DESTINY-Breast 06

Prof Dr Giuseppe Curigliano, a medical oncologist at the European Institute of Oncology and University of Milan, Italy, presented the long-awaited results of the DESTINY-Breast 06 trial at ASCO 2024 and discussed them with Dr Elisa Agostinetto, medical oncologist at Institut Jules Bordet in Brussels, Belgium.

The DESTINY-Breast 06 was a prospective randomized trial that included HR-positive, HER2-low and HER2-ultralow patients, defined as having staining between 0 and 1.

The main objective of the study was to evaluate the activity of T-DXd as an early line of treatment in patients with minimal HER2 expression and no prior chemotherapy. A total of 855 patients, of which 153 with centrally confirmed HER2-ultralow expression, were randomized 1:1 to receive either T-DXd or the physician’s choice of chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel).

The primary endpoint was median PFS in the ITT population, assessed by investigators and blinded independent central review. Secondary endpoints included median PFS in the HER2-ultralow population, ORR, DoR, and QoL. All patients had received at least endocrine therapy plus CDK4/6 inhibitors, with 89% heavily pretreated and many also receiving second-line endocrine therapy. Endocrine resistance, indicated by progression within six months after first-line CDK4/6 inhibitor therapy, was observed in 8.45% of the population.

The median PFS in the ITT population was 13.1 months for the T-DXd arm versus 8.1 months for the chemotherapy arm, with similar data in the HER2-ultralow population. The ORR, a key secondary endpoint, showed that 57% of HER2-low patients and 60% of HER2-ultralow patients achieved either a complete or partial response. With 40% maturity, preliminary data indicated that 71% of patients in the chemotherapy arm were alive versus 83% in the T-DXd arm at 1-year landmark analysis, suggesting a positive impact on OS. This practice-changing trial establishes T-DXd as the new standard option after progression to first- or second-line endocrine therapy plus targeted therapy, replacing chemotherapy.

Experts suggested using T-DXd as a first-line chemotherapy for symptomatic patients or those needing a rapid ORR and as a second-line option for asymptomatic patients or those with low disease burden. Prof. Curigliano noted that in the DESTINY-Breast 06 trial, 96% of patients had visceral disease and 69% had liver metastasis. The five-month increase in median PFS and improvement in OS emphasize the importance of selecting the best first-line treatment rather than delaying it to the second line.

HER2-ultralow is not a distinct pathological entity according to the ASCO-CAP definition, and current immunochemistry techniques struggle to differentiate HER2-ultralow from HER2-zero. Pathologists should specify faint expression between 0 and 10% to identify HER2-ultralow patients. With a 60% response rate, T-DXd treatment should not be denied to these patients. Further research is needed to confirm the lack of effect in HER2-zero or to determine the threshold below which T-DXd is not beneficial.

The experts discussed the risk of ILD in patients treated with T-DXd and Prof Curigliano emphasized the importance of raising patient awareness and conducting regular CT scans, with a baseline scan as part of standard care and follow-up scans every three months to monitor disease progression and assess for ILD.