Treatment with trastuzumab deruxtecan (T-DXd) results in longer progression-free survival (PFS) in patients with hormone receptor?positive, HER2-low or HER2-ultralow metastatic breast cancer (mBC) compared with physician’s choice of chemotherapy, according to the results of the phase III DESTINY-Breast06 study presented at SABCS 2024. In addition, no new safety signals have been identified.

“T-DXd demonstrated a clinically meaningful efficacy benefit versus [chemotherapy], with a >12-month median PFS across first-line endocrine therapy (ET) plus CDK4/6 inhibitor time-to-progression (TTP) subgroups, notably in patients with rapid (<6 months) progression,” said lead author Dr Aditya Bardia, professor of medicine in hematology/oncology at the David Geffen School of Medicine at UCLA, US.

In the DESTINY-Breast06 study, Bardia and his team randomized 866 patients to receive either T-DXd 5.4 mg/kg given intravenously every 3 weeks or chemotherapy (59.8-percent capecitabine, 24.4-percent nab-paclitaxel, 15.8-percent paclitaxel).

Endocrine therapy

Participants had previously received ≥2 lines of endocrine-based therapy for mBC or 1 line if disease progression occurred within 24 months of adjuvant ET or within 6 months of first-line ET plus CDK4/6 inhibitor (the latter considered rapid progression). Subgroups were TTP on first-line ET plus CDK4/6 inhibitor and primary versus secondary endocrine resistance (per 5^th ESO-ESMO ABC criteria).

Bardia and colleagues assessed the following outcomes: PFS, confirmed objective response rate (ORR), and duration of response (DOR) by blinded independent central review in the ITT, and safety.

Of the participants, 713 had HER2-low and 153 had HER2-ultralow disease. The intent-to-treat (ITT) population included 89.3 percent of patients who received at least one prior line of ET plus CDK4/6 inhibitor. The TTP analysis included 65.8 percent of patients in ITT, of which 124 had <6-month, 112 had 6?12-month, and 334 had >12-month TTP. [SABCS 2024, abstract LB1-04]

Patient number, demographics, clinical characteristics at baseline were balanced across subgroups. In the TTP subgroup, 73 patients (<6 months; 58.9 percent), 26 (6?12 months; 23.2 percent), and 24 (>12 months; 7.2 percent) received T-DXd or chemotherapy as a second-line treatment following one line of ET plus CDK4/6 inhibitor.

Survival benefit

T-DXd induced longer PFS than chemotherapy in patients with rapid progression (<6 months; median, 14.0 vs6.5 months; hazard ratio [HR], 0.38, 95 percent confidence interval [CI], 0.25?0.59). A similar trend was observed in the 6?12-month (13.2 vs 6.9 months; HR, 0.69, 95 percent CI, 0.43?1.12) and >12-month subgroups (12.9 vs 8.2 months; HR, 0.67, 95 percent CI, 0.51?0.88).

ORR was significantly better with T-DXd, compared with chemotherapy, in patients with <6-month (67.7 percent vs 25.4 percent), 6?12-month (60.0 percent vs 28.8 percent), and >12-month TTP (59.5 percent vs 33.1 percent). Likewise, T-DXd had better DOR than chemotherapy across TTP subgroups (<6 months: median, 11.1 vs 7.3 months; 6?12 months: 13.7 vs 11.5 months; >12 months: 15.7 vs 11.1 months).

“Efficacy outcomes were consistent in patients with investigator-assessed primary and secondary endocrine resistance,” according to Bardia.

In terms of safety, the incidence of grade ≥3 treatment-emergent adverse events associated with T-DXd versus chemotherapy across TTP subgroups was consistent with the overall safety population (<6 months: 55.4 percent vs 42.2 percent; 6?12 months: 59.3 percent vs 40.8 percent; >12 months: 45.8 percent vs 42.9 percent).

These findings “highlight the potential role of T-DXd as an early-line treatment after ≥1 line of endocrine-based therapy for patients with hormone receptor?positive, HER2-low or -ultralow mBC,” Bardia said.