PFS Benefit of T-DXd Includes Pretreated HR+ HER2-Ultralow Patients With mBC

Giuseppe Curigliano, MD, PhD

Previously treated patients who received fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) metastatic breast cancer had a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy, and in particular those with HER2-ultralow disease (IHC 0 with membrane staining) had PFS benefit, according to a report on the primary analysis of the phase 3 DESTINY-Breast06 trial (NCT04494425).¹

Findings presented at the 2024 ASCO Annual Meeting showed that patients with HER2-low disease treated with the antibody-drug conjugate (ADC; n = 359) experienced a median 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).

In the intention-to-treat (ITT) population comprising patients with HER2-low and -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). 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).

“Including HER2-ultralow [disease], the proportion of patients who could benefit from T-DXd will be close to 85% in hormone receptor–positive, HER2-negative breast cancer,” lead study author Giuseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology, said in a presentation of the data.

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).² Notably, that study enrolled patients irrespective of hormone receptor status, and T-DXd was evaluated in an earlier line of treatment in DESTINY-Breast06.¹

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. 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.

Curigliano noted that clinical validation of diagnostics and cutoffs for HER2-ultralow disease will be needed in the future. Investigators will also conduct additional subgroup analyses, biomarker and translational analyses, and a PRO analysis in the future.

In a discussion of the abstract, Ian Krop, MD, PhD, a professor of internal medicine (medical oncology), director of the Clinical Trials Office, chief clinical research officer, and associate director of Clinical Sciences at Yale Cancer Center in New Haven, Connecticut, explained the importance of improving the sensitivity of HER2 testing for patients with breast cancer.

“Current IHC testing is relatively poor at distinguishing HER2-low and -ultralow cancers from HER2 0 cancers,” Krop said. “There are probably multiple reasons for this, but an important one is that the original test was designed to distinguish high levels of HER2 [IHC 3+] from all the lower levels. It was not designed to distinguish the very low levels to the even lower or 0 cancers.”

REFERENCES:

1. 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

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