Clinical trialPhase 3b/4Breast cancerBrain tumours

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Nat Med · 2024504 patients (263 with stable or active brain metastases, 241 without brain metastases)

Harbeck N, Ciruelos E, Jerusalem G, Müller V, Niikura N, Viale G, et al. Nat Med. 2024. 30:3717-3727

Study type: Clinical trial
Study name: DESTINY-Breast12
Phase: Phase 3b/4
Design: Single-arm, open-label study with two cohorts (with and without brain metastases) and no formal hypothesis testing
Sample size: 504 patients (263 with stable or active brain metastases, 241 without brain metastases)
Source: Nat Med · 2024
Trial registration: NCT04739761

In plain words

In women whose HER2-positive breast cancer had spread to the brain and who had already received anti-HER2 treatment, the drug trastuzumab deruxtecan kept the disease from progressing for a year in about 6 of every 10 patients, even in the brain. Lung inflammation is an important side effect that must be monitored.

Key results

61.6%

12-month progression-free survival (brain metastasis cohort)

95% CI 54.9–67.6

58.9%

12-month CNS progression-free survival (brain metastasis cohort)

95% CI 51.9–65.3

62.7%

Objective response (cohort without brain metastases)

95% CI 56.5–68.8

Drugs in this study:Trastuzumab (Herceptin)Trastuzumab deruxtecan (Enhertu)

Dose and schedule cards

Trastuzumab deruxtecan (DESTINY-Breast12)

Advanced HER2-positive breast cancer that has progressed after at least one anti-HER2 regimen, no more than 2 prior lines in the metastatic setting, no prior tucatinib, ECOG 0 to 1; stable or active brain metastases (untreated ≤2 cm or progressing after local treatment) without an immediate need for local treatmentCycle length: Every 3 weeksOn the page “Brain tumours” · Brain metastases: systemic therapy with intracranial activity

Drug	Dose	Route	Schedule
Trastuzumab deruxtecan	5.4 mg/kg (first infusion over 90 minutes, then 30 minutes if tolerated)	IV	Day 1

Cycle length: Every 3 weeks
Duration: Until extracranial progression per RECIST or unacceptable toxicity

In the trial, dexamethasone up to 3 mg per day was allowed, and intervals of at least 7 days from radiosurgery and at least 21 days from WBRT were required. Do not substitute for trastuzumab or trastuzumab emtansine; premedicate for nausea and vomiting; permanently discontinue for grade 2 or higher ILD; blood counts before each dose and LVEF before starting and periodically. ILD/pneumonitis occurred in 16% of patients with brain metastases.

On the page “Brain tumours” · Brain metastases: systemic therapy with intracranial activity

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Trastuzumab deruxtecan

Trastuzumab deruxtecan 5.4 mg per kg IV every 3 weeks (21-day cycle), until extracranial disease progression by RECIST 1.1, unacceptable toxicity or withdrawal. Patients who received local therapy for isolated intracranial progression could continue until a second progression. Dexamethasone up to 3 mg per day was allowed.

Source of the regimen details: Abstract and Methods section of the full text (Nat Med 2024, PMC11645283)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with advanced or metastatic HER2-positive breast cancer who had previously received at least one anti-HER2-based regimen; with stable or active brain metastases (untreated, or treated and progressing), or without brain metastases.

Inclusion criteria (full text): 18 years or older; progression after one or more anti-HER2 regimens; no more than two prior regimens in the metastatic setting; no prior tucatinib; ECOG 0 or 1; no leptomeningeal disease. Active brain metastases: untreated with lesions of 2 cm or smaller, or progressing after local therapy, without immediate need for further local therapy; at least 7 days since radiosurgery and 21 days since WBRT.

Endpoints

Primary endpoints: progression-free survival (brain metastasis cohort) and objective response rate (cohort without brain metastases). Other endpoints: central nervous system progression-free survival, intracranial objective response, overall survival and safety.

Safety and side effects

Grade 3 or higher adverse events in 51% (brain metastasis cohort) and 49% (cohort without brain metastases). Interstitial lung disease/pneumonitis in 16% (grade 3 or higher: 3%) of patients with brain metastases and 13% (grade 3 or higher: 1%) of patients without brain metastases.

Discontinuation due to adverse events: 15.2% (brain metastasis cohort) and 9.5% (without brain metastases); the most common cause was ILD/pneumonitis (10.3% and 5.4%). Most common grade 3 or higher adverse events in the brain metastasis cohort: neutropenia 16.3%, fatigue 8.7% and anaemia 7.2% (full text).

Clinical significance and place in guidelines

The largest prospective study of T-DXd in brain metastases from HER2-positive breast cancer; it supports its use in patients with stable or active brain metastases. Because of the single-arm design, there is no direct comparison with other regimens.

Limitations

Single-arm and open-label, with no comparator group and no formal hypothesis testing.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.