Trastuzumab deruxtecan confers hope as second-line therapy for HER2+ mBC

Updated results of the DESTINY-Breast03 trial, presented at SABCS 2022, showed that in patients with HER2+ metastatic breast cancer, second-line treatment with trastuzumab deruxtecan conferred better survival benefits than treatment with trastuzumab emtansine.

“The results of this analysis demonstrated remarkable overall survival (OS) and continued progression-free survival (PFS) benefit with trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer who progressed on prior therapy, further supporting the use of trastuzumab deruxtecan over trastuzumab emtansine in the second-line setting,” said study author Professor Sara Hurvitz from the David Geffen School of Medicine at the University of California Los Angeles and Jonsson Comprehensive Cancer Center, Los Angeles, California, US.

Participants in this multinational, open-label, phase III trial were 524 adults aged ≥18 years with HER2+ unresectable or metastatic breast cancer and ECOG performance status 0–1 who had experienced disease recurrence within 6 months of exposure to trastuzumab and a taxane. They were randomized 1:1 to receive intravenous trastuzumab deruxtecan (5.4 mg/kg) or trastuzumab emtansine (3.6 mg/kg) Q3W.

Patients assigned to trastuzumab deruxtecan and trastuzumab emtansine were followed up for a median 28.4 and 26.5 months, respectively.

PFS, as per blinded independent central review (BICR), was significantly improved with trastuzumab deruxtecan compared with trastuzumab emtansine (median 28.8 vs 6.8 months; hazard ratio [HR], 0.33, 95 percent confidence interval [CI], 0.26–0.43; p_nominal<0.0001). PFS rates at 24 months were 53.7 and 26.4 percent in the trastuzumab deruxtecan and trastuzumab emtansine groups, respectively. [SABCS 2022, abstract GS2-02; Lancet 2022;doi:10.1016/S0140-6736(22)02420-5]

The median PFS with trastuzumab deruxtecan was four times longer than with trastuzumab emtansine, Hurvitz commented.

There was also a significant benefit in OS favouring trastuzumab deruxtecan over trastuzumab emtansine (median not reached in both groups; HR, 0.64, 95 percent CI, 0.47–0.87; p=0.0037), with 24-month OS rates of 77.4 and 69.9 percent in the trastuzumab deruxtecan and trastuzumab emtansine groups, respectively.

BICR-assessed objective response rate was also greater with trastuzumab deruxtecan vs trastuzumab emtansine (78.5 percent vs 35.0 percent; p<0.0001), with a greater proportion of patients in the former than the latter experiencing complete response (21.1 percent vs 9.5 percent) and partial response (57.5 percent vs 25.5 percent). The clinical benefit rate was significantly improved with trastuzumab deruxtecan compared with trastuzumab emtansine (89.3 percent vs 46.4 percent; p<0.0001). Patients on trastuzumab deruxtecan had a longer duration of response than those on trastuzumab emtansine (median 36.6 vs 23.8 months).

Manageable adverse event profile

Patients in the trastuzumab deruxtecan and trastuzumab emtansine groups received treatment for a median 18.2 and 6.9 months, respectively.

The incidence of grade ≥3 drug-related treatment-emergent adverse events (TEAEs) was comparable between trastuzumab deruxtecan and trastuzumab emtansine recipients (47.1 percent vs 42.1 percent), and 12.8 percent vs 7.7 percent experienced drug-related serious TEAEs. Grade ≥3 treatment-related AEs occurred in 56.4 and 51.7 percent, respectively.

Drug-related TEAEs were associated with drug discontinuation in 19.8 percent vs 6.5 percent, dose reduction in 25.3 percent vs 14.6 percent, and drug interruption in 42.0 percent vs 17.2 percent. There were six deaths in each group that occurred due to TEAEs, none deemed drug related.

The most common grade ≥3 TEAEs among trastuzumab deruxtecan recipients were decreased neutrophil count, anaemia, and decreased platelet count (16, 9, and 8 percent, respectively), while the most common in trastuzumab emtansine recipients were decreased platelet count, anaemia, and increased alanine aminotransferase and aspartate aminotransferase levels (20, 7, 5, and 5 percent, respectively). Drug-related interstitial lung disease/pneumonitis was documented in 15.2 and 3.1 percent of trastuzumab deruxtecan and trastuzumab emtansine recipients, respectively; none were grade 4–5 (all mild or moderate in severity).

A triumph for trastuzumab deruxtecan

“Almost all patients with HER2+ metastatic breast cancer experience disease progression on first-line treatment, requiring transition to a second-line treatment,” Hurvitz said.

Previous interim analysis of the present trial demonstrated a significant improvement in PFS with trastuzumab deruxtecan over trastuzumab emtansine (median not reached vs 6.8 months; HR, 0.28, 95 percent CI, 0.22–0.37; p<0.001), as well as a potential OS benefit, though this latter finding was not statistically significant (HR, 0.55, 95 percent CI, 0.36–0.86; p=0.007). [N Engl J Med 2022;386: 1143-1154]

Professor Sara Hurvitz (Photo by © MedMeetingImages/Todd Buchanan 2022)

“Based on the strength of DESTINY-Breast03 efficacy and safety data, trastuzumab deruxtecan is considered the preferred second-line treatment and trastuzumab emtansine is an alternative option [in HER2+ metastatic breast cancer],” said Hurvitz.

“While PFS benefits are important, the gold standard measure of efficacy is OS,” Hurvitz pointed out. “With this OS analysis, we can confirm that the previously demonstrated benefit from trastuzumab deruxtecan in PFS improvement transforms into a statistically significant improvement in OS, a substantial advantage for our patients.”

“In addition, trastuzumab deruxtecan continued to demonstrate a manageable and tolerable safety profile, with similar rates of treatment-related AEs between treatment arms,” she concluded.