EMA Accepts Marketing Application for T-DXd in HER2-Low and -Ultralow Metastatic Breast Cancer

Ken Takeshita, MD

The European Medicines Agency (EMA) has validated a type II variation application seeking the approval of single-agent fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ of IHC 2+/in situ hybridization [ISH]–) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who have received at least 1 prior line of endocrine therapy in the metastatic setting.¹

Additionally, the FDA has granted breakthrough therapy designation to T-DXd for the treatment of patients with unresectable or metastatic hormone receptor–positive, HER2-low or -ultralow breast cancer who have received either 2 lines of endocrine therapy in the metastatic setting, or 1 line of endocrine therapy if they experienced disease progression within 6 months of starting first-line treatment with endocrine therapy in combination with a CDK4/6 inhibitor or within 24 months of the start of adjuvant endocrine therapy.²

The marketing application and breakthrough therapy designation are supported by data from the phase 3 DESTINY-Breast06 trial (NCT04494425). Findings presented at the 2024 ASCO Annual Meeting showed that patients with HER2-low breast cancer treated with T-DXd (n = 359) achieved a median progression-free survival (PFS) of 13.2 months compared with 8.1 months for those treated with physician’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.52-0.74; P < .0001).³

In the intention-to-treat (ITT) population, which was comprised of patients with HER2-low or -ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P < .0001). In the HER2-ultralow population, the median PFS was 13.2 months for those treated with T-DXd (n = 76) vs 8.3 months for those given chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

“[The EMA] submission builds on our existing indication for [T-DXd] in patients with HER2-low metastatic breast cancer, and an expanded approval would enable the potential for use in an earlier disease setting as well as in a broader patient population that now includes HER2 ultralow,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.¹ “We look forward to working closely with the EMA to potentially bring this medicine to more patients in the European Union.”

In January 2023, the European Commission approved T-DXd for the treatment of patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.⁴ The FDA approved T-DXd for the treatment of patients with unresectable or metastatic HER2-low breast cancer in August 2022.⁵ Both of those regulatory decisions were supported by data from the phase 3 DESTINY-Breast04 trial (NCT03734029).

Taking a Deep Dive Into DESTINY-Breast06

The randomized, open-label, multicenter study enrolled patients with hormone receptor–positive, HER2-low or -ultralow metastatic breast cancer who were naive to chemotherapy in the metastatic setting. Prior treatment requirements included at least 2 lines of endocrine therapy with or without targeted therapy in the metastatic setting; or 1 prior line of therapy in the metastatic setting and progression within 6 months of starting first-line endocrine therapy plus a CDK4/6 inhibitor or disease recurrence within 24 months of initiating adjuvant endocrine therapy.

Patients were randomly assigned 1:1 to received 5.4 mg/kg of T-DXd once every 3 weeks or physician’s choice of chemotherapy consisting of capecitabine, nab-paclitaxel (Abraxane), or paclitaxel. Patients were stratified by prior CDK4/6 inhibitor use (yes vs no), HER2 expression (IHC 1+vs ICH 2+/ISH– vs IHC 0 with membrane staining), and prior taxane use in the nonmetastatic setting (yes vs no).

PFS per blinded independent central review (BICR) assessment in the HER2-low population served as the trial’s primary end point. Key secondary end points included BICR-assessed PFS in the ITT population, overall survival (OS) in the HER2-low population, and OS in the ITT population.

Additional data showed the OS trends favored T-DXd in the HER2-low (HR, 0.83; 9%% CI, 0.66-1.05; P = .1181), ITT (HR, 0.81; 95% CI, 0.65-1.00), and HER2-ultralow (HR, 0.75; 95% CI, 0.43-1.29) populations. With data at approximately 40% maturity, the 12-month OS rates in the HER2-low population were 87.6% for T-DXd vs 81.7% for chemotherapy. Those rates in the ITT population were 87.0% for T-DXd and 81.1% for chemotherapy; in the HER2-ultralow population, these rates were 84.0% vs 78.7%, respectively.

Moreover, in the HER2-low population, the confirmed overall response rate (ORR) was 56.5% for T-DXd, which included complete response (CR), partial response (PR), and stable disease (SD) rates of 2.5%, 54.0% and 34.8%, respectively. The clinical benefit rate (CBR) was 76.6%, and the median duration of response (DOR) was 14.1 months. In the chemotherapy arm, the confirmed ORR was 32.2%, comprised exclusively of PRs. The SD rate and CBR were 48.0% and 53.7%, respectively, and the median DOR was 8.6 months.

In the ITT population, the confirmed ORR was 57.3% for T-DXd with a CR rate of 3.0%, a PR rate of 54.4%, a SD rate of 33.9%, and a CBR of 76.6%. The median DOR was 14.3 months. For chemotherapy, the confirmed ORR was 31.2%, and the PR rate, SD rate, and CBR were 31.2%, 49.3%, and 51.9%, respectively. The median DOR was 8.6 months.

The confirmed ORR for T-DXd in the HER2-ultralow population was 61.8%, including a CR rate of 5.3%, a PR rate of 56.6%, a SD rate of 28.9%, and a CBR of 76.3%. The median DOR was 14.3 months. For chemotherapy, the confirmed ORR was 26.3%, and the respective PR rate, SD rate, and CBR was 26.3%, 55.3%, and 43.4%. The median DOR was 14.1 months.

Regarding safety, the rate of any-grade treatment-emergent adverse effects (TEAEs) for T-DXd was 98.8% for patients in the safety analysis set (n = 434) vs 95.2% for chemotherapy (n = 417). Treatment-related TEAEs (TR-TEAEs) occurred in 96.1% of patients given T-DXd and 89.4% of those treated with chemotherapy. The rates of grade 3 or higher TR-TEAEs were 40.6% and 31.4%, respectively, and the respective rates of serious TEAEs were 20.3% and 16.1%.

The rates of TEAEs associated with treatment discontinuation, dose interruptions, and dose reductions of T-DXd were 14.3%, 48.4%, and 24.7%, respectively; those respective rates were 9.4%, 38.4%, and 38.6% for chemotherapy. TEAEs led to death in 2.5% of patients treated with T-DXd vs 1.4% of those given chemotherapy. TR-TEAEs led to death in 1.2% of patients in the experimental arm and 0% of those in the chemotherapy arm, per investigator assessment.

The most common TEAE leading to treatment discontinuation was pneumonitis (5.3%) in the T-DXd arm and peripheral sensory neuropathy (1.4%) in the chemotherapy arm. The most common TEAE that led to dose reduction was nausea (4.4%) for T-DXd and Palmar-plantar erythrodysesthesia (PPE; 16.5%) for chemotherapy.

Any-grade TR-TEAEs reported in at least 20% of patients in either arm included nausea (T-DXd, 65.9%; chemotherapy, 23.5%), fatigue (46.8%; 34.3%), alopecia (45.4%; 19.4%), neutropenia (37.6%; 27.6%), increased aminotransaminases (29.3%; 11.0%), anemia (28.1%; 19.4%), vomiting (27.2%; 9.4%), diarrhea (23.7%; 22.5%), decreased appetite (23.5%; 9.4%), leukopenia (23.3%; 14.6%), and PPE (0.5%; 32.4%).

Any-grade interstitial lung disease (ILD)/pneumonitis was reported in 11.3% of patients treated with T-DXd. These AEs occurred at grade 1 (1.6%), grade 2 (8.3%), grade 3 (0.7%), and grade 5 (0.7%). One instance of grade 2 ILD/pneumonitis was observed in the chemotherapy arm.

Additionally, 8.1% of patients in the T-DXd arm experienced any-grade decreased left ventricular ejection fraction (LEVF) vs 2.9% of patients in the chemotherapy arm. Decreased LEVF occurred at grade 1 (0.2%), grade 2 (7.1%), and grade 3 (0.7%) in the T-DXd arm; those respective rates were 0%, 2.6%, and 0.2% in the chemotherapy arm. No patients in the T-DXd arm experienced cardiac failure vs 0.7% of those in the chemotherapy arm; these cases were grade 2, 3, and 4 (0.2% each).

References

1. Enhertu type II variation application validated by EMA for patients with HER2 low or HER2 ultralow metastatic breast cancer following at least one endocrine therapy. News release. Daiichi Sankyo. August 19, 2024. Accessed August 19, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202408/20240819_E2.pdf
2. Enhertu granted breakthrough therapy designation in U.S. for certain patients with HER2 low or HER2 ultralow metastatic breast cancer. News release. Daiichi Sankyo. August 19, 2024. Accessed August 19, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202408/20240819_E1.pdf
3. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000
4. Enhertu approved in the EU as the first HER2 directed therapy for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. January 26, 2023. Accessed August 19, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202301/20230126_E.pdf
5. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed August 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer