datopotamab deruxtecan (DS-1062a) / Daiichi Sankyo, AstraZeneca - LARVOL DELTA

Emerging Therapies for Brain Metastases in NSCLC, Breast Cancer, and Melanoma: A Critical Review. (PubMed, Curr Neurol Neurosci Rep) - "In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases...Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized,..."

IO biomarker • Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ALK • BRAF • EGFR • HER-2

Antibodies to watch in 2025. (PubMed, MAbs) - "In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (®), and antibody-drug conjugate (ADC) sacituzumab tirumotecan (®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key..."

Journal • Review • Oncology

Efficacy and safety of antibody-drug conjugates in pretreated HER2-low metastatic breast cancer: A systematic review and network meta-analysis. (PubMed, Cancer Treat Rev) - "Similar efficacy with T-DXd and SG in HER2-low MBC was observed, regardless of HR status. Safety profile, local drug-approval criteria and guidelines, patients' preferences and overall quality of evidence should ultimately guide therapeutic decision-making. Dato-DXd role remains uncertain."

Journal • Metastases • Retrospective data • Review • Alopecia • Breast Cancer • Cardiovascular • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immunology • Neutropenia • Oncology • Pneumonia • Solid Tumor • Thrombocytopenia • Triple Negative Breast Cancer • HER-2

Datopotamab Deruxtecan Application in the EU for Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer Voluntarily Withdrawn (Businesswire) - "Daiichi Sankyo...and AstraZeneca...have voluntarily withdrawn the marketing authorization application (MAA) in the EU for datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) based on the TROPION-Lung01 phase 3 trial. The decision to withdraw the MAA was informed by feedback from the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA). Daiichi Sankyo and AstraZeneca will continue to work to bring datopotamab deruxtecan to patients with lung cancer in the EU who can benefit and are committed to unlocking the potential of this medicine in lung cancer through our robust clinical development program which includes seven pivotal trials in various lung cancer settings."

CHMP • European regulatory • Non Small Cell Lung Cancer

AVANZAR: Phase III, Open-label, First-line Study of Dato-DXd in Combination With Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations (clinicaltrials.gov) - P3 | N=1350 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2027 ➔ Nov 2027 | Trial primary completion date: Feb 2027 ➔ Nov 2027

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • ROS1 • TACSTD2

Datopotamab deruxtecan: “Pooled Analysis of TROPION-Lung01 and TROPION-Lung05”; Non-small cell lung cancer (Daiichi Sankyo) - Science & Technology Day 2024: “ORR: 42.7% (95% CI: 33.6–52.2); median DOR: 7.0 mo (range: 4.2–9.8); median PFS: 5.8 mo; median OS: 15.6 mo”

Clinical data • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Quantum Leap Healthcare Collaborative Announces Completion of Datopotamab Deruxtecan and Datopotamab Deruxtecan + Durvalumab Arms in the I-SPY2 Trial for Stage 2/3 Neoadjuvant Breast Cancer (GlobeNewswire) - "Quantum Leap Healthcare Collaborative...announces the completion of enrollment for two arms of the I-SPY 2 Trial. The goal was to evaluate the safety and efficacy of datopotamab deruxtecan as single agent therapy or in combination durvalumab."

Enrollment status • Breast Cancer

Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S. for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer (Daiichi Sankyo Press Release) - "Datopotamab deruxtecan (Dato-DXd) has been granted Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFR-mutated) non-small cell lung cancer (NSCLC) with disease progression on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy....The FDA granted this BTD based on data from the TROPION-Lung05 phase 2 trial with supporting data from the TROPION-Lung01 phase 3 trial."

Breakthrough therapy • Evidence highlight • Non Small Cell Lung Cancer • EGFR

NSCLC Care: Predicting Response to Dato-DXd with a TROP2 Biomarker (YouTube) - "Datopotamab deruxtecan (Dato-DXd) is a second-line antibody drug conjugate that could lead to improved progression-free survival in patients with advanced or metastatic non-small cell lung cancer. Given these potential benefits, it's important to identify biomarkers that may predict a patient's response to Dato-DXd, which was the focus of recent research presented at the 2024 World Conference on Lung Cancer. Here with...to discuss a new biomarker for TROP2 is Dr. Marina Garassino..."

Biomarker • Video

Valemetostat and Trastuzumab Deruxtecan in Patients With HER2-Low, Previously Treated, Unresectable or Metastatic Breast Cancer (SABCS 2024) - P1 | "Preclinical data suggest synergistic effects of valemetostat in combination with T-DXd and datopotamab deruxtecan. The relationship between HER2 expression and clinical response will also be explored. If you have a patient who could potentially be eligible for this trial, please contact Daiichi Sankyo for clinical trial information at DS3201-324SiteCommunications@dsi.com."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • EZH2 • HER-2 • SLFN11

COMPASS-TNBC - A phase Ib/II, open-label, modular, dose-finding and dose-expansion study to explore safety and anti-tumor activity of novel therapeutics in patients with early relapsed mTNBC. Module 1: Dato-DXd & Module 2: Dato-DXd + durvalumab. (SABCS 2024) - "In modules 1 and 2, saliva and mouth swab will also longitudinally collected to determine predictors of oral mucositis in patients treated with Dato-DXd. Study enrollment started in June 2024 and is currently ongoing."

Clinical • IO biomarker • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Triple Negative Breast Cancer • CTCs • HER-2

Indirect comparison of sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) in advanced breast cancer (aBC): safety and efficacy analysis. (SABCS 2024) - "Both target humanized anti-trophoblast cell-surface antigen 2 (TROP2) and both have a similar (irinotecan-based) payload. Both Dato-DXd and SG have similar risk of discontinuation without progression and toxic death. The side effect profile of SG is driven by hematological toxicities. AEs such as ILD, ocular and infusion reactions appear unique to Dato-DXd."

Clinical • Metastases • Breast Cancer • Oncology • Solid Tumor

Datopotamab Deruxtecan Demonstrated Meaningful Clinical Activity in Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer in TROPION-Lung05 and TROPION-Lung01 Pooled Analysis (Daiichi Sankyo Press Release) - "These data, along with progression-free and overall survival results from the analysis, were presented during a late-breaking proffered paper session (LBA7) at the 2024 ESMO Asia (#ESMOAsia24) Congress....Datopotamab deruxtecan demonstrated a confirmed objective response rate (ORR) of 42.7% (95% confidence interval [CI]: 33.6-52.2) in a pooled analysis of 117 patients with EGFR-mutated NSCLC from the TROPION-Lung05 (n=78) and TROPION-Lung01 (n=39) trials, as assessed by blinded independent central review (BICR). Five (4.3%) complete responses (CRs), 45 (38.5%) partial responses (PRs) and 48 (41.0%) cases of stable disease (SD) were observed. The median duration of response (DOR) was 7.0 months (95% CI: 4.2-9.8) and the disease control rate (DCR) was 86.3% (95% CI: 78.7-92.0). Median progression-free survival (PFS) was 5.8 months (95% CI: 5.4-8.2) and median overall survival (OS) was 15.6 months (95% CI: 13.1-19.0)."

Late-breaking abstract • Retrospective data • Non Small Cell Lung Cancer

Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): A pooled analysis of TROPION-Lung01 and TROPION-Lung05 (ESMO Asia 2024) - P2, P3 | "Conclusions Dato-DXd elicited encouraging efficacy and manageable safety in previously treated pts with EGFR m NSCLC. These findings suggest a potential clinical role for Dato-DXd in this population with high unmet need."

Late-breaking abstract • Metastases • Retrospective data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in patients (pts) with pre-treated inoperable/metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Results from TROPION-Breast01 China cohort (ESMO Asia 2024) - P3 | "Methods Adult pts with inoperable/metastatic HR+/HER2– BC who had experienced progression on endocrine therapy (ET) and for whom ET was unsuitable and who had received 1‒2 prior lines of systemic CT were randomised 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (capecitabine/eribulin/gemcitabine/vinorelbine) until progression or unacceptable toxicity. Most common TRAEs were nausea (47.7%) with Dato-DXd and anaemia (52.8%) with ICC. Conclusions In this China cohort, Dato-DXd showed improved efficacy with a manageable safety profile compared with ICC, consistent with results in the overall global population Table: 38MO Incidence of AEs, n (%) Dato-DXd (N=44) ICC (N=36) TRAEs Any grade 43 (97.7) 30 (83.3) Grade ≥3 12 (27.3) 20 (55.6) Serious 2 (4.5) 5 (13.9) Any AE leading to discontinuation of treatment 1 (2.3) 0 Any AE leading to dose reduction 6 (13.6) 8 (22.2) Any AE leading to dose interruption 13 (29.5) 11 (30.6) Any AE leading to death 0 0 Any adjudicated drug-related..."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

First-in-human Study of DS-1062a for Advanced Solid Tumors (TROPION-PanTumor01) (clinicaltrials.gov) - P1 | N=890 | Active, not recruiting | Sponsor: Daiichi Sankyo Co., Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Pan tumor • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • CD4 • ER • ERBB3 • HER-2 • PGR • TACSTD2

Innovation in Lung, Breast, Gastric and Biliary Tract Cancer at ESMO Asia (Businesswire) - "Two mini oral presentations will feature results of the TROPION-Breast01 phase 3 trial of datopotamab deruxtecan in Chinese patients with previously treated metastatic HR positive, HER2 low or negative breast cancer and the final results of the DESTINY-Gastric06 phase 2 trial of ENHERTU in Chinese patients with previously treated HER2 positive advanced gastric or gastroesophageal junction (GEJ)...Trials-in-progress posters also will feature the trial designs of three ongoing ENHERTU clinical trials, including the DESTINY-BTC01 phase 3 trial that will evaluate ENHERTU...with previously untreated HER2 expressing, locally advanced or metastatic biliary tract cancer, and the DESTINY-Gastric03 phase 1b/2 trial where a new arm has been added to evaluate ENHERTU in combination with rilvegostomig and chemotherapy in patients with HER2 positive or HER2 low gastric or GEJ adenocarcinoma....A second part of the DESTINY-PanTumor02 phase 2 trial of ENHERTU also will be presented..."

Clinical data • Clinical protocol • Biliary Tract Cancer • Breast Cancer • Cervical Cancer • Endometrial Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

Daiichi Sankyo Highlights Progress Across Oncology Portfolio in Multiple Solid and Blood Cancers at ESMO Asia, SABCS and ASH (Businesswire) - "Data at ESMO Asia, SABCS and ASH will showcase Daiichi Sankyo’s progress towards its goal of creating new standards of care for patients with cancer. Highlights include three late-breaking presentations, including a pooled analysis of data from the TROPION-Lung05 phase 2 and TROPION-Lung01 phase 3 trials of datopotamab deruxtecan (Dato-DXd) in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) at ESMO Asia, as well as a subgroup analysis from the DESTINY-Breast06 phase 3 trial of ENHERTU (trastuzumab deruxtecan) in patients with unresectable or metastatic HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer and the primary analysis from the VALENTINE phase 2 trial of patritumab deruxtecan (HER3-DXd) in patients with early HR positive, HER2 negative breast cancer at SABCS."

Clinical data • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Economic Burden of Grade 3+ Adverse Event Management Associated With Dato-DXd and Docetaxel-Containing Regimens in Previously Treated Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: A European and USA Analysis (ISPOR-EU 2024) - " Incidences of TEAEs were extracted from TROPION-Lung01 data, and publications of LUME-Lung01 (nintedanib plus docetaxel [NIN+Doce]) and REVEL (ramucirumab plus docetaxel [RAM+Doce]), restricting to TEAEs occurring as any-grade in ≥10% of patients in any treatment arm. In previously treated nonsquamous NSCLC, Grade 3+ TEAEs of docetaxel-containing regimens incur significant inpatient costs to healthcare systems across Europe and the USA. In addition to the clinically meaningful benefit observed for Dato-DXd versus docetaxel monotherapy, Dato-DXd has a more manageable and tolerable safety profile and therefore offers reduced toxicity and reduced economic burden for patients and healthcare systems respectively."

Adverse events • HEOR • Metastases • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Exploring the Incidence of Interstitial Lung Disease (ILD) in Metastatic Breast Cancer (MBC): A Comprehensive Meta and Network Analysis of Antibody-Drug Conjugates (ADCs) compared to available treatment options beyond first line (1L) (AIOM 2024) - "Furthermore, a greater ILD rate was observed in pts treated with ADCs such as Trastuzumab-emtansine (T-DM1), Trastuzumab-deruxtecan (T-DXd), Trastuzumabduocarmazine (T-Duo), Sacituzumab govitecan (SG), and Datopotamab-deruxtecan (Dato-DXd) compared to endocrine therapy (ET), chemotherapy (CT) and target therapy [including TKIs like lapatinib/neratinib/tucatinib and PARP inhibitors (PARPi)] (5.55% incidence in ADCs group vs 0.39% in non-ADC group, 95% CI: 2.45-12.09; p-value <0.0001). A higher incidence of ILD was noted in pts treated with ADcs compared to those receiving ET, TKIs, PARPi, and CT, including regimens containing everolimus. These data may inform treatment and monitoring decision making, especially for pts with respiratory risk factors."

Clinical • Metastases • Breast Cancer • Interstitial Lung Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • HER-2

Evaluating the incidence of emesis induced by Antibody-Drug Conjugates (ADCs) in Metastatic Breast Cancer (MBC): a comparison of multiple treatments beyond the first line through Meta-Analysis (AIOM 2024) - "Investigations into ADC-based regimens, considering Trastuzumab-emtansine (T-DM1), Trastuzumab-deruxtecan (T-DXd), Trastuzumabduocarmazine (T-Duo), Sacituzumab govitecan (SG) and Datopotamab-deruxtecan (Dato-DXd), were conducted across 11 trials...Nausea was significantly less frequent in HER2- MBC patients [15.1%, 95% CI: 10.2-21.9] and had a higher rate in those treated with PARP inhibitors (PARPi) [54.8%, 95% CI: 51.0-58.6], ADCs [50.8%, 95% CI: 37.9-63.5], and tyrosine kinase inhibitors (TKIs, lapatinib/neratinib + capecitabine) [46.6%, 95% CI: 42.6-50.6] compared to those receiving endocrine therapy (ET) and chemotherapy (CT). Among the treatment options available, ADCs, TKIs and PARPi show a significantly higher incidence of nausea and vomiting, compared to ET, targeted therapy, and even CT, in patients with MBC treated beyond the first line."

Metastases • Retrospective data • Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • HER-2

MODULE 3: Integrating Novel Agents and Approaches into the Management of Endocrine-Resistant Hormone Receptor (HR)-Positive Mbc (SABCS 2024) - "This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Key efficacy and safety findings from the Phase III TROPiCS-02 trial of sacituzumab govitecan for previously treated HR-positive, HER2-negative mBC Available and emerging findings from the Phase III TROPION-Breast01 trial comparing Dato-DXd to chemotherapy for previously treated HR-positive, HER2-negative mBC; potential clinical role Available data with and appropriate sequencing of T-DXd opposite other standard therapies for previously treated HR-positive, HER2-low and HER2-ultralow advanced breast cancer Incidence of HER2 mutations in HR-positive mBC; rationale for the evaluation of neratinib-based therapy in this setting Published findings with neratinib/fulvestrant/trastuzumab among patients with HR-positive, HER2-mutant mBC who had experienced disease progression on prior CDK4/6 inhibitor therapy in the Phase II SUMMIT basket study;..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

MODULE 4: Tolerability Considerations with Approved and Investigational Antibody-Drug Conjugates (ADCs) (SABCS 2024) - "This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Comparative tolerability/toxicity profiles of sacituzumab govitecan, T-DXd, Dato-DXd and HER3-DXd in mBC Spectrum, incidence and severity of common and unique adverse events (AEs) associated with different ADCs Monitoring and management of acute chemotherapy-like AEs seen with ADCs Recommended algorithms for mitigating serious AEs, such as interstitial lung disease and cardiac dysfunction, with T-DXd and other ADCs Management of oral mucositis/stomatitis, ocular toxicities and other treatment-related AEs with Dato-DXd"

Breast Cancer • Oncology • Solid Tumor • ERBB3

TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer. (PubMed, Future Oncol) - P3 | "We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival.Clinical Trial Registration: NCT05555732 (ClinicalTrials.gov)."

IO biomarker • Journal • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Datopotamab deruxtecan + Keytruda: Data from P3 TROPION-Lung07 trial (NCT05555732) for 1L advanced or metastatic NSCLC post 2025 (AstraZeneca) - Q3 2024 Results

P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology