DESTINY-Breast12: T-DXd Demonstrates Significant Efficacy in Breast Cancer Patients with Brain Metastases
Breakthrough data from the Phase III b/IV open-label DESTINY-Breast12 study, presented at the European Society for Medical Oncology (ESMO) Congress 2024, showed efficacy of the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with HER2-positive metastatic breast cancer and brain metastases who had progressed after at least two prior therapies. The 12-month overall survival rate exceeded 90% regardless of brain metastases.
Dr. Nancy U. Lin, Associate Director of the Breast Oncology Department and Director of the Breast Cancer Brain Metastases Program at Dana-Farber Cancer Institute in Boston, stated, "T-DXd demonstrated significant and durable overall and intracranial clinical activity in a large patient population with HER2-positive metastatic breast cancer and stable or active brain metastases." She emphasized that these data support the use of T-DXd, regardless of whether the patient has brain metastases. Dr. Lin pointed out that previous small prospective studies, retrospective analyses, and exploratory trials have shown "preliminary positive evidence" for T-DXd in intracranial lesions, with intracranial response rates ranging from 44% to 73%. This made DESTINY-Breast12 the largest prospective study to date on T-DXd for patients with stable or active brain metastases. The main results were simultaneously published in *Nature Medicine*. About DESTINY-Breast12: The study included 504 patients, of whom 263 had brain metastases. Of this group, 157 had stable lesions and 106 had active lesions. Among patients with active brain metastases, 39 were treatment-naïve, and 67 had received local treatment or subsequently worsened. The median follow-up period was approximately 16 months. Dr. Lin stated, "The overall 12-month survival rate for T-DXd was consistent regardless of the presence or absence of brain metastases." The 12-month survival rate was 90.6% for patients without brain metastases and 90.3% for those with brain metastases. She subsequently focused on data from patients with stable or active brain metastases. Key Results: Dr. Lin reported excellent performance in progression-free survival (PFS), central nervous system (CNS) progression-free survival, overall response rate (ORR), and CNS response rate (see Table 1). Post-hoc analysis showed a median progression-free survival of 17.3 months in patients with brain metastases. When analyzing only patients with baseline measurable active brain lesions, the CNS response rate rose to 82.6% in untreated patients, compared to 50.0% in treated or worsened patients. Toxicity in Patients with Brain Metastases: The safety profile of T-DXd was consistent with previous reports. Approximately half of the patients experienced grade ≥3 treatment-related adverse events (unrelated to brain metastases), but the proportion leading to discontinuation was 15% in the brain metastasis group and 9% in the non-brain metastasis group. Approximately 3% of patients in both groups died from underlying treatment-related causes. Dr. Lin emphasized that interstitial lung disease (ILD) and pneumonia remain significant risks. Six ILD-related deaths occurred in the brain metastasis group, five of whom were on steroids and none received Pneumocystis pneumonia (PCP) prophylaxis; in fact, four ILD patients had opportunistic infections. Three ILD-related deaths occurred in the non-brain metastasis group. She recommended: "For brain metastasis patients using steroids, careful monitoring for PCP prophylaxis and opportunistic infections is necessary."
Expert Opinion
Dr. Cristina Saura, Head of the Breast Cancer Department at Vall d’Hebron University Hospital in Barcelona, was a panelist in the discussion. She pointed out, "Although DESTINY-Breast12 did not set formal statistical hypotheses, its significance is twofold: First, it allows 500 patients to receive T-DXd according to the indications of the DESTINY-Breast03 trial (which led to the approval of T-DXd for second-line and later-line HER2-positive metastatic breast cancer), and provides access to the drug in countries not covered by health insurance; second, the study covers patients with active brain metastases for whom there is very little evidence." Previously, evidence for systemic treatment of brain metastases was limited, mainly from the HER2CLIMB trial (comparing the efficacy of tucatinib + trastuzumab + capecitabine for second-line and later-line treatment), which had a median progression-free survival of 7.8 months and an overall survival of 21.9 months. Dr. Saura stated that prior to DESTINY-Breast12, the evidence for T-DXd for active brain metastases, "while encouraging, came only from small, non-randomized or retrospective studies." Dr. Lin's data now shows a median progression-free survival of over 17 months in the brain metastasis group, which is very promising for patients with traditionally poor prognoses. She pays particular attention to patients with active brain metastases (usually symptomatic), whose untreated subgroup has a CNS response rate as high as 82.6%. "From a clinical perspective, this reinforces my preference: prioritizing highly effective systemic therapy and delaying the timing of radiotherapy." Dr. Saura summarizes: "In the past, the second-line first-line treatment for patients with active brain metastases was the tucatinib combination, but now it should be changed to T-DXd (regardless of whether there are active brain metastases), while the HER2CLIMB regimen can be moved to third-line." Disclosure of Interests: Dr. Lin has financial ties to pharmaceutical companies such as Seattle Genetics, Daiichi Sankyo, and AstraZeneca; Dr. Saura has collaborations with AstraZeneca, Roche, and Pfizer.
References
Lin N, Ciruelos EM, Jerusalem G, et al. ESMO 2024. Abstract LBA18.
Harbeck N, et al. Nat Med. 2024 (online).
Hurvitz SA, et al. Lancet. 2023;401:105-117.
Murthy RK, et al. NEJM. 2020;382:597-609.
Source: https://ascopost.com/issues/october-10-2024/destiny-breast12-t-dxd-of-benefit-in-patients-with-breast-cancer-and-brain-metastases/