T-DXd Has Intracranial Activity in Meta-Analysis of HER2+ Breast Cancer Brain Metastases

HER2-Positive Breast Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) was associated with significant intracranial activity in patients with HER2-positive breast cancer brain metastases, regardless of subgroup, according to findings from a systematic review and meta-analysis (CRD42023422589) published in ESMO Open.

Across 10 studies (n = 319), the objective response rate (ORR) and intracranial ORR (IC-ORR) with T-DXd were 61% (95% CI, 52%-70%) and 61% (95% CI, 54%-69%), respectively. Investigators observed no significant differences in ORR and IC-ORR between the clinical trials and observational studies included in this meta-analysis (P = .31 and .58, respectively). In the subgroups of patients with stable (n = 169) and active (n = 111) brain metastases, the respective ORRs were 68% (n = 95; 95% CI, 57%-77%) and 60% (n = 109; 95% CI, 48%-72%), in evaluable patients, and there were no significant differences between the 2 groups (P = .35). Among 65 patients with stable intracranial disease, the IC-ORR was 68% (95% CI, 41%-90%). Among 80 patients with active brain lesions, the IC-ORR was 61% (95% CI, 48%-73%). The comparison between these subgroups was not significant (P = .65).

The phase 2 DEBBRAH trial (NCT04420598) evaluated T-DXd in patients with HER2-positive or HER2-low advanced breast cancer with central nervous system (CNS) involvement. Among patients who received T-DXd, the IC-ORR was 50.0% (95% CI, 6.7%-93.2%) in those with asymptomatic brain metastases (n = 4) and 44.4% (95% CI, 13.7%-78.8%) in those with progressing brain metastases after local therapy (n = 9).2 Moreover, among 15 patients in the phase 2 TUXEDO-1 trial (NCT04752059), T-DXd induced a complete intracranial response in 13.3% of patients and a partial intracranial response in 60% of patients with HER2-positive breast cancer with brain metastases.

“Given the small population in clinical trials assessing active brain lesions and that stable brain metastases were only a subgroup analysis in several studies, the current evidence is limited,” lead study author Isabella Michelon, a medical student in the Department of Medicine at the Catholic University of Pelotas in Brazil, and colleagues, wrote.1 “Therefore, we conducted a systematic review and meta-analysis to fully assess the efficacy and effectiveness of T-DXd in patients with HER2-positive breast cancer with both stable and active brain metastases within clinical trials and in the real-world setting.”

Investigators conducted a systematic review and meta-analysis to assess the efficacy and safety of T-DXd in patients with HER2-positive breast cancer brain metastases. This study involved searches of the Embase, Cochrane, and PubMed databases, as well as the ESMO and San Antonio Breast Cancer Symposium proceedings as of May 2023 to find clinical trials and observational studies investigating T-DXd in patients with HER2-positive breast cancer brain metastases. Search terms included “breast cancer;” and “HER2-positive;” or “Human Epidermal Growth Factor Receptor” and “T-DXd;” or “Trastuzumab Deruxtecan.” Investigators also searched the references lists in all included studies, as well as relevant reviews on this topic.

This meta-analysis included all clinical trials and cohort studies evaluating T-DXd in patients with HER2-positive breast cancer brain metastases. Studies were excluded if their populations overlapped with those of other studies; they were not original studies; they did not include the population of interest; they exclusively assessed patients with leptomeningeal metastases and no measurable brain metastases; and if they were case series or case reports.

ORR, IC-ORR, clinical benefit rate (CBR), intracranial CBR (IC-CBR), progression-free survival (PFS), and adverse effect (AE) data were extracted for pooled analysis. Subgroup analyses were conducted based on the design of each study (clinical trial vs observational study) and brain metastases status (active vs stable). Patients with newly diagnosed untreated or progressive brain metastases were classified in the active brain metastases group. Patients with radiographically or clinically inactive or asymptomatic previously treated brain metastases were included in the stable brain metastases group.

Investigators’ initial search for trials produced 1422 results, from which 74 studies were fully assessed. Studies that did not include patients with brain metastases or that were only study protocols were excluded. Among the 10 studies included, 6 were clinical trials (n = 189), and 4 were observational studies (n = 130). The included clinical trials were the phase 2 DESTINY-Breast01 (NCT03248492), phase 3 DESTINY-Breast02 (NCT03523585), phase 3 DESTINY-Breast03 (NCT03529110), phase 2 DAISY (NCT04132960), DEBBRAH, and TUXEDO-1 trials.

Most patients were female (n = 171/173; 98.4%), had hormone receptor–positive tumors (n = 126/210; 60%), had an ECOG performance status of 0 or 1 (n = 196/232; 84.5%), and had non-CNS metastases (n = 108/132; 81.8%). Patients had received between 2 and 6 prior lines of therapy and had a median follow-up ranging from 8.4 to 21.4 months.

The median PFS with T-DXd was 15 months (95% CI, 13.9-16.1), the CBR was 80% (95% CI, 52%-94%), and the IC-CBR was 70% (95% CI, 54%-82%).

An exploratory analysis including 2 randomized clinical trials evaluating the PFS of patients who received T-DXd vs those who received other treatments (T-DM1 or treatment of physician’s choice) demonstrated a 70% reduction in the rate of disease progression with T-DXd vs with other treatments (HR, 0.30; 95% CI, 0.20-0.45. I2 = 0%; P < .001).

Four studies reported any-grade AEs. Among the 60 patients analyzed for safety, 98% (95% CI, 90%-100%) experienced any-grade AEs. Among 164 patients, AEs leading to dose reduction were observed in 29% of patients (95% CI, 10%-60%), and AEs leading to dose interruption or delay were seen in 25% of patients (95% CI, 18%-33%). The most common AEs were fatigue (29%; 95% CI, 14%-52%), nausea (18%; 95% CI, 0%-49%), and neutropenia (17%; 95% CI, 7%-30%). Both fatigue and nausea were more commonly grade 1/2 than grade 3.

A quality assessment classified each study per the Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) as having low, moderate, serious, or critical risk of bias or no information based on 7 domains: bias from confounding, patient selection, intervention classification, deviation from intended intervention, missing data, outcomes measurement, and reported result selection. This analysis revealed that the 5 retrospective studies and 3 nonrandomized trials included in this study had a moderate risk of bias. Investigators noted that these studies lacked adjustment for confounding factors, such as number of therapies prior to T-DXd, thus failing to meet the specified criteria for the first domain. Conversely, the 2 randomized clinical trials met most criteria for all domains and thus were decided to have a low risk of bias. A funnel plot analysis for ORR revealed no indication of a publication bias, a finding that was further supported by a nonsignificant Egger’s test (z = 1.31; P = .19).

Limitations of this study include the small patient population, particularly regarding CBR. Furthermore, the studies included in this analysis used differing criteria to evaluate intracranial and extracranial responses, as well as different definitions of active and stable brain metastases, potentially resulting in some of the high levels of heterogeneity that were seen. Moreover, unavailable data from certain studies prevented analyses of local treatment for brain metastases or their effects on the study results. To mitigate some of these limitations, investigators used random-effect models in all analyses and carried out sensitivity analyses based on the designs of these studies.

“Our findings suggest that T-DXd should be considered for the second-line treatment of patients with HER2-positive breast cancer and stable and active brain metastases,” study authors concluded.

References

1. Michelon I, Vilbert M, Marinho AD, et al. Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: a systematic review and meta-analysis. ESMO Open. 2024;9(2):102233. doi:10.1016/j.esmoop.2024.102233
2. Pérez-García JM, Vaz Batista M, Cortez P, et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial. Neuro Oncol. 2023;25(1):157-166. doi:10.1093/neuonc/noac144
3. Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med. 2022;28(9):1840-1847. doi:10.1038/s41591-022-01935-8