An overall survival benefit has now emerged for sacituzumab govitecan-hziy in women with previously treated, hormone receptor–positive/HER2-negative, locally recurrent, inoperable or metastatic breast cancer, according to a planned second interim analysis of the phase III TROPiCS-02 trial.1 The drug is the first TROP2-directed antibody-drug conjugate to demonstrate a significant improvement in overall survival in this subset of breast cancer.
“Sacituzumab govitecan resulted in a median 3.2-month improvement in survival. The overall survival benefit was consistent across predefined subgroups, including patients with at least three prior chemotherapy regimens in the metastatic setting, visceral metastases, and prior endocrine therapy in the metastatic setting for at least 6 months,” said Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. Dr. Rugo presented the findings at the European Society for Medical Oncology (ESMO) Congress 2022.1
Sacituzumab govitecan resulted in a median 3.2-month improvement in survival, representing a 21% relative reduction in the risk of death over treatment by physician’s choice.— Hope S. Rugo, MD, FASCO
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Answering an Unmet Need
“Hormone receptor–positive HER2-negative disease is the most common subset of breast cancer, comprising about 70% of cases. For metastatic hormone receptor–positive disease, international guidelines recommend sequential endocrine therapy combined with targeted agents, although optimal sequencing of therapy following endocrine resistance remains unclear. For patients with endocrine-resistant disease, sequential single-agent chemotherapy is the standard of care, but it is associated with declining efficacy and cumulative toxicity. Thus, there remains a high unmet clinical need for novel effective therapeutic options for patients with pretreated hormone receptor–positive HER2-negative metastatic breast cancer in the late-line setting,” Dr. Rugo pointed out.
Sacituzumab govitecan has been approved for patients with metastatic triple-negative breast cancer after at least two prior treatments (one or more for metastatic disease). The findings from TROPiCS-02 suggest the drug may be useful in women with hormone receptor–positive tumors as well. In the study, HER2 negativity was defined as an immunohistochemistry score of 0, 1+, or 2+ with a negative in situ hybridization test.
Overall Survival Benefit Attained
Dr. Rugo presented the results of the planned second interim analysis of overall survival based on the occurrence of 390 events at a data cutoff of July 1, 2022. Median follow-up was 12.6 months.
The median overall survival difference, which was not statistically significant in the previous analysis, has now widened to 14.4 months for patients who received sacituzumab govitecan vs 11.2 months for those treated with chemotherapy (hazard ratio [HR] = 0.79; P = .020). Patients receiving sacituzumab govitecan also had a significantly higher objective response rate, 21% vs 14% (HR = 1.63; P = .035); clinical benefit rate, 34% vs 22% (HR = 1.80; P = .003); and median duration of response, 8.1 months vs 5.6 months.
In addition, sacituzumab govitecan offered a benefit in overall health-related quality of life vs treatment by physician’s choice and a delay in deterioration of fatigue (2.2 months vs 1.4 months; HR = 0.73; P = .02) and global health status quality of life (4.3 months vs 3.0 months; HR = 0.75; P = .006). The safety profile for sacituzumab govitecan was consistent with prior studies, with no new safety signals emerging, she reported.
“The statistically significant and clinically meaningful benefit of sacituzumab govitecan over treatment by physician’s choice from the TROPiCS-02 study supports the use of sacituzumab govitecan as a novel therapy for patients with pretreated endocrine-resistant hormone receptor–positive HER2-negative metastatic breast cancer,” Dr. Rugo said.
TROPiCS-02 is a global, multicenter, open-label, phase III study that randomly assigned 543 patients to sacituzumab govitecan (10 mg/kg on days 1 and 8 every 21 days) vs physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine). Patients had received two to four prior lines of therapy (median of three), including endocrine therapy and inhibitors of cyclin-dependent kinases 4 and 6. The median age of patients was 56 years, and 95% of patients had visceral metastases. The median time from metastatic diagnosis to randomization was about 4 years.
The primary progression-free survival analysis of TROPiCS-02 and the first of three planned overall survival analyses was presented at the 2022 ASCO Annual Meeting.2 Meeting the primary endpoint, the study showed a statistically significant improvement in progression-free survival by independent review, based on median progression-free survival of 5.5 months with sacituzumab govitecan and 4.0 months with chemotherapy (HR = 0.66; P = .0003). Overall survival data were immature, but a numerical trend for improvement was seen, with median overall survival of 13.9 months vs 12.3 months (HR = 0.84; P = .14), respectively.
Applying Data in the Clinic
After her presentation, Dr. Rugo was asked where to position sacituzumab govitecan and fam-trastuzumab deruxtecan-nxki (T-DXd) in the treatment of hormone receptor–positive, HER2-negative disease, now that T-DXd proved effective in patients with HER2-low disease in the DESTINY-Breast04 trial.3 Without answers yet for many questions pertaining to the optimal use of these drugs, she described her current approach.
“I think that most, or all, of us would agree that in a patient who has HER2-low, hormone receptor–positive disease, in the second-line setting, we would choose T-DXd because that is the setting where it was tested. In the patient who has HER2-0 disease, I would use sacituzumab govitecan, as we have no data with T-DXd,” she said.
“I would also consider using sequential antibody-drug conjugate therapy, for the specific reason that we know the efficacy of these drugs is related to the antibody target as well as to the toxin,” continued Dr. Rugo. “Even though the toxins are in the same class, they are different, and the antibodies are clearly different. There are also marked differences in toxicity between these drugs. I think sequential therapy should be studied, and it’s a treatment option for our patients as well.”
DISCLOSURE: Dr. Rugo has served as a consultant or advisor to Samsung, Puma, Napo Pharmaceuticals, and Blueprint and has received institutional research funding from multiple companies.
1. Rugo HS, Bardia A, Marmé F, et al: Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HR+/HER2– metastatic breast cancer. ESMO Congress 2022. Abstract LBA76. Presented September 9, 2022.
2. Rugo HS, Bardia A, Marmé F, et al: Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan versus treatment of physician’s choice in patients with hormone receptor-positive/HER2-negative advanced breast cancer. 2022 ASCO Annual Meeting. Abstract LBA1001. Presented June 5, 2022.
3. Modi S, Jacot W, Yamashita Y, et al: Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Results of DESTINY-Breast04, a randomized phase 3 study. 2022 ASCO Annual Meeting. Abstract LBA3. Presented June 5, 2022.
TROPiCS-02 is a statistically positive trial, with the primary endpoint met and also now with an overall survival gain of 3.2 months,” said the study’s invited discussant Meritxell Bellet Ezquerra, MD, PhD, a senior researcher at the Vall d’Hebron Institute of Oncology, Barcelona. “TROPiCS-02 is...