Maintained QOL, Neurological Function Support T-DXd Safety and Efficacy in HER2+ mBC

Treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) induced corresponding health-related quality of life (HRQOL) and neurological function data with that of its overall efficacy and safety profile among patients with HER2-positive metastatic breast cancer regardless of the presence of stable or active brain metastases, according to findings from the phase 3b/4 DESTINY-Breast12 trial (NCT04739761)presented during the 2024 San Antonio Breast Cancer Symposium.¹

T-DXd displayed favorable HRQOL and neurological function results in HER2+ metastatic breast cancer.

At the February 8, 2024, data cutoff, the estimated 12-month deterioration-free rate in terms of global health status (GHS)/QOL was 40.3% (95% CI, 33.6%-46.9%) among all evaluable patients with brain metastases (n = 146). The estimated 12-month deterioration-free rates in terms of cognitive (n = 119), emotional (n = 92), physical (n = 113), role (n = 135), and social functioning (n = 118) were 53.5% (95% CI, 46.3%-68.3%), 63.3% (95% CI, 56.2%-69.6%), 56.8% (95% CI, 49.9%-63.2%), 44.5% (95% CI, 37.4%-51.4%), and 54.3% (95% CI, 47.2%-60.8%), respectively. The estimated 12-month rates regarding pain (n = 113), fatigue (n = 152), and nausea/vomiting (n = 137) were 53.4% (95% CI, 46.2%-60.1%), 40.2% (95% CI, 33.3%-47.0%), and 46.2% (95% CI, 39.4%-52.8%), respectively.

Patients with stable brain metastases (n = 87) experienced an estimated 12-month deterioration-free rate of 41.0% (95% CI, 32.3%-49.6%) in terms of GHS/QOL. The estimated 12-month deterioration-free rates in terms of cognitive (n = 71), emotional (n = 59), physical (n = 65), role (n = 79), and social functioning (n = 72) were 55.3% (95% CI, 46.0%-63.6%), 59.3% (95% CI, 50.0%-67.5%), 58.4% (95% CI, 49.3-66.4%), 44.3% (95% CI, 35.0%-53.1%), and 52.0% (95% CI, 42.8%-60.3%), respectively. The estimated 12-month rates regarding pain (n = 67), fatigue (n = 89), and nausea/vomiting (n = 78) were 52.8% (95% CI, 43.5%-61.3%), 40.3% (95% CI, 31.7%-48.9%), and 49.5% (95% CI, 40.4%-58.0%), respectively.

Patients with active brain metastases (n = 59) had an estimated 12-month deterioration-free rate of 39.2% (95% CI, 28.9%-49.4%) in terms of GHS/QOL. The estimated 12-month deterioration-free rates in terms of cognitive (n = 48), emotional (n = 33), physical (n = 48), role (n = 56), and social functioning (n = 46) were 50.9% (95% CI, 39.4%-61.3%), 70.1% (95% CI, 58.6%-78.9%), 54.6% (95% CI, 43.4%-64.5%), 45.0% (95% CI, 33.8%-55.5%), and 57.8% (95% CI, 46.4%-67.6%), respectively. The estimated 12-month rates in terms of pain (n = 46), fatigue (n = 63), and nausea/vomiting (n = 59) were 54.2% (95% CI, 42.6%-64.5%), 39.7% (95% CI, 28.4%-50.7%), and 41.3% (95% CI, 30.9%-51.3%), respectively.

The median treatment duration among all patients with brain metastases (n = 263) was 11.5 months, and 118 patients were still receiving T-DXd at the data cutoff.

“Estimated deterioration-free rates at 12 months were above 50% for cognitive, emotional, physical, and social functioning, [as well as] pain scores, regardless of the presence or absence of stable/active baseline brain metastases; further, the majority of patients had neurological stability at first score post baseline [86.6%], which was maintained throughout treatment in 55.1% of patients in the baseline brain metastases cohort and 72.9% of patients without baseline brain metastases,” Nadia Harbeck, MD, PhD, and coauthors, wrote in a poster presentation of the data. “In the baseline brain metastases cohort, mean severity on the last 24 hour scores for the majority of brain tumor–specific MDASI symptom items were less than 3 at all timepoints with assessments for more than 10 patients, on a of 0 to 10 scale where 0 was ‘not present’ and 10 was ‘as bad as you can imagine.’”

Harbeck is the director of the Breast Center, as well as the chair for Conservative Oncology and the head of the Oncological Therapy & Clinical Trials Unit in the Department of OB&GYN at LMU University Hospital in Munich, Germany.

In December 2019, the FDA granted accelerated approval to T-DXd for the treatment of patients with unresectable or metastatic HER2-positive breast cancer following 2 or more prior anti-HER2–based regimens in the metastatic setting.² The approval was supported by findings from the phase 2 DESTINY-Breast01 (NCT03248492). The agent then received full approval in May 2022 for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti-HER2–based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.³ That approval was based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110).

DESTINY-Breast12 was a single-arm, open-label study that examined T-DXd in adult patients with HER2-positive metastatic breast cancer with or without baseline brain metastases.¹ To be eligible, patients were allowed to receive up to 2 prior lines of therapy for metastatic brain cancer, excluding tucatinib (Tukysa). Other key inclusion criteria consisted of disease progression on prior HER2-directed regimens, an ECOG performance status of 1 or less, and no known or suspected leptomeningeal metastases.

Patients were divided into 2 cohorts: those with baseline brain metastases and those without (n = 241). Both cohorts received intravenous T-DXd at a dose of 5.4 mg/kg every 3 weeks. Both groups were evaluated using the EORTC QLQ-C30 and NANO scale. Patients with baseline brain metastases were also evaluated using MDASI symptom items.

The primary end points were progression-free survival (PFS) in the brain metastases cohort and objective response rate (ORR) per RECIST 1.1 criteria in the non–brain metastases cohort.⁴ Secondary end points included central nervous system (CNS) PFS, time to progression, duration of response, overall survival, safety, HRQOL, and neurological function.

Primary findings from DESTINY-Breast12 demonstrated that the 12-month PFS rates among all patients with brain metastases (n = 263), those with stable brain metastases (n = 157), and those with active brain metastases (n = 106), were 61.6% (95% CI, 54.9%-67.6%), 62.9% (95% CI, 54.0%-70.5%), and 59.6% (95% CI, 49.0%-68.7%), respectively. The median PFS in the overall population was 17.3 months (95% CI, 13.7-22.1). The 12-month CNS PFS rates were 58.9% (95% CI, 51.9%-65.3%), 57.8% (95% CI, 48.2%-66.1%), and 60.1% (95% CI, 49.2%-69.4%), for all patients with brain metastases, patients with stable brain metastases, and patients with active brain metastases, respectively. The respective confirmed ORRs were 51.7% (95% CI, 45.7%-57.8%), 49.7% (95% CI, 41.9%-57.5%), and 54.7% (95% CI, 45.2%-64.2%).

Additional findings from the QOL analysis showed that the estimated 12-month deterioration-free rate in terms of GHS/QOL was 44.3% (95% CI, 37.0%-51.4%) in evaluable patients without baseline brain metastases (n = 128).¹ The estimated 12-month deterioration-free rates in terms of cognitive (n = 112), emotional (n = 74), physical (n = 101), role (n = 128), and social functioning (n = 112) were 54.9% (95% CI, 47.5%-61.6%), 69.1% (95% CI, 62.0%-75.1%), 61.3% (95% CI, 53.9%-67.8%), 45.3% (95% CI, 37.9%-52.5%), and 51.1% (95% CI, 43.7%-58.1%), respectively. The estimated 12-month rates regarding pain (n = 94), fatigue (n = 142), and nausea/vomiting (n = 143) were 61.2% (95% CI, 53.8%-67.8%), 38.3% (95% CI, 31.2%-45.3%), and 38.6% (95% CI, 31.7%-45.4%), respectively. The median treatment duration in the cohort of patients without brain metastases was 12.0 months.

Most patients without brain metastases (91.9%) had neuroglial stability at first score post baseline. Neuroglial stability was maintained throughout treatment in 72.9% of patients.

Disclosures: Dr Harbeck reports receiving funding from Art Tempi, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi, Seagen, TRIO, Viatris, West Germany Study Group and Zuelig Pharma. She also received consulting fees from Aptitude Health, Gilead Sciences, Pfizer, Sandoz-Hexal, Sanofi, and Seagen.

References

1. Harbeck N, Ciruelos E, Jerusalem G, et al. Effects of trastuzumab deruxtecan (T-DXd) on health-related quality of life (HRQOL) & neurological function in patients (pts) w/ HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12(DB-12) results. Presented at: San Antonio Breast Cancer Conference; December 10-13, 2024; San Antonio, TX. Abstract PS14-10.
2. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. December 20, 2019. Accessed December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer
3. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer
4. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4. Nat Med. Published online September 13, 2024. doi:10.1038/s41591-024-03261-7