T-DXd Improves All Outcomes in Post-Hoc Look of DESTINY-Breast06 in HR+, HER2-Low/-Ultralow Metastatic Breast Cancer

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Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to numerical improvements in progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and time from randomization to second progression or death (PFS2) vs treatment of physician’s choice with capecitabine (Xeloda) or taxane (nab-paclitaxel [Abraxane] or paclitaxel) as second- or later-line therapy in patients with hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer, according to additional data from a post-hoc analysis of the phase 3 DESTINY-Breast06 trial (NCT04494425).1

At a median follow-up of 18.2 months, findings presented during the 2025 ESMO Breast Congress showed that the median PFS by blinded independent central review (BICR) was 13.3 months with T-DXd (n = 266) vs 8.5 months with capecitabine (n = 257; HR, 0.66; 95% CI, 0.53-0.82). The median PFS with T-DXd (n = 170) and taxane (n = 173) was 13.1 months and 7.2 months, respectively (HR, 0.60; 95% CI, 0.46-0.79).

“In this analysis of DESTINY-Breast06, T-DXd demonstrated a clinically meaningful efficacy benefit of both treatment of physician’s choice subgroups, with improved PFS, ORR, DOR, and PFS2,” lead study author Carlos H. Barrios, MD, president of Latin American Cooperative Oncology Group (LACOG) and director at the Oncology Research Center at Hospital São Lucas-PUCRS in Porto Alegre, Brazil, said in a presentation of the data.

Going Back to the Beginning

DESTINY-Breast-06 was a multicenter, open-label trial that enrolled patients with hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization negative) or HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer that had not been treated with chemotherapy in the metastatic setting. This comprised the intention-to-treat (ITT) population. Prior therapy must have included at least 2 lines of endocrine therapy with or without targeted therapy for metastatic disease or 1 line of therapy for metastatic disease and progression within 6 months of starting first-line endocrine therapy and CDK4/6 inhibition or recurrence within 24 months of starting adjuvant endocrine therapy.

After selection between capecitabine and taxane for the control arm patients were randomly assigned 1:1 to 5.4 mg/kg of T-DXd every 3 weeks (n = 436) or treatment of physician’s choice (n = 430; capecitabine, 59.8%; taxane, 40.2%).

Previous findings from the trial demonstrated a statistically significant and clinically meaningful 5.1-month improvement in median PFS with T-DXd vs treatment of physician’s choice in the ITT population (HR, 0.64; 95% CI, 0.54-0.76; P < .001).2

In January 2025, the FDA approved T-DXd for the treatment of patients with unresectable or metastatic hormone receptor–positive, HER2-low or HER2-ultralow breast cancer that has progressed on at least 1 endocrine therapy in the metastatic setting based on these data from DESTINY-Breast06.3 The FDA simultaneously expanded the approval of the Ventana’s PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay as a companion diagnostic device to identify patients with HER2-ultralow breast cancer.

Additional Trial Objectives, Findings, and Implications

To better understand the safety and efficacy profile of T-DXd vs type of treatment of physician’s choice the following outcomes were evaluated in the ITT population of patients with HER2-low and -ultralow disease: PFS, ORR, DOR, PFS2, and safety.1

Additional efficacy data indicated an approximate two-fold increase in ORR and a DOR of more than 1 year according to RECIST 1.1 by BICR, Barrios noted. The confirmed ORR was 57.9% with T-DXd vs 30.7% with capecitabine. The ORRs were 56.5% and 31.8% with T-DXd and taxane, respectively. The confirmed median DOR was 14.6 months with T-DXD vs 11.4 months with capecitabine. The median DOR was more than doubled with T-DXd vs taxane, at 13.7 months and 6.2 months, respectively.

With respect to investigator-assessed PFS2, the median was 22.6 months with T-DXd vs 16.4 months with capecitabine (HR, 0.62; 95% CI, 0.49-0.78). The median PFS2 with T-DXd and taxane was 18.2 months and 13.6 months, respectively (HR, 0.61; 95% CI, 0.47-0.80).

Safety was also individually compared with T-DXd according to treatment of physician’s choice. Any-grade treatment-related adverse effects (TRAEs) that occurred in at least 20% of patients in the T-DXd (n = 265) and capecitabine (n = 249) arms, respectively, included nausea (68.7%; 28.1%), fatigue (48.7%; 34.5%), alopecia (47.5%; 2.8%), neutropenia (35.1%; 17.7%), diarrhea (26.4%; 30.5%), vomiting (25.3%; 10.8%), anemia (23.8%; 12.4%), decreased appetite (23.8%; 11.6%), leukopenia (20.0%; 7.2%), and palmar-plantar erythrodysesthesia (0.4%; 53.4%).

Any-grade TRAEs in the T-DXd (n = 169) and taxane (n = 168) arms, respectively, included nausea (61.5%; 16.7%), fatigue (43.8%; 33.9%), alopecia (42.0%; 44.0%), neutropenia (41.4%; 42.3%), anemia (34.9%; 29.8%), vomiting (30.2%; 7.1%), leukopenia (28.4%; 25.6%), aspartate aminotransferase increase (27.2%; 12.5%), thrombocytopenia (25.4%; 3.6%), decreased appetite (23.1%; 6.0%), alanine aminotransferase increase (20.1%; 14.9%), and peripheral sensory neuropathy (1.8%; 20.8%).

“Neutropenia was the most common grade 3 or greater TRAE with T-DXd and taxane, with similar rates; in the capecitabine arm the most common grade 3 or greater TRAE was palmar-plantar erythrodysesthesia, with rates exceeding 10%,” Barrios said.

“When adjusted for treatment duration, the overall safety profile of T-DXd was generally similar to or better than that of capecitabine or taxane,” Barrios stated. “These findings further support T-DXd as an effective treatment option in hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer after at least 1 line of endocrine therapy, with demonstrable benefits over treatment with capecitabine or a taxane [nab-paclitaxel or paclitaxel],” Barrios concluded.

Disclosures: Barrios disclosed consulting fees from AstraZeneca, Libbs, Lilly, MSD Oncology, Novartis, Pfizer, Roche/Genentech, and United Medical; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Adium Pharma, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, and Zodiac Pharma; support for attending meetings and/or travel from AstraZeneca, BMS Brazil, Lilly, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; and stock or stock options with MedSIR and Tummi.

References

1. Barrios CH, Bardia A, Hu X, et al. DESTINY-Breast06 post-hoc analysis by physician’s choice of chemotherapy (TPC): efficacy and safety of trastuzumab deruxtecan (T-DXd) vs TPC in hormone receptor–positive, HER2-low or -ultralow metastatic breast cancer. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract 299MO.
2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086
3. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer. FDA. Updated February 6, 2025. Accessed May 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-hr-positive-her2-low-or-her2