Trastuzumab Deruxtecan in brain metastases from breast cancer: outcome analysis of real life population

Trastuzumab Deruxtecan in brain metastases from breast cancer: outcome analysis of real life population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Trastuzumab Deruxtecan in brain metastases from breast cancer: outcome analysis of real life population Alessandro Rossi, Alessandra Fabi, Roberta Caputo, Simona Pisegna, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4348533/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Introduction. Tumor dissemination to the central nervous system (CNS) is almost a rule in the treatment journey of advanced HER2+ breast cancer (BC). Recent results from the DEBBRAH and TUXEDO trials demonstrated high intracranial efficacy with Trastuzumab Deruxtecan (T-Dxd), confirmed by a pooled analysis of DESTINY-BREAST 01, 02, and 03 trials. However, a real world evidence is lacking in literature. Methods. We conducted a multicenter, observational, and retrospective real-world analysis on cases collected at 12 Italian Oncological Units. Patients with brain metastases (BMs) from HER2+ BC treated with T-Dxd in various treatment lines were enrolled. Data were extrapolated from the original DE-REAL study database. Primary endpoint was the intracranial overall response rate (iORR). The main secondary endpoints were intra- and global progression free survival (iPFS - gPFS); Other secondary objectives were the intracranial disease control rate (iDCR), intracranial duration of response (iDoR), the intracranial clinical benefit rate at 6 and 12 months (iCBr), the overall survival, and the safety. Results. 39 patients were included in the final analysis. iORR was 59% (23), iPFS was 15.6 months (95% CI: 10.5-20.8), gPFS was 11.8 months (95% CI: 8.5-15.0). i DCR 94.9% (87.9-100.0), iDoR was 11.9 months (10.1-13.7), and iCBr at 6 and 12 months were 69.2% and 59%, respectively. OS was not reached, with an overall rate of 77.9% of patients alive at 12 months. No new safety concerns were reported. Conclusions. This study confirmed the high intracranial efficacy and manageable safety profile of T-Dxd in this first-ever real world analysis. Health sciences/Oncology/Cancer/Breast cancer Biological sciences/Cancer/Cancer therapy/Targeted therapies Health sciences/Medical research/Outcomes research Figures Figure 1 Figure 2 Introduction Almost 30–50% of patients with human epidermal growth factor (HER2)-positive breast cancer (BC) will develop brain metastases (BMs) in its treatment journey [ 1 ]. This is both related to an improvement in overall survival (OS) with new HER2-targeted agents and to an increased detection rate with the latest imaging techniques [ 2 ]. Despite impressive results achieved for extracranial disease, the central nervous system (CNS) compartment remains highly challenging, because the blood-brain barrier (BBB) limits penetration of many compounds, including chemotherapy and targeted agents [ 3 , 4 ]. This reflects the poor prognosis of patients with BMs [ 1 ]. Traditionally, local approaches such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS), and neurosurgery have been and are still today a mainstay in BMs treatment [ 5 ]. Indeed, those therapeutical approaches must be associated with a prompt and adequate systemic intervention. There are growing evidences that support the effectiveness of antibody-drug conjugates (ADCs) for BC BMs in terms of intracranial (IC) response. Ado-trastuzumab emtansine (TDM-1), the first-in class ADC incorporating the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1, demonstrated clinical activity in patients with breast cancer BMs [ 6 – 8 ]. Trastuzumab Deruxtecan (T-Dxd), an ADC consisting of a humanized HER-2 directed monoclonal antibody and deruxtecan, a topoisomerase-I inhibitor, recently obtained impressive results both in heavily pretreated patients that previously received TDM-1 [ 9 ] and in the directly comparative DESTINY BREAST03 phase III trial [ 10 ]. Although there are some evidences for patients with stable BMs in clinical trials, those with active CNS involvement are often excluded and BM-related outcomes are not often included among study endpoints [ 11 , 12 ]. This clearly represents an urgent clinical unmet need. The HER2CLIMB trial paved the way for studies that included patients with active BMs [ 13 ], demonstrating a clinically and statistically meaningful benefit with the addition of tucatinib, an anti-HER2 tyrosine kinase inhibitor, to trastuzumab and capecitabine. To date, this is the preferred treatment regimen for patients with active BMs, as intracranial activity of T-Dxd is less defined [ 14 ]. Preliminary data from the DEBBRAH, a non-randomized single-arm design trial, indicated encouraging intra- and extracranial activity of T-Dxd in different cohort of pretreated patients: 1, with stable BMs after surgery, SRS/SRT, and/or WBRT; 2, with asymptomatic untreated BMs; 3, with progressing BMs after surgery, SRS/SRT, and/or WBRT [ 15 ]. Moreover, the TUXEDO trial, an open-label, single-arm, phase 2 study, met its primary endpoint with an intracranial response rate (IRR) of 73.3% in patients with HER2-positive BC and newly diagnosed untreated or progressing after previous local therapy BMs, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy [ 16 ]. Despite encouraging results, these studies are characterized by a small sample size (21 and 15 patients, respectively), and are more useful to pave the way for larger randomized clinical trials rather than to make definitive conclusions. To date, a real-world evidence focused on intracranial activity for patients with BMs treated with T-Dxd is still lacking. We have recently reported the results of an Italian large retrospective analysis (De-Real study), which evaluated the effectiveness and safety of T-Dxd in a ‘field-practice’ scenario [ 17 ]. In an effort to add further information on the clinical activity and safety of T-Dxd in both naïve and previously treated patients with BMs, we performed a sub-analysis from our database. Patients and Methods Data retrieval This study was a national multicenter, observational, and retrospective analysis (De-Real study n. 0181/2022) conducted on cases collected at 12 Italian Oncological Units, reviewed to identify HER2 positive BC and BMs patients treated with T-Dxd between April 2021 and February 2023 (updated data compared to the first publication). The search rendered a total of 39 out of 153 patients (Fig. 1 ). Eligible patients were required to have a diagnosis of HER2 positive tumor, determined locally and defined as 3 + immunohistochemical (IHC) staining (HercepTest; Dako A/S, Glostrup, Denmark) or 2 + IHC staining and HER2/Vep17 Ratio > 2 at fluorescence in situ hybridization (FISH) (PathVision HER2 DNA probe kit; Vysis Inc., Downers Grove, IL). All patients were age > 18 years and were treated with at least one dose of T-Dxd. Only patients with measurable and/or evaluable advanced disease were included. No restrictions were made based on previous lines of therapy or local treatment received for metastatic disease. Progressive and/or recurrent disease prior to T-Dxd initiation had to be documented in all cases. Only patients who were evaluated with brain magnetic resonance imaging (MRI) for CNS were eligible for the study. Brain MRI was used to assess brain involvement, whereas chest and abdomen tomography scans were used to assess all extracranial metastatic sites. The BM status was determined according to the following definitions by the US FDA Clinical Trial Eligibility Criteria [ 18 ]: treated/stable BMs, in patients with prior CNS-directed therapy for BMs, and CNS stable disease; untreated/active BMs, in patients with new or progressive BMs not subjected to CNS directed therapy since documented progression. Radiological restaging was performed every three cycles of T-Dxd (12 weeks of therapy). Due to the retrospective nature of the study, intra- and extracranial responses were assessed based on the recommendations of the Response Criteria in Solid Tumors 1.1 (RECIST 1.1) [ 19 ]. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments and within the protocol approved by the ethics committee (Policlinico Umberto I Hospital University, examination number: 0181/2022) and all other institutions. All patients alive provided written informed consent to the use of medical records for research purposes. Treatment schedule Patients received T-DXd at the standard dose of 5.4 mg per body weight kilogram every 3 weeks, until progression, unacceptable toxicity, patient’s or physician’s request to discontinuation or patient refusal. Antiemetic and concomitant treatments that did not interfere with the drug, including the use of both G-CSF and bisphosphonates therapy, were allowed. Study objectives and outcomes measures The primary objective of the study was to evaluate the efficacy of T-Dxd on BMs in a real-world population, in terms of intracranial responses (complete and partial responses). The main secondary endpoints were intra- and global progression free survival (iPFS - gPFS) defined as the time elapsed between the first dose of T-Dxd and brain-only or intra-extracranial progression of the disease [ 20 ], respectively. Other secondary objectives were: the intracranial disease control rate (iDCR: the sum of complete, partial and stable diseases), intracranial duration of response (iDoR: the time from the first radiological evidence of response to the progression), the intracranial clinical benefit rate at 6 and 12 months (iCBr: the sum of the complete, partial and stable disease rates over a certain time period) and the overall survival (OS, the time elapsed between the first dose of T-Dxd and death from any cause or censoring at the time of last follow-up). Treatment-related adverse events (AEs) were categorized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 [ 21 ]. AEs were collected at every clinical evaluation performed in the referral centers. Statistical analysis Data were summarized by absolute counts and percentages when related to categorical item and with median and range in case of quantitative variables. Survival curves were estimated using the Kaplan-Meier method and median values were reported alongside their 95% confidence intervals. Differences between survival curves were assessed by the log-rank test. Results The clinical characteristics of the 39 patients are shown in Table 1 . Table 1 Baseline characteristics Patients (n = 39) N (%) Age median (range) 55 (35–72) Performance Status ECOG (n.; %) 0 1 2 12 (30.8) 20 (51.3) 7 (17.9) Hormonal Receptor status (n.; %) Estrogen Positive Progesterone Positive 25 (64.1) 21 (53.8) HER2 Status (IHC) (n.; %) HER2 2 + SISH/FISH^ Amplification HER2 3+ 6 (15.4) 33 (84.6) Previous Neo-adjuvant therapies (n.; %) Trastuzumab with or without Pertuzumab regimens Anthracycline-taxanes regimens Anthracycline-sparing regimens 20 (51.3) 10 (25.6) 10 (25.6) 0 Previous adjuvant therapies (n.; %) Trastuzumab with or without Pertuzumab regimens Anthracycline-taxanes regimens No anthracycline regimen 24 (61.5) 21 (53.8) 11 (28.2) 13 (33.3) Previous Hormonal adjuvant therapies (n.; %) 23 (59) Median lines for metastatic disease (range) 2 (0–5) Previous anti-HER2 lines for metastatic disease (n.; %) 0 1 2 3 > 4 2 (5.1) 15 (38.5) 10 (25.6) 8 (20.5) 4 (10.3) Previous anti-HER2 therapies for metastatic disease (n.; %) Pertuzumab/trastuzumab/taxane T-DM1 Lapatinib/capecitabine Tucatinib/Lapatinib/capecitabine Trastuzumab + chemotherapy: Paclitaxel Vinorelbine Docetaxel + vinorelbine Trastuzumab + Hormonal therapy 37 (94.8) 33 (84.6) 21 (53.8) 12 (30.8) 1 (2.6) 9 (23.1) 3 (7.7) 3 (7.7) 3 (7.7) 1 (2.6) Median Disease Free Interval from BMs (months, range) Since initial diagnosis Since metastatic diagnosis 46 (0-199) 14 (0–96) N° of brain metastases (n.; %) 1 2 3 4 Not reported 6 (15.4) 2 (5.1) 5 (12.8) 23 (59.0) 3 (7.7) N° of patients with neurological symptoms (n.; %) Yes No 18 (46.1) 21 (53.9) Previous BM local therapy (n.; %) No therapy SRS° WBRT § Surgery + SRS Surgery + WBRT WBRT + SRS + surgery 5 (12.8) 16 (41.0) 13 (33.3) 3 (7.7) 1 (2.6) 1 (2.6) Extracranial metastatic sites (n.; %) 0 1 2 3 >=4 missing 7 (17.9) 4 (10.3) 12 (30.8) 5 (12.8) 9 (23.1) 2 (5.1) Dominant metastatic sites (n.; %) Liver Lung Bone Soft tissues Only brain 14 (35.9) 7 (17.9) 7 (17.9) 2 (5.1) 9 (23.1) Median progression Free Survival of previous I line (months and range) 10 (4–96) Median progression Free Survival of previous II lines (months and range) 8 (2–29) Time from the end of local brain treatments to T-Dxd ( median, range ) 7 (0–27) T-Dxd line 1 2 3 4 >=5 2 (5.1) 12 (30.8) 8 (20.5) 8 (20.5) 9 (23.2) * IHC : Immunoistochemistry; ^ SISH/FISH: Silver in situ hybridization/Fluorescent in situ hybridization; °SRS: Stereotactic Radiosurgery; § WBRT: Whole Brain Radiotherapy Median age was 55 years (35–72). Thirty-six (92.3%) patients had estrogen and/or progesterone receptor positive tumors, with 23 (59.0%) previously treated with anti-hormonal treatment in adjuvant setting. In the curative setting, 10 (25.6%) patients received both trastuzumab +/- pertuzumab and anthracycline +/- taxanes based regimens as a neoadjuvant treatment, while 24 (61.5%) patients received adjuvant therapy: 21 (53.8%) trastuzumab +/- pertuzumab of which 11 (28.2%) combined to anthracycline and taxanes based-regimens and 13 (33.3%) combined to anthracycline-sparing therapy. In the advanced setting, 37 (94.8%) patients received previous anti-HER2 treatments: 33 (84.6%) trastuzumab + pertuzumab and taxane (docetaxel/paclitaxel), 21 (53.8%) T-DM1, 12 (30.8%) Lapatinib plus capecitabine, and 9 (23.1%) trastuzumab plus chemotherapy regimens. Only 1 (2.6%) patient received trastuzumab plus anti-hormonal therapy. Before administering T-Dxd, median PFS (mPFS) of first line treatments was 10 months (4–96), while mPFS of second line treatments was 8 months (2–29). Median previous treatment lines for HER2 + metastatic disease was 2 (0–5); T-Dxd was administered as a first line treatment for advanced disease in 2 patients (5.1%), as a second line in 15 patients (38.5%), as a third, fourth, fifth or later line in 10 patients (25.6%), 8 patients (20.5%) and 4 patients (10.3%), respectively. Six (15.4%) out of 36 patients had only one BM, 2 (5.1%) and 5 (12.8%) patients had two and three BMs, respectively, while most patients (23, 59.0%) had four or more brain lesions. The exact number of BMs was not reported for three (7.7%) patients. Eighteen (46.1%) patients reported neurological symptoms while starting T-Dxd. Thirty-four (87.2%) patients received one or more local approach for intracranial control of brain lesions, with most of them receiving Stereotactic Radiosurgery [SRS (16 (41%) and WBRT (15, 38.4%)]. Five (12,8%) had no previous locoregional treatment. The median time from the end of local brain treatments to the first administration of T-DxD was 7 months (range 0–27).Seven (17.9%)patients had no evidence of extracranial involvement, whilst 4 (10.3%), 12 (30.8%), 5 (12.8%), and 9 (23.0%) patients had one, two, three, and four or more extracranial metastatic sites, respectively. Data were missing for two patients (5.1%). Intracranial efficacy Regarding the single outcomes, one patient (2.6%) achieved a complete response (CR), twenty-two (56.4%) a partial response (PR, for an overall response rate of 59.0%), fourteen patients (35.9%) had a stable disease (SD), while two showed (5.1%) an intracranial progressive disease (PD) (Table 2 b). Table 2 a. Intracranial Efficacy of T-Dxd mPFS (months) 15.6 (95% CI: 10.5–20.8) Disease Control Rate (%) 94.9 (87.9–100.0) Duration of Response (months) 11.9 (10.1–13.7) Clinical Benefit (%) 6 months 12 months 27 (69.2) 23 (59.0) Overall Survival at 12 months (%) 76.6 Table 2 b. Intracranial and Global best responses with T-DxD Response to T-Dxd Complete Response Partial Response Overall Response rate Stable Disease Progressive disease Intracranial Best Response n. (%) 1 (2.6) 22 (56.4) 23 (59) 14 (35.9) 2 (5.1) Global Best Response n. (%) 0 27 (69.2) 27 (69.2) 10 (25.6) 2 (5.1) When considering the treatment line, there were one PR and one SD in first line, eleven PR and one SD in second line, one CR, five PR, and two SD in third line, three PR, four SD, and one PD in fourth line, two PR, six SD, and one PD in fifth or later lines (Table 3 a). Table 3. Efficacy of T-DxD based on treatment line Table 3 a. Intracranial Efficacy Line of treatment Complete Response Partial Response Stable Disease Progressive disease Median icPFS (range) I line (n = 2) 0 1 1 0 NE II line (n = 12) 0 11 1 0 14.2 (NE) III line (n = 8) 1 5 2 0 15.5 (10.1–21.1) IV line (n = 8) 0 3 4 1 11.1 (6.8–15.6) >IV line (n = 9) 0 2 6 1 16.5 (NE) ° icPFS: intracranial progression free survival; NE: not evaluable Table 3 b. Global Efficacy Line of Treatment Complete Response Partial Response Stable Disease Progressive disease Median PFS (range) I line (n = 2) 0 2 0 0 NE II line (n = 12) 0 10 2 0 14.1 (6.8–21.3) III line (n = 8) 0 7 1 0 15.5 (8.5–22.4) IV line (n = 8) 0 4 3 1 11.1 (6.9–15.4) >IV line (n = 9) 0 4 4 1 7.9 (5.8–10.6) PFS: progression free survival; NE: not evaluable At a median follow up of 12 months intracranial mPFS was 15.6 months (10.5–20.8). When dividing patients according to the intracranial responses (CR/PR vs SD/PD), a statistically significant difference in mPFS [15.8 (14.1–17.5) vs 11.2 (3.2–19.2), p = 0.01)] was found (Fig. 1 ). No difference (p = 0.75) were observed in mPFS between patients that did [15.6 (10.8–20.4)] or did not 5.8 (n.e.)] receive a local approach. iDCR was 94.9% (87.9–100.0), iDoR was 11.9 months (10.1–13.7), and iCBr at 6 and 12 months were 69.2% and 59%, respectively. OS was not reached, with an overall rate of 77.9% of patients alive at 12 months. Data regarding intracranial activity are summarized in Table 2 a. Global (intra + extracranial) activity For global disease activity, no CR was observed, while twenty-seven (69.2%) PR, ten (25.6%) SD, and two (5.1%) PD were documented. Results of best intra and global responses are summarized in Table 2 b. Data between the two groups were substantially balanced in terms of responses. When considering the global activity, there were two PR in first line, ten PR and two SD in second line, seven PR and one SD in third line, four PR, three SD, and one PD in fourth line, four PR, four SD, and one PD in fifth or later lines. Intra- and global activity of T-Dxd according to treatment line is available at Table 3 . Considering all treatment lines together, global mPFS was 11.8 months (8.5–15.0). Safety Median treatment duration with T-Dxd was 9.5 months (range: 1.5–16.5). 32 patients (82%) experienced an any grade toxicity from treatment with T-Dxd. The main grade 1/2 hematological toxicities were neutropenia (35.9%) and anemia (23.1%). Grade 1/2 non-hematological adverse events (AEs) that occurred in more than 10% of the patients were alopecia (59%), fatigue (53.8%), nausea (46.1%), constipation (30.7%), diarrhea (28.2%), and vomiting (10.2%). Grade 3/4 hematological toxicities consisted of neutropenia (15.3%), anemia (5.1%) and piastrinopenia (2.5%). Grade 3/4 non-hematological AEs were fatigue (18%), diarrhea (10.2%), nausea (7.7%), mucositis (5.1%), vomiting (2.5%), pneumonitis (2.5%), and increase in liver transaminase (2.5%). With regard to AEs of special interest, grade 1 drop of LVEF was observed in one patient (2.5%). Toxicities are available in the supplementary material (Table 1 suppl.). Discussion T-Dxd has revolutionized the treatment algorithm of HER2-positive advanced BC, and there are growing evidences that support its use even in patients with intracranial disease. To date, there was no evidence of outcome in HER2 positive advanced BC patients with BMs in a real world population. A recent retrospective exploratory pooled analysis of DESTINY BREAST 01, 02, and 03 trials [ 22 ] showed superior rates in terms of IC response over comparator in patients with treated/stable and untreated/active BMs, with a particularly favourable trend in iDoR and imPFS for the latter ones. This data strengthen our beliefs that T-Dxd will become a mainstay in our clinical practice even in these crucial subset of patients. It is important to note that in the DESTINY BREAST 02 and 03 trials patients with previously untreated and asymptomatic BM were eligible but, after protocol amendments, only patients with treated, asymptomatic BMs were allowed. Therefore, the population of patients with baseline BMs consists of a mix of treated/stable and untreated/active metastases. This pooled analysis showed that patients in both groups achieved an overall response rate of 45.2% and 45.5% for treated/stable and untreated/active BMs cohorts, respectively. Intracranial CR rates were 16.3% and 15.9%, while iPR rates were 28.8% and 29.5%, respectively. In our study, we registered significantly lower rates of intracranial CR (2.6%) and higher rates of PR (56.4%). Data for SD were substantially in line with Hurvitz et al. results (30.7% in our study, 46.2% and 34.1% in the pooled analysis). This is probably related to the real-world context, with a less selected population that has an intrinsically lower survival. Rates of ORR, iDCR, iDoR, and iCBr at 6 and 12 months witnessed a high intracranial activity of T-Dxd, with mPFS of over 15 months. It is important to note that this was independent from treatment line, and sustained responses documented that the drug was globally safe in terms of timing and dosing. In Table 4 a cautios comparison between real life and trial disease outcomes is listed. We did not provide a difference between treated/stable and non-treated/unstable BMs lesions, as in the first group we had only 5 patients. Table 4 Comparison between intracranial outcomes in DE-REAL and DB 01-02-03 pooled analysis Patient number (n.) DE -REAL real life (39) DB pooled analysis, treated/stable BMs (104) DB pooled analysis, non-treated/unstable BMs (44) ORR, n (%) 23 (59) 47 (45.2) 20 (45.5) Complete response, n (%) 1 (2.6) 17 (16.3) 7 (15.9) Partial response, n (%) 22 (56.4) 30 (28.8) 13 (29.5) Stable disease, n (%) 14 (35.9) 48 (46.2) 15 (34.1) Progressive disease, n (%) 2 (5.1) 3 (2.9) 1 (2.3) Duration of response (months), median (95% CI) 11.9 (10.1–13.7) 12.3 (9.7–17.9) 17.5 (13.6–31.6) PFS (months), median (95% CI) 15.6 (10.5–20.8) 12.3 (11.1–13.8) 18.5 (13.6–23.3) Disease control rate (%,95% CI) 94.9 (87.9–100.0) 91.3 (NA) 79.6 (NA) Clinical benefit (%) 6 months 12 months 27 (69.2) 23 (59.0) NA NA NA NA Overall Survival at 12 months (%) 76.6 NA NA BMs: Brain Metastases; DB: Destiny Breast; NA: Not available; ORR: Overall Response Rate; PFS: Progression-free survival When comparing intracranial responders (CR/PR) to non-responders (SD/PD), a clear improvement in mPFS [15.8 (14.1–17.5) vs 11.2 (3.2–19.2), p = 0.01), Fig. 1 ] was achieved. This witnesses and supports the strong prognostic value of intracranial response, regardless of treatment line. It is clear that, with only 2 patients that experienced intracranial PD, no correct comparison can be made with all other patients that had at least a SD. Interestingly, no difference in mPFS was found for patients that did or did not receive a local approach for BMs (15.8 vs 15.6 months p = 0.45). This probably reflects the fact that there are resistance mechanisms related to pharmacological pressure, with intratumoral heterogeneity and number of previous anti-HER2 lines received that certainly play a role, along with the efficacy of T-Dxd in this district. Our findings seem to endorse the concept that we are moving to a “paradigm shift”, in which a RT deferral may be a valid option for certain patients with BMs who are eligible for a systemic therapy with a strong intracranial activity [ 23 ]. We obviously must consider that only 5 patients did not receive a local approach for BMs in our study, therefore these data needs careful and proper evaluation. In the TUXEDO and DEBBRAH trials there were no comparison between patient that did or did not receive a local treatment in terms of survival, therefore we do not have reliable data. Toxicities were substantially in line with what previously reported with the use of T-Dxd in various settings. After growing experience with the drug, it is clear that there is an improvement in the support care management for signs and symptoms related to T-Dxd, in particular nausea/vomiting and neutropenia. Also the incidence of lung infections were poorly detected (moderate/severe grade: 2.5%), even in this at-risk population (disease spreading, both systemic and locoregional previous treatments). It is important to highlight that median treatment duration was 9.5 months, that is substantially in line with what previously reported for heavily pretreated patients in the DESTINY BREAST-04 trial (8.2 months) [ 24 ]. This real world analysis have its limitations. First of all, real world data were retrospectively collected from clinical databases that were originally not designed to collect data for research. The retrospective design presents threats to both internal and external validity. Moreover, due to its nature there was no Blinded Independent Central Review (BICR) to determine disease progression. However, there are several strenghts. To our knowledge, this is the first real world analysis that investigates intracranial outcomes with the use of T-Dxd, with a larger sample size of patients than the already cited DEBBRAH and TUXEDO trials. Moreover, patients were properly evaluated with brain MRI to perform a correct evaluation of the intracranial compartment, and this should be emphasized as in routinary clinical practice the whole body TC scan is the mainstay for practical reasons and MRI is often used solely to deepen the TC results. Furthermore, as for some real life evidences, more outcomes measures are investigated, such as the duration of response, the disease control rate and the clinical benefit other than progression free survival. In conclusion, due to the intrinsic therapeutic power of this drug, we are witnessing an intracranial benefit from a systemic therapy; this is important as it not only delays loco-regional treatment in some cases, but also improves quality of life in patients with intracranial responses. The oncological community is waiting for the results of T-DXd in the early setting [Destiny BREAST-011 (NCT 202100060321), and SHAMROCK (NCT05710666) trials in neoadjuvant setting; Destiny BREAST-05 (NCT04622319) trial in adjuvant setting] that will also provide information on the potential ability of the drug to prevent or delay CNS spreading in HER2 positive BC. In the context of a real-world study, our data supports the use of T-Dxd for both patients with treated/stable and untreated/active BMs. Declarations AUTHOR CONTRIBUTION: Conceptualization, Methodology, Investigation, Writing, review, and editing. Visualization: A.F., A.R., S.P.,A.B. Investigation: A.F.,A.R, R.C., S.P., F.P., G.D., P.F, A.F.,C.V.,M.P.,L.C.,G.F.,E.DM., I.P., F.P.,O.G.,D.G.,M.DL., G.F., G.S., A.B. Manuscript Editing: All ; Approval to submission: All ACKNOWLEDGEMENTS We would like to thank Mrs Elisabetta Bozzoli for the data management. CONFLICT OF INTEREST : The Authors declare no conflict of interest. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author, AR, upon reasonable request. References Garcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain metastases in HER2-positive breast cancer: current and novel treatment strategies. Cancers. 2021;13(12):2927. Venur VA, Leone JP. Targeted therapies for brain metastases from breast cancer. Int J Mol Sci 2016;17:1543. Hurvitz SA, O’Shaughnessy J, Mason G, et al. Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs. Clin Cancer Res 2019;25:2433–41. Steeg PS. The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol. 2021 Nov;18(11):696-714. doi: 10.1038/s41571-021-00529-6. Epub 2021 Jul 12. PMID: 34253912. Soffietti, R. et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). 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Patel RR, Verma V, Miller AB, et al. Exclusion of patients with brain metastases from cancer clinical trials. Neuro Oncol. 2020;22(4):577–579. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597–609. Stavrou E, Winer EP, Lin NU. How we treat HER2-positive brain metastases. ESMO Open. 2021;6(5):100256. Pérez-García JM, Batista MV, Cortez P, et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial. Neuro. Oncol. noac144 (2022). 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 Sep;28(9):1840-1847. doi: 10.1038/s41591-022-01935-8. Epub 2022 Aug 8. PMID: 35941372; PMCID: PMC9499862. Botticelli A, Caputo R, Scagnoli S, et al18. Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. Oncologist. 2023 Nov 23:oyad308. doi: 10.1093/oncolo/oyad308. Epub ahead of print. PMID: 37995313. U.S. Department of Health and Human Services – Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Brain Metastases. 2020. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. PMID: 19097774. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016 Jul;62:132-7. doi: 10.1016/j.ejca.2016.03.081. Epub 2016 May 14. PMID: 27189322; PMCID: PMC5737828. National Institute of Health. National Cancer Institute Common Terminology Criteria for Adverse Events ( CTCAE ) version 5.0. NIH Publication (2017). S.A. Hurvitz, S. Modi, W. Li , et al. A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINYBreast (DB) -01, -02, and -03. Ann. Onc. Abstract 377O| volume 34, supplement 2, s335-s336, october 2023. doi: https://doi.org/10.1016/j.annonc.2023.09.554. Ippolito E, Silipigni S, Matteucci P, et al. Radiotherapy for HER 2 Positive Brain Metastases: Urgent Need for a Paradigm Shift. Cancers (Basel). 2022 Mar 15;14(6):1514. doi: 10.3390/cancers14061514. PMID: 35326665; PMCID: PMC8946529. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4348533","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":306853585,"identity":"024ee8dd-6def-49a4-bcf9-a63c519afec1","order_by":0,"name":"Alessandro Rossi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-0479-9732","institution":"Fondazione Policlinico Universitario Agostino Gemelli","correspondingAuthor":true,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Rossi","suffix":""},{"id":306853586,"identity":"c71ae14c-caad-4bc7-9cb3-ef0113eb0c83","order_by":1,"name":"Alessandra Fabi","email":"","orcid":"","institution":"Fondazione Policlinico Universitario A. 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Gemelli IRCCS, Rome, Italy","correspondingAuthor":false,"prefix":"","firstName":"Riccardo","middleName":"","lastName":"Masetti","suffix":""},{"id":306853608,"identity":"85159137-be7d-414b-bfc1-d360ac0c43a0","order_by":23,"name":"Andrea Botticelli","email":"","orcid":"","institution":"Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy.","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Botticelli","suffix":""}],"badges":[],"createdAt":"2024-04-30 11:01:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4348533/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4348533/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58151486,"identity":"1c96b30c-888a-496f-bb6b-d42d02afc7db","added_by":"auto","created_at":"2024-06-11 20:11:37","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":197931,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatients selection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4348533/v1/57f49f456f740fe3f4739e7e.jpeg"},{"id":58152304,"identity":"ac9e6296-1a29-496c-9a82-4b1e22ab42be","added_by":"auto","created_at":"2024-06-11 20:19:37","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":197001,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression Free Survival of Intracranial Responders vs no Responders (Kaplan-Meier Curve).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResponders : patients achieving intracranial complete or partial response (total 23).\u003c/p\u003e\n\u003cp\u003eNon-Responders: patients with an intracranial stable disease or progression (total 16).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4348533/v1/00f317c16bffdb9c6ab6fc80.jpeg"},{"id":58153381,"identity":"3cb896bf-ab17-402a-a8a3-cc69c89d443b","added_by":"auto","created_at":"2024-06-11 20:27:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1298407,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4348533/v1/b6070d10-b773-4a67-a13a-d3359cd667ae.pdf"},{"id":58151485,"identity":"dbc1443e-69d4-4e37-bf34-53a16499a4e6","added_by":"auto","created_at":"2024-06-11 20:11:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15335,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SUPPLEMENTARYFILESDEREAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-4348533/v1/ea450f3e165d138ae6e6bfe5.docx"}],"financialInterests":"(Not answered)","formattedTitle":"Trastuzumab Deruxtecan in brain metastases from breast cancer: outcome analysis of real life population","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAlmost 30\u0026ndash;50% of patients with human epidermal growth factor (HER2)-positive breast cancer (BC) will develop brain metastases (BMs) in its treatment journey [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This is both related to an improvement in overall survival (OS) with new HER2-targeted agents and to an increased detection rate with the latest imaging techniques [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite impressive results achieved for extracranial disease, the central nervous system (CNS) compartment remains highly challenging, because the blood-brain barrier (BBB) limits penetration of many compounds, including chemotherapy and targeted agents [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This reflects the poor prognosis of patients with BMs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTraditionally, local approaches such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS), and neurosurgery have been and are still today a mainstay in BMs treatment [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Indeed, those therapeutical approaches must be associated with a prompt and adequate systemic intervention.\u003c/p\u003e \u003cp\u003eThere are growing evidences that support the effectiveness of antibody-drug conjugates (ADCs) for BC BMs in terms of intracranial (IC) response. Ado-trastuzumab emtansine (TDM-1), the first-in class ADC incorporating the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1, demonstrated clinical activity in patients with breast cancer BMs [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Trastuzumab Deruxtecan (T-Dxd), an ADC consisting of a humanized HER-2 directed monoclonal antibody and deruxtecan, a topoisomerase-I inhibitor, recently obtained impressive results both in heavily pretreated patients that previously received TDM-1 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and in the directly comparative DESTINY BREAST03 phase III trial [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although there are some evidences for patients with stable BMs in clinical trials, those with active CNS involvement are often excluded and BM-related outcomes are not often included among study endpoints [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This clearly represents an urgent clinical unmet need.\u003c/p\u003e \u003cp\u003eThe HER2CLIMB trial paved the way for studies that included patients with active BMs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], demonstrating a clinically and statistically meaningful benefit with the addition of tucatinib, an anti-HER2 tyrosine kinase inhibitor, to trastuzumab and capecitabine. To date, this is the preferred treatment regimen for patients with active BMs, as intracranial activity of T-Dxd is less defined [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreliminary data from the DEBBRAH, a non-randomized single-arm design trial, indicated encouraging intra- and extracranial activity of T-Dxd in different cohort of pretreated patients: 1, with stable BMs after surgery, SRS/SRT, and/or WBRT; 2, with asymptomatic untreated BMs; 3, with progressing BMs after surgery, SRS/SRT, and/or WBRT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, the TUXEDO trial, an open-label, single-arm, phase 2 study, met its primary endpoint with an intracranial response rate (IRR) of 73.3% in patients with HER2-positive BC and newly diagnosed untreated or progressing after previous local therapy BMs, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite encouraging results, these studies are characterized by a small sample size (21 and 15 patients, respectively), and are more useful to pave the way for larger randomized clinical trials rather than to make definitive conclusions.\u003c/p\u003e \u003cp\u003eTo date, a real-world evidence focused on intracranial activity for patients with BMs treated with T-Dxd is still lacking. We have recently reported the results of an Italian large retrospective analysis (De-Real study), which evaluated the effectiveness and safety of T-Dxd in a \u0026lsquo;field-practice\u0026rsquo; scenario [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn an effort to add further information on the clinical activity and safety of T-Dxd in both na\u0026iuml;ve and previously treated patients with BMs, we performed a sub-analysis from our database.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData retrieval\u003c/h2\u003e \u003cp\u003e This study was a national multicenter, observational, and retrospective analysis (De-Real study n. 0181/2022) conducted on cases collected at 12 Italian Oncological Units, reviewed to identify HER2 positive BC and BMs patients treated with T-Dxd between April 2021 and February 2023 (updated data compared to the first publication). The search rendered a total of 39 out of 153 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Eligible patients were required to have a diagnosis of HER2 positive tumor, determined locally and defined as 3\u0026thinsp;+\u0026thinsp;immunohistochemical (IHC) staining (HercepTest; Dako A/S, Glostrup, Denmark) or 2\u0026thinsp;+\u0026thinsp;IHC staining and HER2/Vep17 Ratio\u0026thinsp;\u0026gt;\u0026thinsp;2 at fluorescence \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH) (PathVision HER2 DNA probe kit; Vysis Inc., Downers Grove, IL).\u003c/p\u003e \u003cp\u003eAll patients were age\u0026thinsp;\u0026gt;\u0026thinsp;18 years and were treated with at least one dose of T-Dxd.\u003c/p\u003e \u003cp\u003eOnly patients with measurable and/or evaluable advanced disease were included. No restrictions were made based on previous lines of therapy or local treatment received for metastatic disease. Progressive and/or recurrent disease prior to T-Dxd initiation had to be documented in all cases.\u003c/p\u003e \u003cp\u003eOnly patients who were evaluated with brain magnetic resonance imaging (MRI) for CNS were eligible for the study. Brain MRI was used to assess brain involvement, whereas chest and abdomen tomography scans were used to assess all extracranial metastatic sites.\u003c/p\u003e \u003cp\u003eThe BM status was determined according to the following definitions by the US FDA Clinical Trial Eligibility Criteria [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]: treated/stable BMs, in patients with prior CNS-directed therapy for BMs, and CNS stable disease; untreated/active BMs, in patients with new or progressive BMs not subjected to CNS directed therapy since documented progression.\u003c/p\u003e \u003cp\u003eRadiological restaging was performed every three cycles of T-Dxd (12 weeks of therapy). Due to the retrospective nature of the study, intra- and extracranial responses were assessed based on the recommendations of the Response Criteria in Solid Tumors 1.1 (RECIST 1.1) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments and within the protocol approved by the ethics committee (Policlinico Umberto I Hospital University, examination number: 0181/2022) and all other institutions. All patients alive provided written informed consent to the use of medical records for research purposes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment schedule\u003c/h2\u003e \u003cp\u003ePatients received T-DXd at the standard dose of 5.4 mg per body weight kilogram every 3 weeks, until progression, unacceptable toxicity, patient\u0026rsquo;s or physician\u0026rsquo;s request to discontinuation or patient refusal. Antiemetic and concomitant treatments that did not interfere with the drug, including the use of both G-CSF and bisphosphonates therapy, were allowed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy objectives and outcomes measures\u003c/h2\u003e \u003cp\u003eThe primary objective of the study was to evaluate the efficacy of T-Dxd on BMs in a real-world population, in terms of intracranial responses (complete and partial responses). The main secondary endpoints were intra- and global progression free survival (iPFS - gPFS) defined as the time elapsed between the first dose of T-Dxd and brain-only or intra-extracranial progression of the disease [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], respectively.\u003c/p\u003e \u003cp\u003eOther secondary objectives were: the intracranial disease control rate (iDCR: the sum of complete, partial and stable diseases), intracranial duration of response (iDoR: the time from the first radiological evidence of response to the progression), the intracranial clinical benefit rate at 6 and 12 months (iCBr: the sum of the complete, partial and stable disease rates over a certain time period) and the overall survival (OS, the time elapsed between the first dose of T-Dxd and death from any cause or censoring at the time of last follow-up). Treatment-related adverse events (AEs) were categorized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. AEs were collected at every clinical evaluation performed in the referral centers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were summarized by absolute counts and percentages when related to categorical item and with median and range in case of quantitative variables. Survival curves were estimated using the Kaplan-Meier method and median values were reported alongside their 95% confidence intervals. Differences between survival curves were assessed by the log-rank test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe clinical characteristics of the 39 patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (35\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePerformance Status ECOG (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (30.8)\u003c/p\u003e \u003cp\u003e20 (51.3)\u003c/p\u003e \u003cp\u003e7 (17.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHormonal Receptor status (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEstrogen\u003c/em\u003e Positive\u003c/p\u003e \u003cp\u003e\u003cem\u003eProgesterone\u003c/em\u003e Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (64.1)\u003c/p\u003e \u003cp\u003e21 (53.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHER2 Status (IHC) (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHER2 2\u0026thinsp;+\u0026thinsp;SISH/FISH^ Amplification\u003c/p\u003e \u003cp\u003eHER2 3+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003cp\u003e33 (84.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious Neo-adjuvant therapies (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTrastuzumab with or without Pertuzumab regimens\u003c/p\u003e \u003cp\u003eAnthracycline-taxanes regimens\u003c/p\u003e \u003cp\u003eAnthracycline-sparing regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (51.3)\u003c/p\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious adjuvant therapies (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTrastuzumab with or without Pertuzumab regimens\u003c/p\u003e \u003cp\u003eAnthracycline-taxanes regimens\u003c/p\u003e \u003cp\u003eNo anthracycline regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (61.5)\u003c/p\u003e \u003cp\u003e21 (53.8)\u003c/p\u003e \u003cp\u003e11 (28.2)\u003c/p\u003e \u003cp\u003e13 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious Hormonal adjuvant therapies (n.; %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian lines for metastatic disease (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious anti-HER2 lines for metastatic disease (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003cp\u003e15 (38.5)\u003c/p\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003cp\u003e8 (20.5)\u003c/p\u003e \u003cp\u003e4 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious anti-HER2 therapies for metastatic disease (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePertuzumab/trastuzumab/taxane\u003c/p\u003e \u003cp\u003eT-DM1\u003c/p\u003e \u003cp\u003eLapatinib/capecitabine\u003c/p\u003e \u003cp\u003eTucatinib/Lapatinib/capecitabine\u003c/p\u003e \u003cp\u003eTrastuzumab\u0026thinsp;+\u0026thinsp;chemotherapy:\u003c/p\u003e \u003cp\u003ePaclitaxel\u003c/p\u003e \u003cp\u003eVinorelbine\u003c/p\u003e \u003cp\u003eDocetaxel\u0026thinsp;+\u0026thinsp;vinorelbine\u003c/p\u003e \u003cp\u003eTrastuzumab\u0026thinsp;+\u0026thinsp;Hormonal therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (94.8)\u003c/p\u003e \u003cp\u003e33 (84.6)\u003c/p\u003e \u003cp\u003e21 (53.8)\u003c/p\u003e \u003cp\u003e12 (30.8)\u003c/p\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003cp\u003e9 (23.1)\u003c/p\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian Disease Free Interval from BMs (months, range)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSince initial diagnosis\u003c/p\u003e \u003cp\u003eSince metastatic diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (0-199)\u003c/p\u003e \u003cp\u003e14 (0\u0026ndash;96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN\u0026deg; of brain metastases (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003cp\u003e5 (12.8)\u003c/p\u003e \u003cp\u003e23 (59.0)\u003c/p\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN\u0026deg; of patients with neurological symptoms (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (46.1)\u003c/p\u003e \u003cp\u003e21 (53.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious BM local therapy (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNo therapy\u003c/p\u003e \u003cp\u003eSRS\u0026deg;\u003c/p\u003e \u003cp\u003eWBRT\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSurgery\u0026thinsp;+\u0026thinsp;SRS\u003c/p\u003e \u003cp\u003eSurgery\u0026thinsp;+\u0026thinsp;WBRT\u003c/p\u003e \u003cp\u003eWBRT\u0026thinsp;+\u0026thinsp;SRS\u0026thinsp;+\u0026thinsp;surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (12.8)\u003c/p\u003e \u003cp\u003e16 (41.0)\u003c/p\u003e \u003cp\u003e13 (33.3)\u003c/p\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtracranial metastatic sites (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e\u0026gt;=4\u003c/p\u003e \u003cp\u003emissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (17.9)\u003c/p\u003e \u003cp\u003e4 (10.3)\u003c/p\u003e \u003cp\u003e12 (30.8)\u003c/p\u003e \u003cp\u003e5 (12.8)\u003c/p\u003e \u003cp\u003e9 (23.1)\u003c/p\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDominant metastatic sites (n.; %)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eLiver\u003c/p\u003e \u003cp\u003eLung\u003c/p\u003e \u003cp\u003eBone\u003c/p\u003e \u003cp\u003eSoft tissues\u003c/p\u003e \u003cp\u003eOnly brain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (35.9)\u003c/p\u003e \u003cp\u003e7 (17.9)\u003c/p\u003e \u003cp\u003e7 (17.9)\u003c/p\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003cp\u003e9 (23.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian progression Free Survival of previous I line\u003c/b\u003e \u003cem\u003e(months and range)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4\u0026ndash;96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian progression Free Survival of previous II lines\u003c/b\u003e \u003cem\u003e(months and range)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (2\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime from the end of local brain treatments to T-Dxd\u003c/b\u003e (\u003cem\u003emedian, range\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (0\u0026ndash;27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-Dxd line\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e\u0026gt;=5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003cp\u003e12 (30.8)\u003c/p\u003e \u003cp\u003e8 (20.5)\u003c/p\u003e \u003cp\u003e8 (20.5)\u003c/p\u003e \u003cp\u003e9 (23.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* IHC : Immunoistochemistry; ^ SISH/FISH: Silver in situ hybridization/Fluorescent in situ hybridization;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026deg;SRS: Stereotactic Radiosurgery; \u003csup\u003e\u0026sect;\u003c/sup\u003eWBRT: Whole Brain Radiotherapy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMedian age was 55 years (35\u0026ndash;72). Thirty-six (92.3%) patients had estrogen and/or progesterone receptor positive tumors, with 23 (59.0%) previously treated with anti-hormonal treatment in adjuvant setting.\u003c/p\u003e \u003cp\u003eIn the curative setting, 10 (25.6%) patients received both trastuzumab +/- pertuzumab and anthracycline +/- taxanes based regimens as a neoadjuvant treatment, while 24 (61.5%) patients received adjuvant therapy: 21 (53.8%) trastuzumab +/- pertuzumab of which 11 (28.2%) combined to anthracycline and taxanes based-regimens and 13 (33.3%) combined to anthracycline-sparing therapy.\u003c/p\u003e \u003cp\u003eIn the advanced setting, 37 (94.8%) patients received previous anti-HER2 treatments: 33 (84.6%) trastuzumab\u0026thinsp;+\u0026thinsp;pertuzumab and taxane (docetaxel/paclitaxel), 21 (53.8%) T-DM1, 12 (30.8%) Lapatinib plus capecitabine, and 9 (23.1%) trastuzumab plus chemotherapy regimens. Only 1 (2.6%) patient received trastuzumab plus anti-hormonal therapy.\u003c/p\u003e \u003cp\u003eBefore administering T-Dxd, median PFS (mPFS) of first line treatments was 10 months (4\u0026ndash;96), while mPFS of second line treatments was 8 months (2\u0026ndash;29).\u003c/p\u003e \u003cp\u003eMedian previous treatment lines for HER2\u0026thinsp;+\u0026thinsp;metastatic disease was 2 (0\u0026ndash;5); T-Dxd was administered as a first line treatment for advanced disease in 2 patients (5.1%), as a second line in 15 patients (38.5%), as a third, fourth, fifth or later line in 10 patients (25.6%), 8 patients (20.5%) and 4 patients (10.3%), respectively.\u003c/p\u003e \u003cp\u003eSix (15.4%) out of 36 patients had only one BM, 2 (5.1%) and 5 (12.8%) patients had two and three BMs, respectively, while most patients (23, 59.0%) had four or more brain lesions. The exact number of BMs was not reported for three (7.7%) patients. Eighteen (46.1%) patients reported neurological symptoms while starting T-Dxd.\u003c/p\u003e \u003cp\u003eThirty-four (87.2%) patients received one or more local approach for intracranial control of brain lesions, with most of them receiving Stereotactic Radiosurgery [SRS (16 (41%) and WBRT (15, 38.4%)]. Five (12,8%) had no previous locoregional treatment.\u003c/p\u003e \u003cp\u003eThe median time from the end of local brain treatments to the first administration of T-DxD was 7 months (range 0\u0026ndash;27).Seven (17.9%)patients had no evidence of extracranial involvement, whilst 4 (10.3%), 12 (30.8%), 5 (12.8%), and 9 (23.0%) patients had one, two, three, and four or more extracranial metastatic sites, respectively. Data were missing for two patients (5.1%).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIntracranial efficacy\u003c/h2\u003e \u003cp\u003eRegarding the single outcomes, one patient (2.6%) achieved a complete response (CR), twenty-two (56.4%) a partial response (PR, for an overall response rate of 59.0%), fourteen patients (35.9%) had a stable disease (SD), while two showed (5.1%) an intracranial progressive disease (PD) (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ea. Intracranial Efficacy of T-Dxd\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003emPFS (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003cp\u003e(95% CI: 10.5\u0026ndash;20.8)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Control Rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94.9\u003c/p\u003e \u003cp\u003e(87.9\u0026ndash;100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of Response (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.9\u003c/p\u003e \u003cp\u003e(10.1\u0026ndash;13.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical Benefit (%)\u003c/p\u003e \u003cp\u003e6 months\u003c/p\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (69.2)\u003c/p\u003e \u003cp\u003e23 (59.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall Survival at 12 months (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eb. Intracranial and Global best responses with T-DxD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eResponse to T-Dxd\u003c/b\u003e\u003c/p\u003e \u003cp\u003eComplete Response\u003c/p\u003e \u003cp\u003ePartial Response\u003c/p\u003e \u003cp\u003e\u003cem\u003eOverall Response rate\u003c/em\u003e\u003c/p\u003e \u003cp\u003eStable Disease\u003c/p\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIntracranial Best Response n. (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003cp\u003e22 (56.4)\u003c/p\u003e \u003cp\u003e23 (59)\u003c/p\u003e \u003cp\u003e14 (35.9)\u003c/p\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eGlobal Best Response n. (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e27 (69.2)\u003c/p\u003e \u003cp\u003e27 (69.2)\u003c/p\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen considering the treatment line, there were one PR and one SD in first line, eleven PR and one SD in second line, one CR, five PR, and two SD in third line, three PR, four SD, and one PD in fourth line, two PR, six SD, and one PD in fifth or later lines (Table \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003ea).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Efficacy of T-DxD based on treatment line\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ea. Intracranial Efficacy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLine of treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eComplete Response\u003c/p\u003e \u003cp\u003ePartial Response\u003c/p\u003e \u003cp\u003eStable Disease\u003c/p\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003cp\u003eMedian icPFS (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI line (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII line (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e11\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e14.2 (NE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII line (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e15.5 (10.1\u0026ndash;21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV line (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e11.1 (6.8\u0026ndash;15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;IV line (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e16.5 (NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003e\u0026deg; icPFS: intracranial progression free survival; NE: not evaluable\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eb. Global Efficacy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLine of Treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eComplete Response\u003c/p\u003e \u003cp\u003ePartial Response\u003c/p\u003e \u003cp\u003eStable Disease\u003c/p\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003cp\u003eMedian PFS (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eI line (n\u0026thinsp;=\u0026thinsp;2)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eII line (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e14.1 (6.8\u0026ndash;21.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eIII line (n\u0026thinsp;=\u0026thinsp;8)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e15.5 (8.5\u0026ndash;22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eIV line (n\u0026thinsp;=\u0026thinsp;8)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e11.1 (6.9\u0026ndash;15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;IV line (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e7.9 (5.8\u0026ndash;10.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003ePFS: progression free survival; NE: not evaluable\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt a median follow up of 12 months intracranial mPFS was 15.6 months (10.5\u0026ndash;20.8).\u003c/p\u003e \u003cp\u003eWhen dividing patients according to the intracranial responses (CR/PR vs SD/PD), a statistically significant difference in mPFS [15.8 (14.1\u0026ndash;17.5) vs 11.2 (3.2\u0026ndash;19.2), p\u0026thinsp;=\u0026thinsp;0.01)] was found (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNo difference (p\u0026thinsp;=\u0026thinsp;0.75) were observed in mPFS between patients that did [15.6 (10.8\u0026ndash;20.4)] or did not 5.8 (n.e.)] receive a local approach.\u003c/p\u003e \u003cp\u003eiDCR was 94.9% (87.9\u0026ndash;100.0), iDoR was 11.9 months (10.1\u0026ndash;13.7), and iCBr at 6 and 12 months were 69.2% and 59%, respectively.\u003c/p\u003e \u003cp\u003eOS was not reached, with an overall rate of 77.9% of patients alive at 12 months.\u003c/p\u003e \u003cp\u003eData regarding intracranial activity are summarized in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGlobal (intra\u0026thinsp;+\u0026thinsp;extracranial) activity\u003c/h2\u003e \u003cp\u003eFor global disease activity, no CR was observed, while twenty-seven (69.2%) PR, ten (25.6%) SD, and two (5.1%) PD were documented.\u003c/p\u003e \u003cp\u003eResults of best intra and global responses are summarized in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb. Data between the two groups were substantially balanced in terms of responses.\u003c/p\u003e \u003cp\u003eWhen considering the global activity, there were two PR in first line, ten PR and two SD in second line, seven PR and one SD in third line, four PR, three SD, and one PD in fourth line, four PR, four SD, and one PD in fifth or later lines.\u003c/p\u003e \u003cp\u003eIntra- and global activity of T-Dxd according to treatment line is available at Table \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eConsidering all treatment lines together, global mPFS was 11.8 months (8.5\u0026ndash;15.0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eMedian treatment duration with T-Dxd was 9.5 months (range: 1.5\u0026ndash;16.5).\u003c/p\u003e \u003cp\u003e32 patients (82%) experienced an any grade toxicity from treatment with T-Dxd.\u003c/p\u003e \u003cp\u003eThe main grade 1/2 hematological toxicities were neutropenia (35.9%) and anemia (23.1%). Grade 1/2 non-hematological adverse events (AEs) that occurred in more than 10% of the patients were alopecia (59%), fatigue (53.8%), nausea (46.1%), constipation (30.7%), diarrhea (28.2%), and vomiting (10.2%).\u003c/p\u003e \u003cp\u003eGrade 3/4 hematological toxicities consisted of neutropenia (15.3%), anemia (5.1%) and piastrinopenia (2.5%). Grade 3/4 non-hematological AEs were fatigue (18%), diarrhea (10.2%), nausea (7.7%), mucositis (5.1%), vomiting (2.5%), pneumonitis (2.5%), and increase in liver transaminase (2.5%).\u003c/p\u003e \u003cp\u003eWith regard to AEs of special interest, grade 1 drop of LVEF was observed in one patient (2.5%).\u003c/p\u003e \u003cp\u003eToxicities are available in the supplementary material (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e suppl.).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eT-Dxd has revolutionized the treatment algorithm of HER2-positive advanced BC, and there are growing evidences that support its use even in patients with intracranial disease. To date, there was no evidence of outcome in HER2 positive advanced BC patients with BMs in a real world population. A recent retrospective exploratory pooled analysis of DESTINY BREAST 01, 02, and 03 trials [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] showed superior rates in terms of IC response over comparator in patients with treated/stable and untreated/active BMs, with a particularly favourable trend in iDoR and imPFS for the latter ones. This data strengthen our beliefs that T-Dxd will become a mainstay in our clinical practice even in these crucial subset of patients.\u003c/p\u003e \u003cp\u003eIt is important to note that in the DESTINY BREAST 02 and 03 trials patients with previously untreated and asymptomatic BM were eligible but, after protocol amendments, only patients with treated, asymptomatic BMs were allowed. Therefore, the population of patients with baseline BMs consists of a mix of treated/stable and untreated/active metastases.\u003c/p\u003e \u003cp\u003eThis pooled analysis showed that patients in both groups achieved an overall response rate of 45.2% and 45.5% for treated/stable and untreated/active BMs cohorts, respectively. Intracranial CR rates were 16.3% and 15.9%, while iPR rates were 28.8% and 29.5%, respectively.\u003c/p\u003e \u003cp\u003eIn our study, we registered significantly lower rates of intracranial CR (2.6%) and higher rates of PR (56.4%). Data for SD were substantially in line with Hurvitz et al. results (30.7% in our study, 46.2% and 34.1% in the pooled analysis). This is probably related to the real-world context, with a less selected population that has an intrinsically lower survival.\u003c/p\u003e \u003cp\u003eRates of ORR, iDCR, iDoR, and iCBr at 6 and 12 months witnessed a high intracranial activity of T-Dxd, with mPFS of over 15 months. It is important to note that this was independent from treatment line, and sustained responses documented that the drug was globally safe in terms of timing and dosing.\u003c/p\u003e \u003cp\u003eIn Table \u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e4\u003c/span\u003ea cautios comparison between real life and trial disease outcomes is listed. We did not provide a difference between treated/stable and non-treated/unstable BMs lesions, as in the first group we had only 5 patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison between intracranial outcomes in DE-REAL and DB 01-02-03 pooled analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient number (n.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDE -REAL real life (39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDB pooled analysis, treated/stable BMs (104)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDB pooled analysis, non-treated/unstable BMs (44)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (45.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (15.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (56.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (28.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (29.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (34.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of response (months), median (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.9 (10.1\u0026ndash;13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.3 (9.7\u0026ndash;17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.5 (13.6\u0026ndash;31.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFS (months), median (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6 (10.5\u0026ndash;20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.3 (11.1\u0026ndash;13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.5 (13.6\u0026ndash;23.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease control rate (%,95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94.9 (87.9\u0026ndash;100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91.3 (NA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79.6 (NA)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical benefit (%)\u003c/p\u003e \u003cp\u003e6 months\u003c/p\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (69.2)\u003c/p\u003e \u003cp\u003e23 (59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall Survival at 12 months (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMs: Brain Metastases; DB: Destiny Breast; NA: Not available; ORR: Overall Response Rate; PFS: Progression-free survival\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen comparing intracranial responders (CR/PR) to non-responders (SD/PD), a clear improvement in mPFS [15.8 (14.1\u0026ndash;17.5) vs 11.2 (3.2\u0026ndash;19.2), p\u0026thinsp;=\u0026thinsp;0.01), Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e] was achieved. This witnesses and supports the strong prognostic value of intracranial response, regardless of treatment line. It is clear that, with only 2 patients that experienced intracranial PD, no correct comparison can be made with all other patients that had at least a SD.\u003c/p\u003e \u003cp\u003eInterestingly, no difference in mPFS was found for patients that did or did not receive a local approach for BMs (15.8 vs 15.6 months p\u0026thinsp;=\u0026thinsp;0.45). This probably reflects the fact that there are resistance mechanisms related to pharmacological pressure, with intratumoral heterogeneity and number of previous anti-HER2 lines received that certainly play a role, along with the efficacy of T-Dxd in this district.\u003c/p\u003e \u003cp\u003eOur findings seem to endorse the concept that we are moving to a \u0026ldquo;paradigm shift\u0026rdquo;, in which a RT deferral may be a valid option for certain patients with BMs who are eligible for a systemic therapy with a strong intracranial activity [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. We obviously must consider that only 5 patients did not receive a local approach for BMs in our study, therefore these data needs careful and proper evaluation. In the TUXEDO and DEBBRAH trials there were no comparison between patient that did or did not receive a local treatment in terms of survival, therefore we do not have reliable data.\u003c/p\u003e \u003cp\u003eToxicities were substantially in line with what previously reported with the use of T-Dxd in various settings. After growing experience with the drug, it is clear that there is an improvement in the support care management for signs and symptoms related to T-Dxd, in particular nausea/vomiting and neutropenia. Also the incidence of lung infections were poorly detected (moderate/severe grade: 2.5%), even in this at-risk population (disease spreading, both systemic and locoregional previous treatments). It is important to highlight that median treatment duration was 9.5 months, that is substantially in line with what previously reported for heavily pretreated patients in the DESTINY BREAST-04 trial (8.2 months) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis real world analysis have its limitations. First of all, real world data were retrospectively collected from clinical databases that were originally not designed to collect data for research. The retrospective design presents threats to both internal and external validity. Moreover, due to its nature there was no Blinded Independent Central Review (BICR) to determine disease progression.\u003c/p\u003e \u003cp\u003eHowever, there are several strenghts. To our knowledge, this is the first real world analysis that investigates intracranial outcomes with the use of T-Dxd, with a larger sample size of patients than the already cited DEBBRAH and TUXEDO trials. Moreover, patients were properly evaluated with brain MRI to perform a correct evaluation of the intracranial compartment, and this should be emphasized as in routinary clinical practice the whole body TC scan is the mainstay for practical reasons and MRI is often used solely to deepen the TC results. Furthermore, as for some real life evidences, more outcomes measures are investigated, such as the duration of response, the disease control rate and the clinical benefit other than progression free survival.\u003c/p\u003e \u003cp\u003eIn conclusion, due to the intrinsic therapeutic power of this drug, we are witnessing an intracranial benefit from a systemic therapy; this is important as it not only delays loco-regional treatment in some cases, but also improves quality of life in patients with intracranial responses.\u003c/p\u003e \u003cp\u003eThe oncological community is waiting for the results of T-DXd in the early setting [Destiny BREAST-011 (NCT 202100060321), and SHAMROCK (NCT05710666) trials in neoadjuvant setting; Destiny BREAST-05 (NCT04622319) trial in adjuvant setting] that will also provide information on the potential ability of the drug to prevent or delay CNS spreading in HER2 positive BC.\u003c/p\u003e \u003cp\u003eIn the context of a real-world study, our data supports the use of T-Dxd for both patients with treated/stable and untreated/active BMs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTION:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConceptualization, Methodology, Investigation, Writing, review, and editing. Visualization: A.F., A.R., S.P.,A.B. Investigation: A.F.,A.R, R.C., S.P., F.P., G.D., P.F, A.F.,C.V.,M.P.,L.C.,G.F.,E.DM., I.P., F.P.,O.G.,D.G.,M.DL., G.F., G.S., A.B. Manuscript Editing: All ; Approval to submission: All\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Mrs Elisabetta Bozzoli for the data management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST :\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Authors declare no conflict of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, AR, upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGarcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain metastases in HER2-positive breast cancer: current and novel treatment strategies. Cancers. 2021;13(12):2927.\u003c/li\u003e\n\u003cli\u003eVenur VA, Leone JP. Targeted therapies for brain metastases from breast cancer. Int J Mol Sci 2016;17:1543.\u003c/li\u003e\n\u003cli\u003eHurvitz SA, O\u0026rsquo;Shaughnessy J, Mason G, et al. Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs. Clin Cancer Res 2019;25:2433\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eSteeg PS. The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol. 2021 Nov;18(11):696-714. doi: 10.1038/s41571-021-00529-6. Epub 2021 Jul 12. PMID: 34253912.\u003c/li\u003e\n\u003cli\u003eSoffietti, R. et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro. Oncol. 19, 162\u0026ndash;174 (2017).\u003c/li\u003e\n\u003cli\u003eBartsch, R. et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin. Exp. Metastasis 32, 729\u0026ndash;737 (2015).\u003c/li\u003e\n\u003cli\u003eJacot, W. et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res. Treat. 157, 307\u0026ndash;318 (2016).\u003c/li\u003e\n\u003cli\u003eFabi A, Alesini D, Valle E, et al. T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. Breast. 2018 Oct;41:137-143. doi: 10.1016/j.breast.2018.07.004. Epub 2018 Jul 12. PMID: 30092500.\u003c/li\u003e\n\u003cli\u003eModi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610\u0026ndash;621 (2020).\u003c/li\u003e\n\u003cli\u003eCort\u0026eacute;s, J. et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N. Engl. J. Med. 386, 1143\u0026ndash;1154 (2022).\u003c/li\u003e\n\u003cli\u003eLin NU, Gaspar LE, Soffietti R. Breast cancer in the central nervous system: multidisciplinary considerations and management. Am Soc Clin Oncol Educ Book. 2017;37:45\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003ePatel RR, Verma V, Miller AB, et al. Exclusion of patients with brain metastases from cancer clinical trials. Neuro Oncol. 2020;22(4):577\u0026ndash;579.\u003c/li\u003e\n\u003cli\u003eMurthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597\u0026ndash;609.\u003c/li\u003e\n\u003cli\u003eStavrou E, Winer EP, Lin NU. How we treat HER2-positive brain metastases. ESMO Open. 2021;6(5):100256.\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Garc\u0026iacute;a JM, Batista MV, Cortez P, et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial. Neuro. Oncol. noac144 (2022).\u003c/li\u003e\n\u003cli\u003eBartsch 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 Sep;28(9):1840-1847. doi: 10.1038/s41591-022-01935-8. Epub 2022 Aug 8. PMID: 35941372; PMCID: PMC9499862.\u003c/li\u003e\n\u003cli\u003eBotticelli A, Caputo R, Scagnoli S, et al18. Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. Oncologist. 2023 Nov 23:oyad308. doi: 10.1093/oncolo/oyad308. Epub ahead of print. PMID: 37995313.\u003c/li\u003e\n\u003cli\u003eU.S. Department of Health and Human Services \u0026ndash; Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Brain Metastases. 2020.\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. PMID: 19097774.\u003c/li\u003e\n\u003cli\u003eSchwartz LH, Liti\u0026egrave;re S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016 Jul;62:132-7. doi: 10.1016/j.ejca.2016.03.081. Epub 2016 May 14. PMID: 27189322; PMCID: PMC5737828.\u003c/li\u003e\n\u003cli\u003eNational Institute of Health. National Cancer Institute Common Terminology Criteria for Adverse Events ( CTCAE ) version 5.0. \u003cem\u003eNIH Publication\u003c/em\u003e (2017).\u003c/li\u003e\n\u003cli\u003eS.A. Hurvitz, S. Modi, W. Li , et al. A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINYBreast (DB) -01, -02, and -03. Ann. Onc. Abstract 377O| volume 34, supplement 2, s335-s336, october 2023. doi: https://doi.org/10.1016/j.annonc.2023.09.554.\u003c/li\u003e\n\u003cli\u003eIppolito E, Silipigni S, Matteucci P, et al. Radiotherapy for HER 2 Positive Brain Metastases: Urgent Need for a Paradigm Shift. Cancers (Basel). 2022 Mar 15;14(6):1514. doi: 10.3390/cancers14061514. PMID: 35326665; PMCID: PMC8946529.\u003c/li\u003e\n\u003cli\u003eModi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4348533/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4348533/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction. \u003c/strong\u003eTumor dissemination to the central nervous system (CNS) is almost a rule in the treatment journey of advanced HER2+ breast cancer (BC). Recent results from the DEBBRAH and TUXEDO trials demonstrated high intracranial efficacy with Trastuzumab Deruxtecan (T-Dxd), confirmed by a pooled analysis of DESTINY-BREAST 01, 02, and 03 trials. However, a real world evidence is lacking in literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eWe conducted a multicenter, observational, and retrospective real-world analysis on cases collected at 12 Italian Oncological Units. Patients with brain metastases (BMs) from HER2+ BC treated with T-Dxd in various treatment lines were enrolled. Data were extrapolated from the original DE-REAL study database. Primary endpoint was the intracranial overall response rate (iORR). The main secondary endpoints were intra- and global progression free survival (iPFS - gPFS); Other secondary objectives were the intracranial disease control rate (iDCR), intracranial duration of response (iDoR), the intracranial clinical benefit rate at 6 and 12 months (iCBr), the overall survival, and the safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003e39 patients were included in the final analysis. iORR was 59% (23), iPFS was 15.6 months (95% CI: 10.5-20.8), gPFS was 11.8 months (95% CI: 8.5-15.0). i DCR 94.9% (87.9-100.0), iDoR was 11.9 months (10.1-13.7), and iCBr at 6 and 12 months were 69.2% and 59%, respectively. OS was not reached, with an overall rate of 77.9% of patients alive at 12 months. No new safety concerns were reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions. \u003c/strong\u003eThis study confirmed the high intracranial efficacy and manageable safety profile of T-Dxd in this first-ever real world analysis.\u003c/p\u003e","manuscriptTitle":"Trastuzumab Deruxtecan in brain metastases from breast cancer: outcome analysis of real life population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-11 20:11:32","doi":"10.21203/rs.3.rs-4348533/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-06-13T23:09:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-13T18:38:19+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-06T13:08:59+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-03T16:26:30+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-03T15:36:14+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-01T23:14:43+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-26T13:22:11+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-26T10:22:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-14T02:26:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-03T11:10:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Precision Oncology","date":"2024-04-30T10:59:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"add4d6f6-fd2f-4152-b32f-dbf6aee58e24","owner":[],"postedDate":"June 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":32411061,"name":"Health sciences/Oncology/Cancer/Breast cancer"},{"id":32411062,"name":"Biological sciences/Cancer/Cancer therapy/Targeted therapies"},{"id":32411063,"name":"Health sciences/Medical research/Outcomes research"}],"tags":[],"updatedAt":"2024-11-05T09:40:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-11 20:11:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4348533","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4348533","identity":"rs-4348533","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}