T-DXd New Standard of Care Following ET in HER2-Low, -Ultralow HR+ Metastatic Breast Cancer

Data from the phase 3 DESTINY-Breast06 trial (NCT04494425) demonstrated that fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu; AstraZeneca and Daiichi Sankyo) showed statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care (SoC) chemotherapy in patients with hormone receptor-positive (HR+), HER2-low (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization (ISH)-) metastatic breast cancer (mBC) following 1 or more lines of endocrine therapy (ET), according to principal trial investigator Giuseppe Curigliano, MD, PhD, professor of medical oncology at the University of Milan and head of the Division of Early Drug Development at the European Institute of Oncology, during a plenary session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.^1,2

Additionally, based on these study results, T-DXd is the first HER2-directed therapy and antibody drug conjugate (ADC) with clinically meaningful benefit for patients in this setting.¹

T-DXd is the first HER2-directed therapy and antibody drug conjugate with clinically meaningful benefit for patients in this setting. Image Credit: © Oksana Smyshliaeva - stock.adobe.com

“We have actually 40 years of clinical data on [ADCs, with] 339 ADCs under development, and 11 approved by FDA. [However, there are] 182 inactive clinical trials for ADCs, and 146 were discontinued due to toxicity or neuroactivity,” Curigliano said during the ASCO presentation.¹

Curigliano explained further that T-DXd is a monoclonal antibody targeting HER2 that has been approved for unresectable or metastatic HER2-positive solid tumors (IHC3+), HER2-low breast cancer, HER2+ advanced stomach cancer, and HER2-mutant metastatic non–small cell lung cancer. With data gathered from the DESTINY-Breast06, DESTINY-Breast03 (NCT03529110), and DESTINY-Breast07 (NCT04538742) trials in HER2-positive mBC, the role of T-DXd as SoC in the second-line setting is reinforced, with additional potential highlighted in the first-line setting, according to Curigliano.^1-4

“These results also represent a potential shift in how we classify and treat [mBC], as we may have the opportunity to use [T-DXd] earlier in the treatment of HR+ [mBC] and expand T-DXd into new patients [with mBC] who previously have not been able to benefit from a targeted medicine post-[ET],” Curigliano said.¹

During the trial, investigators looked at T-DXd in patients with HER2-low or -ultralow (IHC 0 with membrane staining), HR+ mBC after disease progression on ET and no prior chemotherapy for mBC. Patients (N=866) with HER2-low (n=713) or -ultralow (n=153), HR+ mBC were randomly assigned to receive T-DXd at 5.4 mg/kg or physician’s choice of chemotherapy. The trial’s primary end point was progression-free survival (PFS) by blinded independent central review (BICR) in HER2-low, with key secondary end points being PFS in intent-to-treat (ITT = HER2-low and -ultralow) and overall survival (OS). Other end points included objective response rate (ORR) and safety.¹

Patients enrolled in the trial had no prior chemotherapy, with 2 or more lines of ET, or 1 line of ET if disease progression occurred after 24 months or less of adjuvant ET, or 6 months or less of ET plus a CDK4/6 inhibitor. As of Mar 18, 2024, 90.4% of patients had received a prior CDK4/6 inhibitor, according to Curigliano. Patients receiving physician’s choice of chemotherapy were selected for capecitabine (59.8%, Xeloda; Genentech), nab-paclitaxel (24.4%, Abraxane; Bristol-Myers Squibb), or paclitaxel (15.8%).¹

Results showed T-DXd significantly improved PFS when compared to chemotherapy in HER2-low disease (HR, 0.62 [95% CI 0.51, 0.74], P<0.0001; median, 13.2 vs 8.1 months). The ITT and HER2-ultralow arms showed results that were consistent with the HER2-low arm results. For patients with HER2-low cancer, the ORR was 56.5% for T-DXd compared to 32.3% for chemotherapy. For those with HER2-ultralow cancer, the ORR more than doubled among those who received T-DXd compared to chemotherapy at 61.8% vs 26.3%, respectively. Overall, patients with HER2-low cancer who received T-DXd had a 38% decreased likelihood of their cancer growing or spreading compared to those who received chemotherapy.¹

Among patients who received T-DXd, they were able to receive treatment for a longer duration without experiencing severe adverse effects (AEs) compared to chemotherapy, with a median treatment duration of 11.0 months (T-DXd) vs 5.6 months (chemotherapy). Additionally, the OS data were immature at first interim analysis (HER2-low HR, 0.83 [95% CI 0.66, 1.05], P=0.1181; median follow up, 18.6 months).¹

Serious AEs were most common in the T-DXd group, with 40.6% of participants experiencing serious AEs vs about 31.4% among those who received chemotherapy. Adjudicated pneumonitis occurred in 49 (11.3%; 0.7% Gr 3/4, 0.7% Gr 5) vs 1 (0.2% Gr 2) patients receiving T-DXd vs chemotherapy. With these results, Curigliano noted that the safety profile demonstrated in the trial was in line with known profiles.¹

Overall, T-DXd showed a statistically significant and clinically meaningful PFS benefit compared to chemotherapy in patients with HER2-low mBC. Further, the results for patients with HER2-ultralow disease were consistent with HER2-low. According to Curigliano, these data establish T-DXd as a SoC following 1 or more line of ET in pts with HER2-low and -ultralow, HR+ mBC.¹

“[ADCs] are an exciting and effective part of breast cancer care with a growing role in our treatment paradigms. T-DXd, an antibody-drug conjugate approved for pretreated metastatic HER2-positive and HER2-low breast cancer, was evaluated in the DESTINY-Breast06 trial as the first therapy for patients with HR-positive, HER2-low, and HER2-ultralow breast cancer after [ET],” said ASCO expert commentator Erica L. Mayer, MD, MPH, a breast cancer clinician and researcher in the Breast Oncology Center of the Dana-Farber Cancer Institute, during the presentation. “These data suggest that T-DXd may become a preferred first-line treatment option for most patients with HR+ [mBC] after progression on [ET]. It is important to note, however, that [T-DXd] resulted in more serious toxicities compared to traditional chemotherapy and may not be the right choice for every patient.”¹

REFERENCES

1. Curigliano G, Mayer EL. On-Site Briefing on Plenary Abstracts. 2024 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2024; Chicago, Illinois.
2. Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (DB-06). ClinicalTrials.gov. Updated April 12, 2024. Accessed June 2, 2024. https://clinicaltrials.gov/study/NCT04494425
3. DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03]. ClinicalTrials.gov. Updated April 16, 2024. Accessed June 2, 2024. https://classic.clinicaltrials.gov/ct2/history/NCT03529110?V_25=View
4. A Phase 1b/​2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (DB-07). ClinicalTrials.gov. Updated March 18, 2024. Accessed June 2, 2024. https://clinicaltrials.gov/study/NCT04538742