Enhertu Boosts PFS in Pretreated, HR-Positive, HER2-Low and -Ultralow Breast Cancer

Enhertu (fam-trastuzumab deruxtecan-nxki; Enhertu) improved progression-free survival (PFS) over chemotherapy in pretreated patients with hormone receptor (HR)-positive, HER2-low metastatic breast cancer. A similar benefit was observed in patients with HER2-ultralow disease, too, according to findings from the phase 3 DESTINY-Breast06 trial.

PFS is a statistic that refers to the time patients live after treatment without their disease worsening.

Findings presented at the 2024 ASCO Annual Meeting showed that in the 359 patients with HER2-low disease treated with Enhertu the median PFS of 13.2 months compared with 8.1 months for the 354 patients given investigator’s choice of chemotherapy.

In the Enhertu population comprising patients with HER2-low and -ultralow disease (meaning that there are low levels of the HER2 protein expressed on cancer cells), the median PFS was 13.2 months for Enhertu (436 patients) versus 8.1 months for chemotherapy (430 patients). Patients with HER2-ultralow disease treated with Enhertu (76 patients) achieved a median PFS of 13.2 months compared with 8.3 months for those given chemotherapy (76 patients).

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

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

In the DESTINY-Breast06 study, investigators enrolled patients with HR-positive metastatic breast cancer that was either HER2-low or -ultralow, and patients needed to not have undergone chemotherapy treatment in the metastatic setting. Prior treatment requirements included at least two lines of endocrine therapy with or without targeted therapy for metastatic breast cancer; or one line of treatment in the metastatic setting with either progression within six 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 to receive Enhertu once every three weeks or investigator’s choice of chemotherapy consisting of Xeloda (capecitabine; 59.8%), Abraxane (nab-paclitaxel; 24.4%) or paclitaxel (15.8%). Stratification factors included prior CDK4/6 inhibitor use (yes versus no), HER2 expression (low versus ultralow) and prior taxane use in the non-metastatic setting (yes versus no).

Goals, Outcomes of DESTINY-Breast06

PFS, as assessed by an independent committee not associated with the trial served as the trial’s main goal. Secondary end points included PFS; overall survival (OS; time until death of any cause) in the HER2-low and; investigator-assessed PFS in the HER2-low population; overall response rate (ORR; percentage of patients whose disease shrinks or disappears) in the HER2-low and overall populations; safety; and patient-reported outcomes (PROs). Notably, PFS and OS in the HER2-ultralow population were exploratory end points.

In the study population, the median age was 58.0 years (range, 28 to 87) in the Enhertu group and 57.0 years (range, 32 to 83) in the chemotherapy group. Most patients in the Enhertu group (57.8%) and chemotherapy group (59.8%) had an ECOG performance status of 0, meaning that they had no physical restrictions on daily tasks.

Primary endocrine resistance (meaning that the disease did not respond to endocrine therapies) at baseline was seen in 29.4% of patients in the Enhertu group and 32.6% of patients in the chemotherapy group. In the Enhertu group, 30.5% of patients had de novo disease at diagnosis (new cancer that arises for the first time), 3% 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 group.

Among the 436 patients randomly assigned to the Enhertu group and the 430 assigned to the chemotherapy group, 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 overall population, 79.5% of patients in the Enhertu group discontinued study treatment due to progressive disease (57.1%), side effects (4.4%), patient decision (4.4%), other reasons (3.9%) and death (1.2%). In the chemotherapy group, 92.8% of patients discontinued study treatment due to progressive disease (70.0%), side effects (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, meaning that the researchers did not have enough data to determine the average time until death. 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 Enhertu in the HER2-low population and overall population. Patients in the HER2-low population treated with Enhertu 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 study population for Enhertu and chemotherapy, respectively. Notably, 20.1% of patients in the HER2-low population who received chemotherapy were given Enhertu following treatment discontinuation. This rate was 17.9% in the study population.

An OS trend favoring Enhertu was also observed in the HER2-ultralow population. The 12-month OS rates were 84.0% and 78.7% for Enhertu and chemotherapy, respectively.

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

Additional data showed patients in the HER2-low population treated with Enhertu experienced a confirmed ORR of 56.5%, including a complete response (CR; disappearance of cancer) 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 Enhertu and 53.7% for chemotherapy, and the median duration of response (DOR) was 14.1 months and 8.6 months, respectively.

In the entire study population, those administered Enhertu 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 Enhertu 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 Enhertu and 26.3% for chemotherapy. The CR, PR and SD rates were 5.3%, 56.6% and 28.9% for Enhertu, respectively. Those respective rates were 0%, 26.3% and 55.3% for chemotherapy. The CBR was 76.3% for Enhertu and 43.4% for chemotherapy, and the respective median DORs were 14.3 months and 14.1 months.

Side Effects from Enhertu, Chemotherapy

Regarding safety for all treated patients, any-grade side effects occurred in 98.8% of patients given Enhertu (434 patients) and 95.2% of patients given chemotherapy (417 patients). Treatment-related side effects were reported in 96.1% of patients administered Enhertu and 89.4% of those given chemotherapy. The rates of grade 3 (severe) or higher side effects were 40.6% and 31.4%, respectively, and the respective rates of serious side effects were 20.3% and 16.1%.

In the Enhertu group, the rates of side effects 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 group. Side effects led to death in 2.5% of patients in the Enhertu group versus 1.4% of patients in the chemotherapy group. Notably, treatment-related side effects led to death in 1.2% of patients in the experimental group and 0% of patients in the chemotherapy group, per investigator assessment.

The median treatment duration was 11 months (range, 0.4 to 39.6) for Enhertu and 5.6 months (range, 0.1 to 35.9) for chemotherapy. The most common side effects associated with treatment discontinuation was pneumonitis (5.3%) in the Enhertu group and peripheral sensory neuropathy (1.4%) in the chemotherapy group. The most common side effects linked to dose reduction was nausea (4.4%) for Enhertu and palmar-plantar erythrodysesthesia (hand-foot syndrome; 16.5%) for chemotherapy.

Any-grade side effects reported in at least 20% of patients in either group included nausea (Enhertu, 65.9%; chemotherapy, 23.5%), fatigue (46.8%; 34.3%), hair loss (45.4%; 19.4%), neutropenia (lower levels of white blood cells; 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 (lower levels of circulating white blood cells; 23.3%; 14.6%) and hand-foot syndrome (0.5%; 32.4%).

Any-grade interstitial lung disease (ILD; inflamed lungs)/pneumonitis occurred in 11.3% of patients treated with Enhertu, including grade 1 (mild; 1.6%), grade 2 (serious; 8.3%), grade 3 (0.7%) and grade 5 (fatal; 0.7%). Only one instance of ILD/pneumonitis (grade 2) was reported in the chemotherapy group. Any-grade decreased left ventricular ejection fraction (difficulty of the heart pumping blood) was reported in 8.1% of patients in the Enhertu group and 2.9% of patients in the chemotherapy group. For Enhertu, 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 Enhertu group. For the chemotherapy group, 0.7% of patients experienced any-grade cardiac failure, including 0.2% each for grades 2 through 4 (life-threatening).

Curigliano noted that further research 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, Dr. Ian Krop, 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 [immunohistochemistry testing] 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.”

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