreated disease with median number of prior chemotherapies in the metastatic setting as one, along with other differences.

This study has some potential limitations. In particular 22 patients (8%) randomly assigned to the chemotherapy group were not treated, likely because of patient preference not to receive standard chemotherapy. Most patients had visceral metastases (95%), consistent with aggressive disease, and had received multiple lines of chemotherapy, which are the factors associated with shorter PFS and higher neutropenia risk. The heterogeneity of prior treatments and chemotherapy of physician’s choice options might have affected efficacy findings. Hormone receptor status was determined locally at any stage of disease, which has historically presented challenges for accurate assessment. The study did not require real-time BICR assessment of progressive disease, potentially increasing censoring.

The authors commented that sacituzumab govitecan may represent an important treatment option for patients with HR-positive, HER2-negative breast cancer after prior treatment including endocrine therapy, a CDK4/6 inhibitor and at least two lines of chemotherapy, including a taxane for advanced breast cancer. Neutropenia and diarrhoea are known adverse events with sacituzumab govitecan and should be prevented and managed according to established guidelines. Additional phase III studies evaluating sacituzumab govitecan in HR-positive breast cancer are underway, including GBG102-SASCIA and EVER-132-002.

Findings from the second interim results of the TROPiCS-02 study

Per protocol, OS was analyzed after approximately 350 events. In the statistical testing hierarchy, objective response rate (ORR) and patient-reported outcomes are tested sequentially if OS is significant. At data cut-off on 1 July 2022 with median follow-up of 12.5 month, 390 OS events occurred.

Sacituzumab govitecan significantly improved OS compared with chemotherapy with median 14.4 versus 11.2 month (HR 0.79; p = 0.020). The ORR of 21% versus 14% (odds ratio 1.63, CI 1.03-2.56; p = 0.035), time to deterioration of global health score / quality-of-life of 4.3 versus 3.0 month (HR 0.75, CI 0.61-0.92; p = 0.006) and time to deterioration of fatigue of 2.2 versus 1.4 month (HR 0.73, CI 0.60-0.89; p = 0.002) favoured the treatment with sacituzumab govitecan. Safety of sacituzumab govitecan was consistent with prior reports with no new safety signals identified. These latest findings were presented at the ESMO 2022 Congress in Paris, France (9-13 September).

The authors concluded that sacituzumab govitecan demonstrated statistically significant and clinically meaningful improvement in OS, and significant improvement in ORR and quality of life with manageable safety in patients with endocrine treatment resistant, HR-positive, HER2-negative metastatic breast cancer, a population with limited treatment options.

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

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