Supplements and Featured Publications
Reviewing Key Updates in the Realm of HER2+ and HER2-Low Breast Cancer
Volume 1
Issue 1

Second-Line T-DXd Data Remain Strong in HER2+ Metastatic Breast Cancer

Key Takeaways

  • T-DXd showed a median PFS of 29.0 months compared to 7.2 months with T-DM1.
  • The median OS was 52.6 months for T-DXd versus 42.7 months for T-DM1.
Erika Hamilton, MD

Erika Hamilton, MD

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) demonstrated sustained improvement in response rates as well as progression-free survival (PFS) and overall survival (OS) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer following prior exposure to trastuzumab (Herceptin) and taxane chemotherapy, according to updated findings from an exploratory analysis of the phase 3 DESTINY-Breast03 trial (NCT03529110) that were presented at the 2024 ASCO Annual Meeting.1

The median PFS per investigator assessment was 29.0 months (95% CI, 23.7-40.0) with T-DXd (n = 261) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (n = 263; HR, 0.30; 95% CI, 0.24-0.38). The 36-month PFS rates with T-DXd and T-DM1 were 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%-17.7%), respectively. The median investigator-assessed OS was 52.6 months (95% CI, 48.7-not evaluable [NE]) and 42.7 months (95% CI, 35.4-NE) with T-DXd and T-DM1, respectively (HR, 0.73; 95% CI, 0.56-0.94). The 36- and 42-month OS rates with T-DXd were 67.6% (95% CI, 61.3%-73.0%) and 62.5% (95% CI, 56.2%-68.3%), respectively; the respective rates with T-DM1 were 55.7% (95% CI, 49.2%-61.7%) and 50.1% (95% CI, 43.6%-56.2%).

“These data continue to support the use of T-DXd as standard of care in patients with HER2-positive metastatic breast cancer whose disease progressed after trastuzumab and taxane and show the longest OS in this setting,” Erika Hamilton, MD, lead study author and director of breast cancer and gynecologic cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, and coauthors, wrote in the poster presentation.

DESTINY-Breast03 is an open-label, multicenter, phase 3 trial studying the activity and safety of second-line treatment with T-DXd vs T-DM1 in patients with unresectable or metastatic HER2-positive breast cancer. To be eligible for enrollment, patients had to have been previously treated with trastuzumab and taxane chemotherapy in the advanced or metastatic setting. Prior exposure to T-DM1 was not allowed.

Patients were randomized 1:1 to 5.4 mg/kg of T-DXd every 3 weeks or 3.6 mg/kg of T-DM1 every 3 weeks. PFS by blinded independent central review (BICR) served as the primary end point, with secondary end points of OS, objective response rate (ORR) and duration of response (DOR) by BICR as well as ORR, DOR, PFS, and PFS2 per investigator assessment, and safety. Stratification factors included hormone receptor status, prior exposure to pertuzumab (Perjeta), and history of visceral disease.

In prior findings from the first interim analysis of the trial, the median PFS per BICR with T-DXd was not reached vs 6.8 months with T-DM1 (HR, 0.28; P <.001), meeting the primary end point of the trial. At the time of the second interim analysis, the median PFS per BICR was 28.8 months with T-DXd vs 6.8 months with T-DM1 (HR, 0.33; nominal P <.0001). Moreover, T-DXd led to a statistically significant improvement in OS vs T-DM1 (HR, 0.64; P =.0037).

Data from the trial served as the basis for the agent’s approval in 2022 for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.2,3

The present analysis was conducted to better understand median OS, the only end point that had not been reached in either treatment arm at the first or second interim OS analysis.1

As of the data cutoff date of November 30, 2023, 19.5% of patients in the T-DXd arm and 3.8% of patients in the T-DM1 arm remained on study therapy. The most common reasons for treatment cessation were progressive disease (T-DXd, 41.6%; T-DM1, 70.1%) and adverse effects ([AEs] 23.7%; 9.2%).

“Patient baseline demographics and characteristics were similar in both treatment groups,” the study authors said. “The median age was 54.3 years [range, 27.9-83.1) in the T-DXd group and 54.2 years [range, 20.2-83.0] in the T-DM1 group, and most patients in both groups had a HER2 immunohistochemistry score of 3+ [T-DXd, 89.7%; T-DM1, 88.2%]. Patients had also received a median of 2 prior lines of therapy in the metastatic setting in both treatment groups.”

The median follow-up was 43.0 months (range, 0.0-62.9) in the T-DXd arm and 35.4 months (range, 0.0-60.9) in the T-DM1 arm. The median treatment duration was 18.2 months (range, 0.7-56.6) in the T-DXd arm vs 6.9 months (range, 0.7-55.2) in the T-DM1 arm.

Additional findings indicated that the confirmed investigator-assessed ORR was 78.9% (95% CI, 73.5%-83.7%) with T-DXd vs 36.9% (95% CI, 31.0%-43.0%) with T-DM1. Most patients in both the T-DXd and T-DM1 arms experienced partial responses (T-DXd, 66.3%; T-DM1, 32.7%), although complete responses (12.6%; 4.2%) were also seen. Stable disease occurred in 18.4% and 45.2% of patients in the T-DXd and T-DM1 arms, respectively; progressive disease occurred in 0.8% and 12.9% of patients, respectively, and 1.9% and 4.9% were not evaluable.

The median DOR was 30.5 months (95% CI, 23.0-NE) and 17.0 months (95% CI, 14.1-23.7) with T-DXd and T-DM1, respectively; the 36-month DOR rates were 48.9% (95% CI, 41.3%-56.1%) and 28.7% (95% CI, 18.9%-39.2%), respectively.

In terms of safety, any-grade drug-related treatment-emergent adverse effects (TEAEs) occurred in 98.1% and 87.4% of patients in the T-DXd and T-DM1 arms, respectively. The most frequent events in the T-DXd arm were nausea (77.0%), fatigue (53.3%), and vomiting (52.9%), compared with thrombocytopenia (55.9%), increased transaminases (47.5%), and fatigue (35.2%).

Additionally, exposure-adjusted incidence rates (EAIRs) taking into account differences between treatment durations were consistently lower with T-DXd for any-grade TEAEs (T-DXd, 0.53; T-DM1, 1.10), grade 3 or greater TEAEs (0.31; 0.60), and serious TEAEs (0.15; 0.26).

“Despite longer treatment duration, the safety profile of T-DXd remained manageable, with no cumulative toxicities observed with longer follow-up, and was consistent with the previous analysis,” study authors explained.

Updated safety findings also showed 4 new cases of grade 2 adjudicated drug-related interstitial lung disease (ILD) and pneumonitis with T-DXd and 1 case of grade 1 ILD with T-DM1. One event had not recovered or resolved, 2 had recovered or resolved with sequelae, and 1 recovered or resolved completely. The EAIRs for ILD and pneumonitis were 0.09 with T-DXd and 0.04 with T-DM1. Regarding the time to first ILD and pneumonitis event in the T-DXd arm, 5.4%, 4.6%, 4.2%, and 2.3% of cases occurred within 6 months, between 6 and 12 months, between 12 and 24 months, and after 24 months of the time of diagnosis, respectively.

Regarding subsequent therapy post-trial, of the 80.5% and 96.2% of patients in the T-DXd and T-DM1 arms, respectively, who discontinued study treatment, 69.6% and 78.9% received additional systemic therapy. The remaining 2.9% and 12.6% of patients in the T-DXd arm underwent surgery and radiation, respectively. In the T-DXd arm, subsequent systemic treatments included trastuzumab (39.6%), T-DXd (8.3%), T-DM1 (52.1%), pertuzumab (11.8%), taxane (15.3%), taxane plus trastuzumab (8.3%), other HER2-directed therapy (39.6%: HER2-directed TKI, 36.1%; other HER2-directed antibody or antibody-drug conjugate, 9.0%), hormone therapy (20.1%), or other systemic therapy (69.4%).

The median PFS from the time of randomization to progression on next line of therapy or death per investigator assessment was 45.2 months (95% CI, 39.3-NE) with T-DXd and 23.1 months (95% CI, 17.8-29.7) months with T-DM1 (HR, 0.53; 95% CI, 0.41-0.68).

A sensitivity analysis for OS adjusted for post-trial treatment with T-DXd was also conducted in the T-DM1 arm, revealing a median OS of 39.8 months (95% CI, 32.4-NE) and a hazard ratio of 0.66 (95% CI, 0.51-0.87).

“Results of this long-term follow-up further support previously demonstrated superiority of T-DXd over T-DM1 for the treatment of patients with HER2-positive metastatic breast cancer whose disease progressed after trastuzumab and taxane,” study authors concluded.


  1. Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY-Breast03. J Clin Oncol. 2024;42(suppl 16):1025. doi:10.1200/JCO.2024.42.16_suppl.1025
  2. FDA D.I.S.C.O. Burst Edition: FDA approval of Enhertu (fam-trastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive breast cancer. FDA. May 24, 2022. Accessed June 5, 2024.
  3. Trastuzumab deruxtecan. Prescribing information. Daiichi Sankyo; 2024. Accessed June 5, 2024.
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