The DESTINY-Breast03 clinical trial was a study evaluating trastuzumab deruxtecan versus T-DM1. We presented the updated results for this study at San Antonio. The first-line standard of care for patients with HER2 positive metastatic breast cancer is trastuzumab taxane plus pertuzumab, based on the CLEOPATRA trial, and up until recently the standard second-line therapy for patients after trastuzumab and a taxane was the treatment trastuzumab emtansine, or T-DM1, based on the EMILIA clinical trial.

The DESTINY-Breast03 clinical trial, however, challenged that approach. It went head-to-head against T-DM1 with T-DXd in patients who had previously received trastuzumab and a taxane for advanced disease. The first reporting of these data was in September 2021 and demonstrated a significantly improved median progression free survival with a hazard ratio of 0.28 at that time in favour of T-DXd, making T-DXd the preferred second-line therapy and making T-DM1 an alternative treatment regimen.

At San Antonio we presented the updated results, including overall survival which was a key secondary endpoint. It’s notable in this clinical trial that about 40% of patients were being treated in the second-line setting; the remainder of patients were being treated in a later line setting. In other words, they had had more than one prior line of therapy in the metastatic setting. About 60% of the patients had received prior pertuzumab.

At our reporting, the key secondary endpoint of overall survival was demonstrated to be statistically significantly longer, or higher, with T-DXd compared to T-DM1 with a hazard ratio of 0.64 and a p-value of 0.0037 which crossed the pre-specified threshold for significance. Although neither arm had reached its median overall survival, the percentage of patients at two years who were still alive in the T-DXd arm was 77.4% versus 69.9% of patients in the T-DM1 arm. Subgroup analysis demonstrated that T-DXd benefitted patients regardless of hormone receptor status, prior use of pertuzumab, presence of visceral metastases, number of lines of prior therapy or baseline brain metastases. Progression free survival was also updated at this analysis and the median PFS with T-DXd was 28.8 months which was about four times longer than seen with T-DM1 where the median PFS was 6.8 months. The objective response rate with T-DXd was 78.5%, with 21% of patients having a complete response, in contrast with T-DM1 the objective response rate was 35% with 9.5% of patients experiencing a complete response.

In terms of safety, the rates of grade 3/4 AEs with T-DXd and T-DM1 were fairly similar. With T-DXd there were more patients who experienced all grades nausea and vomiting as well as alopecia. In terms of grade 3/4 AEs anaemia and neutropenia were more commonly seen with T-DXd whereas thrombocytopenia and alteration in liver enzymes were more common with T-DM1. In terms of interstitial lung disease, 15.2% of patients treated with T-DXd had any grade of ILD but there were no grade 4 or 5 events. Although this total rate of ILD of 15.2% was higher than we reported at the first reporting in 2021 of this study where it was 10.5%, all of the additional events reported with longer follow-up were grade 1 or 2.

So, in summary, this study demonstrates that T-DXd is associated with a statistically significant improvement in overall survival with a reduced risk of death of 36% as well as a significantly prolonged progression free survival and objective response rate. With a longer treatment duration the safety of T-DXd appears similar to previous reports with no grade 4 or 5 ILD events. These data overall place T-DXd firmly in the second line position now, after trastuzumab and taxane, for metastatic breast cancer that’s HER2 positive.