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Sacituzumab govitecan displayed encouraging progression-free survival rates compared with single-agent chemotherapy in patients with locally recurrent inoperable or metastatic hormone receptor–positive, HER2-negative breast cancer, according to findings from the phase 3 TROPiCS-02 study.
Sacituzumab govitecan-hziy (Trodelvy) displayed encouraging progression-free survival (PFS) rates compared with single-agent chemotherapy in patients with locally recurrent inoperable or metastatic hormone receptor–positive, HER2-negative breast cancer, according to findings from the phase 3 TROPiCS-02 study (NCT03901339) published in the Journal of Clinical Oncology.
The median PFS per blinded independent central review (BICR) assessment was 5.5 months (95% CI, 4.2-7.0) with sacituzumab govitecan (n = 272) vs 4.0 months (95% CI, 3.1-4.4) with chemotherapy (n = 271; HR, 0.66; 95% CI, 0.53-0.83; P = .0003). The risk reduction of disease progression or death with sacituzumab govitecan was consistent in the local investigator assessment (HR, 0.73; 95% CI, 0.60-0.88; P = .001).
“Sacituzumab deruxtecan demonstrated a statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant, hormone receptor–positive, HER2-negative advanced breast cancer [who have] limited treatment options,” lead study authors Hope S. Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and Aditya Bardia, MD, MPH, of Massachusetts General Hospital, and colleagues, wrote.
First-line endocrine therapy plus CDK4/6 inhibitors has extended overall survival (OS) in metastatic hormone receptor–positive, HER2-negative breast cancer to over 5 years, and subsequent combinations with PI3K or mTOR inhibitors can be beneficial. However, endocrine resistance eventually develops. Although sequential single-agent chemotherapy is the next therapeutic option, this approach is associated with poor outcomes, including declines in response rates and disease control and increased toxicity.
Sacituzumab govitecan is a first-in-class antibody-drug conjugate with an SN-38 payload that targets the epithelial antigen Trop-2 through a hydrolysable CL2A linker. TROP-2 is a transmembrane calcium signal transducer that is highly expressed in solid tumors, particularly hormone receptor–positive, HER2-negative and triple-negative breast cancers, and it is associated with tumor progression and poor prognosis. SN-38, a membrane-permeable free molecule that is released in the tumor microenvironment, may demonstrate a bystander effect in adjacent non–TROP-2 expressing tumor cells.
To be eligible for the global, randomized, multicenter TROPiCS-02 trial, patients needed to have histologically locally confirmed measurable hormone receptor–positive, HER2-negative metastatic breast cancer and 2 to 4 prior lines of systemic chemotherapy for metastatic disease. One of these prior regimens could have been neoadjuvant or adjuvant therapy for early-stage disease, if early relapse occurred. Additionally, patients must have received at least 1 anticancer hormonal treatment, taxane, and CDK4/6 inhibitor.
From May 2019 to April 2021, 543 patients were randomly assigned 1:1 to receive sacituzumab govitecan (n = 272) or physician’s choice of chemotherapy (n = 271). Those in the control arm could have received eribulin (Halaven; 48%), capecitabine (Xeloda; 8%), gemcitabine (21%), or vinorelbine (23%).
Sacituzumab govitecan was administered intravenously at 10 mg/kg once weekly on days 1 and 8 every 21 days. The chemotherapy agents and their recommended doses were determined per locally approved prescribing information or the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Breast Cancer.
IV eribulin was recommended for administration at 1.4 mg/m2 in North America or 1.23 mg/m2 in Europe once weekly on days 1 and 8 every 21 days. Capecitabine was recommended to be given orally at a twice daily dose ranging from 1000 mg/m2 to 1250 mg/m2 for 2 weeks, followed by a 1-week rest period, every 21 days. IV gemcitabine was recommended to be given at 800 mg/m2 to 1200 mg/m2 once weekly on days 1, 8, and 15 every 28 days. Vinorelbine was recommended to be administered intravenously at a once weekly dose of 25 mg/m2.
Patients were treated until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. Treatment beyond progression was allowed if determined to be clinically beneficial per the investigator.
The primary end point of this trial was PFS by BICR per RECIST v1.1 criteria. The key secondary end point was OS. Other secondary end points included objective response rate (ORR), duration of response (DOR), clinical benefit rate, patient-reported outcomes, and safety. All end points were measured by computed tomography or magnetic resonance imaging every 6 weeks for the first 54 weeks and every 12 weeks thereafter.
The median age of the patients was 56 years (range, 27-86). In total, 95% of patients had visceral metastases and 86% had received endocrine therapy in the metastatic setting for at least 6 months. Ninety-nine percent of patients had previously received a CDK4/6 inhibitor; 40% of these patients had received CDK4/6 therapy for over 12 months. All these factors are associated with shorter PFS and a higher risk for neutropenia. Patients had received a median of 3 (range, 0-8) prior lines of chemotherapy for advanced disease, with 57% of patients having received at least 3 lines.
Overall, 99% (n = 268) of the sacituzumab govitecan group and 92% (n = 249) of the chemotherapy group received study treatment. Of the 26 patients who were randomized but not treated, comprised of 4 in the sacituzumab group and 22 in the chemotherapy group, 16 withdrew consent, including 1 in the sacituzumab govitecan group and 15 in the chemotherapy group.
At a data cutoff of January 3, 2022, 7% (n = 18) of the sacituzumab govitecan group and 1.5% (n = 4) of the chemotherapy group remained on study treatment. The median duration of follow-up was 10.2 months for all patients, including 11.3 months for the sacituzumab govitecan arm and 9.8 months for the chemotherapy arm. Patients in the sacituzumab govitecan group received a mean of 8.2 (range, 1.0-35.0) treatment cycles, with a median relative dose intensity of 99%.
The intent-to-treat population included all randomized patients and was used as the efficacy population. All patients who received at least 1 dose of study drug were included in the safety analysis.
Additional data showed that the 6-month PFS rate was 46% (95% CI, 39%-53%) with sacituzumab govitecan vs 30% (95% CI, 24%-37%) with chemotherapy; the 12-month PFS rates were 21% (95% CI, 15%-28%) and 7% (95% CI, 3%-14%), respectively. The PFS benefit observed with sacituzumab govitecan was maintained in most predefined subgroups, including those with visceral metastases, those aged 65 years or older, and those who had received at least 2 prior chemotherapy regimens in the metastatic setting.
Because the PFS results were statistically significant, OS was sequentially tested. The median OS at the time of the first planned interim analysis was 13.9 months (95% CI, 12.7-15.4) for sacituzumab govitecan and 12.3 months (95% CI, 10.8-14.2) for chemotherapy (HR, 0.84; 95% CI, 0.67-1.06; P = .14). However, OS results were was not yet mature, and further follow-up is ongoing.
Because the OS results were not significant, ORR and QOL end points were not formally tested. The ORR by BICR was 21% with sacituzumab govitecan vs 14% with chemotherapy; 2 patients (1%) in the sacituzumab govitecan arm achieved a complete response (CR) vs no patients on the chemotherapy arm. The median time to response was 2.9 months (range, 1.2-11.3) with sacituzumab govitecan vs 2.7 months (range, 1.2-10.5) with chemotherapy. The median DOR was 7.4 months (95% CI, 6.5-8.6) in the investigative arm vs 5.6 months (95% CI, 3.8-7.9) in the control arm.
Patient-reported outcomes were reported using the European Organization for Research and Treatment of Cancer QOL questionnaire. The completion rate of this questionnaire was at least 85% through day 1 of cycle 13 for both treatment groups. Per this assessment, the median time to deterioration for global health status/QOL was 4.0 months with sacituzumab govitecan vs 2.9 months with chemotherapy (HR, 0.74; 95% CI, 0.59-0.91). In the investigative and control arms, the median time to deterioration for fatigue was 2.1 months vs 1.4 months, respectively (HR, 0.76; 95% CI, 0.62-0.93); the median time to deterioration for pain was 3.7 months vs 3.4 months, respectively (HR, 0.92; 95% CI, 0.74-1.14).
The safety profile of sacituzumab govitecan proved manageable and consistent with findings from previous studies. Patients were permitted to use premedications, such as antipyretics and H1 blockers, to prevent and treat chemotherapy-induced nausea, vomiting, and diarrhea.
As of the data cutoff date, 77% of those in the sacituzumab group and 73% of those in the chemotherapy group had discontinued study treatment because of progressive disease. In the safety population, the median duration of treatment was 4.1 months (range, 0.03-24.2) with sacituzumab govitecan and 2.3 months (range, 0.03-22.3) with chemotherapy.
The most common treatment-related adverse effects (TRAEs) of any grade in the investigative and control arms, respectively, were neutropenia (70% vs 54%), diarrhea (57% vs 16%), nausea (55% vs 31%), alopecia (46% vs 16%), fatigue (37% vs 29%), and anemia (34% vs 25%). The most common grade 3 or higher TRAEs included neutropenia (51% vs 38%), leukopenia (9% vs 5%), diarrhea (9% vs 1%), anemia (6% vs 3%), and fatigue (6% vs 2%).
These 2 approaches elicited a low incidence of treatment-related febrile neutropenia (sacituzumab govitecan, 5%; chemotherapy, 4%), interstitial lung disease (0; 1%), and neuropathy (9%; 15%).
Investigators observed serious TRAEs in 14% (n = 37) of those who received sacituzumab govitecan vs 10% (n = 25) of those given chemotherapy. The most common serious TRAEs reported with sacituzumab govitecan were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), and neutropenic colitis (2%). The most common serious TRAEs experienced with chemotherapy were febrile neutropenia (4%), dyspnea (2%), nausea (2%), and pneumonia (2%).
AEs leading to study treatment discontinuation occurred in 6% (n = 17) of those in the sacituzumab govitecan group and 4% (n = 11) of those in the chemotherapy group.
In total, 6 patients in the sacituzumab govitecan group experienced AEs leading to death, although only 1 patient had a TRAE leading to death, in the form of septic shock from neutropenic colitis. The remaining 5 patients each experienced 1 of the following AEs that resulted in death: pulmonary embolism, arrhythmia, pneumonia, COVID-19 pneumonia, and nervous system disorder. The patients with fatal infections of pneumonia and COVID-19 pneumonia were not neutropenic at the time of the onset of these AEs. No AEs leading to death were noted in the chemotherapy group.
Additional phase 3 studies of sacituzumab govitecan in hormone receptor–positive breast cancer are ongoing, including the phase 3 GBG102-SASCIA (NCT04595565) and EVER-132-002 (NCT04639986) trials.
“The magnitude of PFS benefit should be considered in the context of the totality of efficacy data from this trial in the late-line setting, which all favored sacituzumab govitecan over chemotherapy, with a substantially higher proportion of patients alive and progression-free at all landmark time points,” the study authors concluded. “This novel agent directed to a highly expressed target may represent an important treatment option for these patients, addressing a critical unmet medical need.”
Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor–positive/human epidermal growth receptor 2–negative metastatic breast cancer. J Clin Oncol. Published online August 26, 2022. doi:10.1200/JCO.22.01002