TROPiCS-02 is a global, multicenter, randomized phase 3 trial that compared the antibody drug conjugate sacituzumab govitecan to chemotherapy of physician choice in patients with heavily pretreated endocrine-resistant hormone receptor positive HER2-negative metastatic or locally advanced inoperable breast cancer. This trial targeted hormone receptor positive HER2-negative disease in patients who had previously received both endocrine therapy, targeted agents, and chemotherapy because this patient population represents an unmet need, where the only options are sequential chemotherapy associated with worse quality of life, and also declining response rates and increasing toxicity. Sacituzumab govitecan in TROPiCS-02 is given IV day one and day 8, every 21 days. And then patients were randomized one to one to receive sacituzumab or chemotherapy of physician choice, with a standard group of chemotherapy options based on NCCN and ASCO guidelines. Eligible patients had to have received at least one endocrine therapy treatment in the metastatic setting and two to four lines of chemotherapy for metastatic disease. In addition, they had to have received treatment with a CDK4/6 inhibitor and a taxane in any line. The primary endpoint for TROPiCS-02 was progression-free survival by a blinded independent central review, and secondary endpoints of course include overall survival as well as safety and quality of life endpoints. Patients were stratified by the number of visceral metastases, endocrine therapy for more than six months, and the chemotherapy. The demographics and baseline characteristics are important to understand the results of this study. The median age was 56. 95% of patients had visceral metastases, and a large number of patients had actually received CDK4/6 inhibitors for more than 6 months and more than 12 months, with 40% of patients actually receiving their CDK4/6 inhibitor for more than 12 months. In addition, these patients were heavily pretreated. More than 50% of patients had received at least three lines of chemotherapy for metastatic disease in the sacituzumab arm and in the chemotherapy arm, with a range in the sacituzumab arm of zero to eight lines. Progression-free survival was significantly longer by blinded independent review in patients receiving sacituzumab versus chemotherapy of physician choice at 4 months versus 5.5 months with a hazard ratio of 0.66, corresponding to a 34% relative improvement in outcome. And this was highly statistically significant. Safety also was manageable and comparable to previous studies. The primary toxicities that were grade three or greater were neutropenia or diarrhea, similar again to previous results. There were six deaths on the sacituzumab arm and no deaths that were considered adverse events from treatment in the chemotherapy arm. However, only one of these events was attributable to sacituzumab by the investigator, a patient who developed colitis and neutropenia. We also looked at quality of life in patients receiving sacituzumab. And using the ERTC QLQ-C30 scales, we found that overall global quality of life was improved in patients receiving sacituzumab versus chemotherapy, as was fatigue, and pain was similar. In summary, sacituzumab versus chemotherapy resulted in a significant improvement in progression-free survival and a manageable safety profile. Because many of these patients were so heavily pretreated and had a rapid progression, we actually looked at landmark analyses. And what we found was that at one year, 21% of patients were progression-free who received sacituzumab versus only 7% in the patients receiving chemotherapy. This is a very important endpoint because in these patients where we see rapid early progression, the separation occurs over time, and the number of patients who were progression-free and alive at 12 months is a very important endpoint for our patients. Overall survival is still immature at the first interim analyses with two additional analyses to go. One of the questions that's come up regarding this trial is the impact based on the data that will be presented at this meeting from DESTINY-Breast04 in patients classified as having HER2-low disease. 65% of patients with hormone receptor positive disease have HER2-low disease, so there is still a substantial number of patients who have HER2-0 disease who could benefit from sacituzumab earlier. And then it's important for us to have sequential treatment options and to understand the efficacy of these options when given sequentially.
