Trastuzumab deruxtecan 100mg powder for solution for infusion vials

PURPOSE Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2–mutant ( HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non–small-cell lung cancer (mNSCLC). METHODS DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review. RESULTS One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively. CONCLUSION T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

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Abstract Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2 + ) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 + gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 ( ERBB2 ) plasma gene amplification. Other key driver gene amplifications, specifically MET , EGFR and FGFR2 , in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

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Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.

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PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

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The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).

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BACKGROUND: Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab + pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) versus dose-dense doxorubicin + cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3) HER2-positive disease. PATIENTS AND METHODS: This open-label, phase III trial (147 sites, 18 countries) randomised adults 1 : 1 : 1 to T-DXd (×8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles). T-DXd-alone arm enrolment closed early following the Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set). RESULTS: Between 25 October 2021 and 12 March 2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n = 123), 67.3% (T-DXd-THP, n = 216), and 56.3% (ddAC-THP, n = 180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% [95% confidence interval (CI), 4.0% to 18.3%, P = 0.003], with benefit in hormone receptor (HR)-positive [61.4% (n/N = 145/236) versus 52.3% (n/N = 123/235); difference in pCR (ΔpCR) 9.1% (95% CI 0.2% to 17.9%)] and HR-negative [83.1% (n/N = 69/83) versus 67.1% (n/N = 57/85); ΔpCR 16.1% (95% CI 3.0% to 28.8%)] subgroups. Median EFS (T-DXd-THP versus ddAC-THP, maturity 4.5%) hazard ratio was 0.56 (95% CI 0.26 to 1.17). Grade ≥3 adverse events (AE; T-DXd, 22.6% (n = 64); T-DXd-THP, 37.5% (n = 120); ddAC-THP, 55.8% (n = 174)], serious AE [T-DXd, 10.2% (n = 29); T-DXd-THP, 10.6% (n = 34); ddAC-THP, 20.2% (n = 63)], and all-grade left-ventricular dysfunction [T-DXd, 0.7% (n = 2); T-DXd-THP, 1.3% (n = 4); ddAC-THP, 6.1% (n = 19)] rates were lower for T-DXd and T-DXd-THP than ddAC-THP. All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms [T-DXd, 4.9% (n = 14); T-DXd-THP, 4.4% (n = 14); ddAC-THP, 5.1% (n = 16)]. Three treatment-related deaths occurred [T-DXd-THP, 0.3% (n = 1); ddAC-THP, 0.6% (n = 2)]. CONCLUSIONS: Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.

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Abstract Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs ( n = 263) and no BMs ( n = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

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