The antibody-drug conjugate sacituzumab tirumotecan extended overall survival as well as progression-free survival vs chemotherapy in patients with previously treated triple-negative breast cancer, according to the results of OptiTROP-Breast01, a phase III study presented at the 2024 ASCO Annual Meeting.1
“The clinical benefits were consistent and independent of TROP2 expression; however, a trend was observed toward longer progression-free survival in patients with high TROP2 expression,” said lead author Binghe Xu, MD, PhD, of the Cancer Hospital, Chinese Academy of Medicine, Beijing. “More than 80% of triple-negative breast cancers overexpress TROP2, providing a rationale for targeting it.”
Binghe Xu, MD, PhD
Chemotherapy has been used for previously treated triple-negative breast cancer, but survival has been poor, and it has associated toxicities. Sacituzumab govitecan-hziy is recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology as a preferred second-line treatment of advanced triple-negative breast cancer, and it is the only TROP2 antibody-drug conjugate approved for this indication so far.
Sacituzumab tirumotecan incorporates the same antibody as sacituzumab govitecan, but it has a different payload and linker. The linker is a novel methyl sulfonyl pyrimidine linker that conjugates the payload, a belotecan-derivative topoisomerase I inhibitor. Extracellular pH-sensitive cleavage and intracellular enzymatic cleavage in tumor cells affect the linker, which then releases the payload (a TROP2 inhibitor) into the tumor cells, he explained.
Study Details and Results
OptiTROP-Breast01 is an open-label study of patients with locally recurrent or metastatic triple-negative breast cancer treated with at least two prior chemotherapies. Patients were randomly assigned 1:1 to receive sacituzumab tirumotecan (n = 130) or physician’s choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine, n = 133). At a median follow-up of 5.1 months, sacituzumab tirumotecan achieved a 69% reduced risk of disease progression or death compared with physician’s choice of chemotherapy, which was statistically significant (P < .00001). In the final analysis by blinded independent committee review, median progression-free survival was 5.7 months with sacituzumab tirumotecan vs 2.3 months with chemotherapy.
“Sacituzumab tirumotecan performed better in all subgroups, but the magnitude of difference was most pronounced in the subgroup with high TROP2 expression,” Dr. Xu said. In the group with high TROP2 expression, median progression-free survival was 8.3 months vs 2.3 months, respectively. In the group with low/medium TROP2 expression, median progression-free survival was 5.7 vs 2.6 months.
An interim analysis performed at a median follow-up of 10.4 months showed that median overall survival was not reached with sacituzumab tirumotecan vs 9.4 months with chemotherapy (P = .0005). Median duration of response was 7.1 months with sacituzumab tirumotecan vs 3 months with chemotherapy.
Regarding overall safety, treatment-related adverse events were reported in 100% of those treated with the antibody-drug conjugate vs 96.2% of patients given a placebo. The rate of grade 3 or higher adverse events was similar (57.7% vs 56.6%, respectively). Serious adverse events were reported in 20.8% vs 12.9%, respectively.
Expert Point of View
Invited discussant of the OptiTROP-Breast01 study, Giampaolo Bianchini, MD, of the Universita Vita-Salute San Raffaele, Italy, discussed challenges in testing for target expression in the context of antibody-drug conjugates. “For antibody-drug conjugates, target expression matters, but it is not always clinically relevant. The clinical relevance depends on the complex interplay between the target, the type of antibody-drug conjugate, and the molecular/histologic context,” he said.
Giampaolo Bianchini, MD
Dr. Bianchini continued: “This has to be considered in the context of limitations of staining for target expression, including variability of tests, intratumoral and intertumoral heterogeneity, and temporal heterogeneity of antibody-drug conjugate target expression. Biomarker studies do not report timing.”
“The design of the present trial is similar to that of the ASCENT trial comparing sacituzumab govitecan vs physician’s choice of chemotherapy in patients with relapsed or refractory metastatic triple-negative breast cancer.2 Patients were enrolled in OptiTROP-Breast01 regardless of TROP2 expression. This trial shows an important clinical benefit of sacituzumab tirumotecan compared to chemotherapy. The benefit of antibody-drug conjugate vs chemotherapy in OptiTROP-Breast01 is comparable to that observed in the ASCENT trial,” he said. For the biomarker analysis in OptiTROP-Breast01, the investigators combined low/medium TROP2 expression and compared that with high expression of TROP2.
“The magnitude of sacituzumab govitecan activity in the ASCENT trial is moderately dependent on TROP2 expression, but those investigators separated low, medium, and high TROP2 expression. It would be interesting to have the data on the magnitude of sacituzumab tirumotecan activity in the subgroup with low TROP2 expression,” he continued. “It is an open question whether trastuzumab deruxtecan (T-DXd) should be preferred to an anti-TROP2 antibody-drug conjugate in the HER2-low/TROP2-low triple-negative breast cancer group…. Target assessment may become relevant in the competitive and crowded antibody-drug conjugate landscape. T-DXd compared to ado-trastuzumab emtansine demonstrated that hitting the same target with a different antibody-drug conjugate can have very different activity and efficacy. T-DXd breaks the glass of a long-lasting dogma that anti-HER2 therapy could work only in HER2 highly expressing or amplified tumors.”
“In summary, selecting patients based on target expression is not strictly necessary for sacituzumab tirumotecan in triple-negative breast cancer. Evaluating target expression is challenging because of analytical issues, arbitrary cutoffs, and spatial and temporal heterogeneity, and improvements are needed,” he said.
REFERENCES
1. Xu B, Yin Y, Fan Y, et al: Sacituzumab tirumotecan in patients with previously treated locally advanced or recurrent metastatic triple-negative breast cancer. 2024 ASCO Annual Meeting. Abstract 104. Presented June 2, 2024.
2. Bardia A, Hurvitz SA, Tolaney SM, et al: Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529-1541, 2021.
DISCLOSURE: The OptiTROP-Breast01 study was supported by the Sichuan Kelun-Biotech Biopharmaceutical Company. Dr. Xu reported no conflicts of interest. Dr. Bianchini has received honoraria from AstraZeneca/Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; has served as a consultant or advisor to Agendia, AstraZeneca/Daiichi Sankyo, Daiichi Sankyo Europe GmbH, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; has received institutional research funding from Gilead Sciences; and has received reimbursement for travel, accommodations, and expenses from AstraZeneca/Daiichi Sankyo, Gilead Sciences, Novartis, Pfizer, and Roche.
