FDA Grants Priority Review to T-DXd for HR+, HER2-Low/Ultralow Breast Cancer

The FDA has granted a priority review designation to a supplemental Biologics License Application (sBLA) for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-low or HER2-ultralow breast cancer after at least one endocrine therapy in the metastatic setting, according to AstraZeneca and Daiichi Sankyo, the developers of T-DXd.¹

The sBLA is supported by results from the phase IIIDESTINY-Breast06 trial (NCT04494425), which showed that patients with HER2-low disease (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) treated with T-DXd (n = 359) experienced a median progression-free survival (PFS) of 13.2 months per blinded independent central review (BICR) assessment compared with 8.1 months for those given investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P <.0001).²

In the intention-to-treat (ITT) population comprising patients with HER2-low and -ultralow (IHC 0 with membrane staining) 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). Patients with HER2-ultralow disease treated with T-DXd (n = 76) achieved a median PFS of 13.2 months compared with 8.3 months for those given chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

The FDA previously granted T-DXd a Breakthrough Therapy Designation for use in this setting.

“While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is associated with poor response rates and outcomes. The results from DESTINY-Breast06 show that Enhertu has the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, stated in a press release.¹

In August 2022, the FDA approved T-DXd for the treatment of patients with unresectable or metastatic HER2-low breast cancer, based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029).³ Notably, that study enrolled patients irrespective of hormone receptor status, and T-DXd was evaluated in an earlier line of treatment in DESTINY-Breast06.

In the multicenter, open-label, randomized DESTINY-Breast06 study, investigators enrolled patients with hormone receptor–positive metastatic breast cancer that was either HER2-low or -ultralow, and patients needed to be naive to chemotherapy in the metastatic setting.² Prior treatment requirements included at least 2 lines of endocrine therapy with or without targeted therapy for metastatic breast cancer; or 1 line of treatment in the metastatic setting with either progression within 6 months of beginning first-line treatment with endocrine therapy plus a CDK4/6 inhibitor or recurrence within 24 months of beginning adjuvant endocrine therapy.

Patients were randomly assigned 1:1 to receive 5.4 mg/kg of T-DXd once every 3 weeks or investigator’s choice of chemotherapy consisting of capecitabine (Xeloda; 59.8%), nab-paclitaxel (Abraxane; 24.4%), or paclitaxel (15.8%). Stratification factors included prior CDK4/6 inhibitor use (yes vs no), HER2 expression (low vs ultralow), and prior taxane use in the non-metastatic setting (yes vs no).

BICR-assessed PFS in the HER2-low population served as the trial’s primary end point. Secondary end points included PFS in the ITT population; overall survival (OS) in the HER2-low and ITT populations; investigator-assessed PFS in the HER2-low population; overall response rate (ORR) in the HER2-low and ITT populations; safety; and patient-reported outcomes (PROs). Notably, PFS and OS in the HER2-ultralow population were exploratory end points.

In the ITT population, the median age was 58.0 years (range, 28-87) in the T-DXd arm and 57.0 years (range, 32-83) in the chemotherapy arm. Most patients in the T-DXd arm (57.8%) and chemotherapy arm (59.8%) had an ECOG performance status of 0. HER2 status included IHC 0 with membrane staining (T-DXd, 17.4%; chemotherapy, 17.7%), IHC 1+ (54.8%; 54.4%), and IHC 2+/ISH– (26.8%; 27.4%). Additionally, patients had either estrogen receptor (ER)–positive/progesterone receptor (PR)–positive disease (58.0%; 55.1%), ER-positive/PR-negative disease (38.3%; 42.1%), or ER-negative/PR-positive disease (0.7%; 0.5%).

Primary endocrine resistance at baseline was seen in 29.4% of patients in the T-DXd arm and 32.6% of patients in the chemotherapy arm. In the T-DXd arm, 30.5% of patients had de novo disease at diagnosis, 3.0% had bone-only disease at baseline, 86.2% had visceral disease at baseline, and 67.9% had liver metastases at baseline. Those respective rates were 30.7%, 3.0%, 84.7%, and 65.8% in the chemotherapy arm.

In the ITT population, the median number of lines of endocrine therapy in the metastatic setting was 2.0 (range, 1-4) for the T-DXd group vs 2.0 (range, 1-5) for the chemotherapy group. Specifically, patients received either 1 prior line of endocrine therapy in the metastatic setting (T-DXd, 14.9%; chemotherapy, 19.2%), 2 prior lines of endocrine therapy (67.8%; 67.3%), or at least 3 prior lines of endocrine therapy (17.2%; 13.6%). Notably, 8.5% and 9.3% of patients received first-line endocrine therapy plus a CDK4/6 inhibitor within 6 months of enrollment in the T-DXd and chemotherapy arms, respectively. Prior therapies in the metastatic setting included endocrine therapy alone (52.8%; 51.9%), endocrine therapy plus a CDK4/6 inhibitor (89.0%; 89.5%), and endocrine therapy plus other targeted therapy (32.8%; 29.5%).

In the adjuvant/neoadjuvant setting, prior therapies included endocrine therapy (T-DXd, 63.1%; chemotherapy, 59.5%) and cytotoxic chemotherapy (52.3%; 54.4%), which included a taxane (41.1%; 41.2%) and anthracycline (45.2%; 47.9%).

Among the 436 patients randomly assigned to the T-DXd arm and the 430 assigned to the chemotherapy arm, 99.5% and 97.0% of patients were treated, respectively. At the March 18, 2024, data cutoff and a median follow-up of 18.2 months for the ITT population, 79.5% of patients in the T-DXd arm discontinued study treatment due to progressive disease (57.1%), adverse effects (AEs; 4.4%), patient decision (4.4%), other reasons (3.9%), and death (1.2%). In the chemotherapy arm, 92.8% of patients discontinued study treatment due to progressive disease (70.0%), AEs (9.4%), patient decision (8.2%), protocol noncompliance (0.2%), other reasons (5.0%), and death (1.0%).

At data cutoff, OS data were only 40% mature. Second interim and final OS analyses will be performed at approximately 56% and 74% maturity, respectively.

Data from the primary analysis showed OS trends favoring T-DXd in the HER2-low population (HR, 0.83; 95% CI, 0.66-1.05; P = .1181) and ITT population (HR, 0.81; 95% CI, 0.65-1.00). Patients in the HER2-low population treated with T-DXd experienced a 12-month OS rate of 87.6% compared with 81.7% for those given chemotherapy. The 12-month OS rates were 87.0% and 81.1% in the ITT population for T-DXd and chemotherapy, respectively. Notably, 20.1% of patients in the HER2-low population who received chemotherapy were given T-DXd following treatment discontinuation. This rate was 17.9% in the ITT population.

An OS trend favoring T-DXd was also observed in the HER2-ultralow population (HR, 0.75; 95% CI, 0.43-1.29). The 12-month OS rates were 84.0% and 78.7% for T-DXd and chemotherapy, respectively.

A subgroup analysis of the HER2-low population showed that the PFS benefit for T-DXd was observed across all prespecified subgroups.

Additional data showed patients in the HER2-low population treated with T-DXd experienced a confirmed ORR of 56.5%, including a complete response (CR) rate of 2.5%, a partial response (PR) rate of 54.0%, and a stable disease (SD) rate of 34.8%, compared with an ORR of 32.2% for those given chemotherapy. The respective CR, PR, and SD rates for chemotherapy were 0%, 32.2%, and 48.0%. The clinical benefit rate (CBR) was 76.6% for T-DXd and 53.7% for chemotherapy, and the median duration of response (DOR) was 14.1 months and 8.6 months, respectively.

In the ITT population, those administered T-DXd experienced a confirmed ORR of 57.3%, including a CR rate of 3.0%, a PR rate of 54.4%, and a SD rate of 33.9%, compared with an ORR of 31.2% for those given chemotherapy. The respective CR, PR, and SD rates for chemotherapy were 0%, 31.2%, and 49.3%. The CBR was 76.6% for T-DXd and 51.9% for chemotherapy, and the median DOR was 14.3 months and 8.6 months, respectively.

For patients with HER2-ultralow disease, the confirmed ORR was 61.8% for T-DXd and 26.3% for chemotherapy. The CR, PR, and SD rates were 5.3%, 56.6%, and 28.9% for T-DXd, respectively. Those respective rates were 0%, 26.3%, and 55.3% for chemotherapy. The CBR was 76.3% for T-DXd and 43.4% for chemotherapy, and the respective median DORs were 14.3 months and 14.1 months.

Regarding safety for all treated patients, any-grade treatment-emergent AEs (TEAEs) occurred in 98.8% of patients given T-DXd (n = 434) and 95.2% of patients given chemotherapy (n = 417). Treatment-related TEAEs (TR-TEAEs) were reported in 96.1% of patients administered T-DXd and 89.4% of those given 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%.

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

The median treatment duration was 11.0 months (range, 0.4-39.6) for T-DXd and 5.6 months (range, 0.1-35.9) for chemotherapy. The most common TEAE associated with 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 linked 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 occurred in 11.3% of patients treated with T-DXd, including grade 1 (1.6%), grade 2 (8.3%), grade 3 (0.7%), and grade 5 (0.7%). Only 1 instance of ILD/pneumonitis (grade 2) was reported in the chemotherapy arm. Any-grade decreased left ventricular ejection fraction was reported in 8.1% of patients in the T-DXd arm and 2.9% of patients in the chemotherapy arm. For T-DXd, patients experienced grade 1 (0.2%), grade 2 (7.1%), and grade 3 (0.7%) decreased left ventricular ejection fraction. Those respective rates were 0% for grade 1, 2.6% for grade 2, and 0.2% for grade 3.

Cardiac failure was not reported in any patients in the T-DXd arm. For the chemotherapy arm, 0.7% of patients experienced any-grade cardiac failure, including 0.2% each for grades 2 through 4.

REFERENCES:

1. Enhertu granted Priority Review in the US for patients with HER2-low or HER2-ultralow metastatic breast cancer who have received at least one line of endocrine therapy. Published online. AstraZeneca. Published online and accessed October 1, 2024. https://tinyurl.com/yubxhnk5

2. 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

3. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed June 2, 2024. https://tinyurl.com/zdbkwzhn