News
Article
The EMA has validated a type II variation application for trastuzumab deruxtecan for select patients with HER2-low or -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).
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).