T-DXd Effective in Some With HER2+ Breast Cancer

A study demonstrated the efficacy of trastuzumab deruxtecan (Enhertu) in patients with HER2-positive advanced or metastatic breast cancer, including those with brain metastases. 
Senior author Nancy Lin, MD, presented these primary results of the DESTINY-Breast12 trial at the European Society for Medical Oncology Congress 2024. These findings were published simultaneously in the journal Nature Medicine. 
Brain metastases are a significant concern in HER2-positive breast cancer, affecting approximately half of patients with metastatic disease, said Lin, of the Dana-Farber Cancer Institute in Boston. Historically, these patients have faced limited treatment options and poor prognoses, she continued.
“Although tucatinib-based regimens can be effective, the median progression-free survival in patients with brain metastases in the HER2CLIMB clinical trial was less than 8 months, and additional effective treatment options are needed,” she said. That trial compared tucatinib vs placebo in combination with capecitabine and trastuzumab in patients with advanced HER2+ breast cancer.
The DESTINY-Breast12 study, a phase 3b/4 multicenter, open-label trial, aimed to address this critical unmet need.
Study Design and Patient Population 
DESTINY-Breast12 enrolled 504 patients, with 263 in the brain metastases cohort and 241 in the non-brain metastases cohort. Patients received trastuzumab deruxtecan (T-DXd) at a dose of 5.4 mg/kg intravenously every 3 weeks. The primary endpoints were progression-free survival (PFS) for the brain metastases cohort and objective response rate (ORR) for the non-brain metastases cohort.
Lin explained that of the 263 patients with brain metastases, 157 had stable brain metastases, and 106 had active brain metastases. Of the patients with active brain metastases, 39 had previously untreated disease, and 67 had previously treated but progressive disease at study entry.
The study included patients who had received zero to two prior lines of therapy in the metastatic setting, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Lin emphasized that patients who received prior tucatinib-based therapy were excluded. Approximately two thirds of patients had hormone receptor-positive disease, and the majority had measurable disease.
Cristina Saura Manich, MD, PhD, head of the Breast Cancer Unit of the Service of Medical Oncology at Vall d’Hebron University Hospital in Barcelona, emphasized the importance of this study. “This not only provided access to the drug in countries where it was not yet reimbursed, but also enabled professionals to gain experience in managing the drug in the clinical trial setting.” She also noted that the study provides crucial evidence for a population with limited treatment options, particularly those with active brain metastases. Manich was not involved with the DESTINY-Breast12 trial and served as study discussant.
Efficacy of T-DXd in HER2+ Advanced or Metastatic BC
Lin reported promising results for patients with brain metastases. The 12-month PFS was 61.6% (95% CI, 54.9% – 67.6%) after treatment with T-DXd, with a median PFS of 17.3 months (95% CI, 13.7 – 22.1). This outcome was consistent across patients with both stable and active brain metastases, she said.
The 12-month central nervous system (CNS) PFS was 58.9% (95% CI, 51.9% – 65.3%) overall, and it was also consistent between stable and active brain metastases groups.
According to Lin, the intracranial objective response rate was particularly noteworthy, with 71.7% of patients with measurable CNS disease at baseline showing a response. This rate was 79.2% in patients with stable brain metastases and 62.3% in those with active brain metastases. 
“Looking carefully at the patients with active brain metastases, the response rate in the brain was 82.6% in those with previously untreated disease,” she noted. 
For patients without brain metastases, the ORR was 62.7% (95% CI, 56.5% – 68.8%), which, according to Lin, “aligns with previous phase 3 trastuzumab deruxtecan trials in this setting.”
When restricting the analysis to patients with measurable disease at baseline, the ORR increased to 68.4% (95% CI, 62.2% – 74.6%).
The 12-month overall survival (OS) rate was high in both cohorts, reaching 90.3% in patients with brain metastases and 90.6% in patients without brain metastases. Median OS was not reached at the time of data cutoff.
Safety of Trastuzumab Deruxtecan in Trial
According to Lin, the safety profile of T-DXd was consistent with previous reports, with no new safety signals identified. Grade 3 or higher adverse events occurred in approximately half of the patients in both cohorts, she noted, during her presentation. 
Lin added that treatment discontinuation due to toxicity was relatively uncommon, occurring in 15.2% of patients with brain metastases and 9.5% of patients without brain metastases.
According to data presented by Lin, interstitial lung disease (ILD) remains an important risk after treatment with T-DXd, occurring in 16% of patients in the brain metastases cohort and 12.9% in the non-brain metastases cohort. There were six cases of grade 5 ILD in patients with brain metastases, with four of these cases reported as co-occurring with opportunistic infections. 
T-DXd demonstrated promising efficacy in this setting. But Lin cautioned that “careful attention to pneumocystis pneumonia prophylaxis and workup for opportunistic infections is warranted, particularly in patients with brain metastases on concomitant steroids.”
Clinical Implications and Future Work
Lin emphasized the significance of these findings.
“Results from DESTINY-Breast12 support the use of T-DXd for patients with HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases,” she said.
Comparing the DESTINY-Breast12 results to previous studies, Manich commented, “The HER2CLIMB study, which led to the approval of the triplet of tucatinib, trastuzumab, and capecitabine in combination for this indication, is the only randomized study with a significant number of patients with active brain metastases that reported statistically positive and clinically meaningful results.” 
She added that the evidence for T-DXd in this population had been limited until now.
Manich concluded the discussion by suggesting potential changes to treatment recommendations based on these results.
“After today’s presentation, I believe the preferred option for second-line treatment should now be trastuzumab deruxtecan, regardless of whether the patient has active brain metastases or not. Additionally, for third-line treatment, the preferred option would be tucatinib, trastuzumab, and capecitabine in my opinion.”
She also highlighted the importance of future real-world data analysis, stating, “It will be very important to perform real-world data analysis to understand the efficacy of tucatinib in this setting after progression to trastuzumab deruxtecan.”
Manich reported financial relationships with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, Pint-Pharma, Puma, Roche Farma, sanofi-aventis, Seagen, Zymeworks, Genentech, Innoup, Millenium, and Pharmalex Spain SLU (advisory board); Sociedade Portuguesa de Oncología (invited speaker); AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche Ltd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, sanofi-aventis, and Seattle Genetics (institutional research grant); and Byondis B.V. (coordinating PI). 
Lin reported financial relationships with Artera, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Eisai, Janssen, Olema Pharmaceuticals, Seagen, and Stemline Therapeutics (consulting or advisory roles); Olema Pharmaceuticals (travel support); AstraZeneca, Genentech, Olema Pharmaceuticals, Pfizer, Seagen, and Zion (institutional research support); and UpToDate (royalties for book chapters). 
 
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