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

Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. (PubMed, Nat Med) - P2 | "The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 ."

Journal • P2 data • Breast Cancer • Dental Disorders • Endocrine Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Nephrology • Oncology • Renal Disease • Solid Tumor • Stomatitis • HER-2 • PD-L1

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. (PubMed, Nat Med) - P2 | "I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 ."

Journal • P2 data • Breast Cancer • Dental Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Stomatitis • DRD • HER-2

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Rates of pathologic complete response (pCR) after datopotamab deruxtecan (Dato) plus durvalumab (Durva) treatment strategy in the neoadjuvant setting: Results from the I-SPY 2.2 trial (ESMO 2024) - P2 | "RPS incorporates expression-based immune (Im), DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to classify patients into 6 subtypes. All HER2- subtypes were eligible for Dato+Durva in Block A. Predicted responders at the end of Block A or B may go to surgery early; otherwise, they proceed to Block B +/- C. Randomization to Block B included a taxane-based regimen specific to RPS: paclitaxel +/- carboplatin +/- pembrolizumab (pembro). Patients who proceeded to Block C received doxorubicin + cyclophosphamide +/- pembro... The Dato + Durva treatment strategy showed high rates of pCR in Im(+) subtype (79%) and HR-/HER2- (62%), with >50% of these pCRs achieved with Block A alone and > 90% after Block A+B, avoiding taxane and anthracycline treatment. Table: LBA15"

Clinical • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • DRD • HER-2

Rates of pathologic complete response (pCR) after datopotamab deruxtecan (Dato) in the neoadjuvant setting: Results from the I-SPY 2.2 trial (ESMO 2024) - P2 | "RPS incorporates expression-based immune (Im), DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to classify patients into 6 subtypes. HER2(-) subtypes were eligible for Dato in Block A. Predicted responders at the end of Block A or B may go to surgery early, or they proceed to Block B +/- C. Randomization to Block B includes a taxane-based regimen specific to RPS: paclitaxel +/- carboplatin +/- pembrolizumab [pembro]. Patients who proceed to Block C receive doxorubicin + cyclophosphamide +/-pembro... Dato was particularly active in the HR(-)HER2(-)Im(-)DRD(-) signature, and was safe in other subtypes, in patients who followed the treatment strategy, highlighting the importance and benefit of adherence to protocol treatment recommendations. Table: LBA16"

Clinical • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • DRD • HER-2

First-in-human Study of DS-1062a for Advanced Solid Tumors (TROPION-PanTumor01) (clinicaltrials.gov) - P1 | N=890 | Recruiting | Sponsor: Daiichi Sankyo Co., Ltd. | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Metastases • Pan tumor • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal 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 • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • CD4 • ER • ERBB3 • HER-2 • PGR • TACSTD2

Intracranial response in patients (pts) with baseline (BL) brain metastases (BM) and extensive-stage (ES) small cell lung cancer (SCLC) treated with ifinatamab deruxtecan (I-DXd) in the IDeate-Lung01 study (ESMO 2024) - P2 | "Antibody–drug conjugates (ADCs) containing the DXd payload (T-DXd, HER3-DXd, and Dato-DXd) have shown encouraging intracranial responses. CNS responses with I-DXd appear consistent with those seen with other DXd ADCs, with promising intracranial efficacy in ES-SCLC pts who have a poor prognosis."

Clinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • ERBB3

Datopotamab deruxtecan (Dato-DXd) vs docetaxel (DTX) in patients (pts) with advanced nonsquamous (NSQ) non-small cell lung cancer (NSCLC) with brain metastases (mets): Results from TROPION-Lung01 (ESMO 2024) - P3 | "Dato-DXd showed improved efficacy and a manageable safety profile vs DTX in advanced NSQ NSCLC regardless of BL brain met status. Assessment of intracranial activity of Dato-DXd is ongoing. Table: 1312P ∗ NSQ histology"

Clinical • Metastases • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the TROPION-Breast01 study of datopotamab deruxtecan (Dato-DXd) vs investigator's choice of chemotherapy (ICC) in patients (pts) with pretreated, inoperable/metastatic HR+/HER2– breast cancer (BC) (ESMO 2024) - P3 | "After adjusting for Tx duration, Dato-DXd is more tolerable vs ICC across all AE categories and for a majority of individual AEs, further emphasising the potential for Dato-DXd as a well tolerated Tx option."

Adverse events • Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Assessing interstitial lung disease (ILD) risk 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) (ESMO 2024) - "Furthermore, a greater ILD risk was observed in pts treated with ADCs such as Trastuzumab-emtansine (T-DM1), Trastuzumab-deruxtecan (T-DXd), Trastuzumab-duocarmazine (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). Pts treated with ADCs demonstrated a higher risk of ILD 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 • Oncology • Solid Tumor • HER-2

Datopotamab deruxtecan (Dato-DXd) in patients with endometrial (EC) or ovarian cancer (OC): Results from the phase II TROPION-PanTumor03 study (ESMO 2024) - P2 | "Dato-DXd monotherapy demonstrated encouraging efficacy and a manageable safety profile in pts with recurrent endometrial or ovarian cancer."

Clinical • P2 data • Pan tumor • Endometrial Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • TACSTD2

Datopotamab deruxtecan: "Tropion-Lung01 met its dual primary endpoint of PFS with a statistically significant improvement for dato-dxd over docetaxel in the overall population"; Non small cell lung cancer (Daiichi Sankyo) - WCLC 2024

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

Datopotamab deruxtecan: Data readout from P3 TROPION-Breast02 trial (NCT05374512) for 1L TNBC in 2024 (AstraZeneca) - ESMO 2024

P3 data • Breast Cancer • Oncology • Triple Negative Breast Cancer

Dato-DXd Shows Promising Efficacy in Endometrial and Ovarian Cancer (Targeted Oncology) - P2 | N=582 | TROPION-PanTumor03 (NCT05489211) | Sponsor: AstraZeneca | "The TROP2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) showed promising antitumor activity with manageable toxicity in patients with advanced/metastatic ovarian and endometrial cancer and progressive disease following platinum chemotherapy...In the ovarian cancer cohort (n = 35), the confirmed objective response rate (ORR; RECIST v1.1) at a median follow-up of 14.5 months (range, 10.4-15.4) was 42.9% (95% CI, 26.3%-60.6%), comprising a complete response (CR) rate of 2.9% (n = 1) and a partial response (PR) rate of 40.0%...In the endometrial cancer cohort (n = 40), the confirmed ORR at a median follow-up of 13.6 months (range, 2.1-19.6) was 27.5% (95% CI, 14.6%-43.9%), comprising a CR rate of 2.5% (n = 1) and a PR rate of 25.0%...Grade 3 or higher treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.3% vs 57.5% and 28.6% vs 27.5% of the 2 arms, respectively."

P2 data • Endometrial Cancer • Ovarian Cancer

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) - No abstract available

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

Datopotamab deruxtecan: “In the ovarian cohort ORR was 42.9% and median DoR was 5.7 (95% Cl: 2.9-NC) months; Solid tumor (Daiichi Sankyo) - ESMO 2024: “In the endometrial cohort, ORR was 27.5% and median DoR was 16.4 (95% Cl: 7.1-NC) months”

P2 data • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor

Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. (ASCO 2024) - P2 | "Dato-DXd showed encouraging IC activity consistent with systemic responses in pts with a/m NSCLC with AGAs, supporting further investigation of Dato-DXd in pts with brain mets."

Clinical • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ICARUS-LUNG01: A phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome. (ASCO 2024) - P2 | "In the phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement of PFS over docetaxel in previously treated pts with advanced NSCLC. In this heavily pretreated population, Dato-DXd showed similar efficacy and safety results to those reported in TROPION-Lung01. Patients with NSQ appeared to derive the greatest benefit. Translational analyses to determine biomarkers associated with response and/or resistance will be presented."

Biomarker • Biopsy • Clinical • IO biomarker • Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TACSTD2

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Primary Results From TROPION-Breast01 (J Clin Oncol) - P3 | N=732 | TROPION-Breast01 (NCT05104866) | Sponsor: AstraZeneca | "Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC."

P3 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Variable pCR Rates Seen With Neoadjuvant Dato-DXd/Durvalumab in Stage II/III Breast Cancer (Targeted Oncology) - P2 | N=5,000 | I-SPY 2.2 (NCT01042379) | "Datopotamab deruxtecan (Dato-DXd) combined with durvalumab (Imfinzi) led to an overall pathologic complete response (pCR) rate of 50% in patients with stage II/III high-risk HER2-negative breast cancer, which showed the utility of evaluating treatment response according to response predictive subtype...Baseline characteristics of the overall population (n = 106) indicated that the median age at screening was 50.5 years (range, 25.0-77.0) and most patients were not Hispanic/Latino (76.4%) and were White (59.4%)...Of the 106 patients who were treated in block A, 64 went on to receive treatment in block B, and 25 in block C...Among all patients (n = 106) the cumulative percentages of observed pCR rates by the end of blocks A, B, and C were 47% (n = 25/53), 89% (n = 47/53), and 100% (n = 53/53), respectively."

P2 data • HER2 Negative Breast Cancer

Datopotamab Deruxtecan Vs Docetaxel in Patients with Non-Small Cell Lung Cancer: Final Overall Survival from TROPION-Lung01 (IASLC-WCLC 2024) - P3 | "TROPION-Lung01 did notmeet the second dual primary endpoint of OS, however, Dato-DXd showed a numerical improvement in OS overdocetaxel in the full NSCLC analysis set. In the prespecified nonsquamous NSCLCsubgroup, Dato-DXd demonstrated a clinically meaningful trend towards prolongedOS compared with docetaxel. Theoverall safety and efficacy profile of Dato-DXd supports its use as a potentialnew therapeutic option for patients with nonsquamous NSCLC whoare eligible for subsequent therapy."

Clinical • Alopecia • Dental Disorders • Hematological Disorders • Immunology • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis

Normalized Membrane Ratio of TROP2 by Quantitative Continuous Scoring is predictive of Clinical Outcomes in TROPION-Lung 01 (IASLC-WCLC 2024) - "Optimization of QCS-NMR for PFS was performed in the biomarker-evaluable patient subgroup with non-squamous (NSQ) NSCLC without actionable genomic alterations (non-AGA) in the phase 3 TROPION-Lung01 trial (Dato-DXd vs docetaxel in 2L+ advanced/metastatic NSCLC); association of TROP2 QCS-NMR status with clinical outcomes was assessed in all biomarker-evaluable patients. TROP2 NMR determined by QCS demonstrated potential as a predictive biomarker for Dato-DXd. Further investigation of this biomarker to inform patient benefit in 1L advanced/metastatic NSCLC trials is ongoing."

Clinical • Clinical data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TACSTD2

Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents + CT and Adjuvant D ± Novel Agents in Resectable NSCLC (IASLC-WCLC 2024) - P2 | "Methods : Patients with untreated, histologicallyconfirmed, resectable Stage IIA-IIIB NSCLC were stratified by PD-L1 expression(<1% vs ≥1%) and randomised to Arm 1: neoadjuvant D + platinum-doublet CT +oleclumab (anti-CD73 mAb), Arm 2: D + platinum-doublet CT + monalizumab (anti-NKG2AmAb), or Arm 4: D + single-agent platinum CT + Dato-DXd (TROP2 directed antibody-drug conjugate [ADC]).Neoadjuvant therapy was given Q3W for 4 cycles prior to surgery, followed byadjuvant treatment with D + oleclumab (Arm 1) or monalizumab (Arm 2) or alone(Arm 4) until disease progression per RECIST v1.1 or for up to 1 year. Treatments in all arms led to improvementsin mPR rates along with a manageable safety profile and surgical ratescomparable to currently approved neoadjuvant and perioperativeimmunotherapy-based regimens (Forde NEJM 2022; Wakelee NEJM 2023). This is the first global Ph2 platform study showing encouragingefficacy and a manageable safety profile of an ADC in the..."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1

Valemetostat and Datopotamab Deruxtecan in Previously Treated, Advanced, Unresectable, or Metastatic Non-squamous NSCLC (IASLC-WCLC 2024) - P1 | "This study is structured as a Master Protocol trial evaluating the clinical activity and safety of valemetostat in combination with DXd-ADCs, including Dato-DXd and the human epidermal receptor 2 (HER2)-directed ADC, trastuzumab deruxtecan (T-DxD), in patients with NSCLC or other solid tumors, respectively. An interim futility analysis will be performed when 20 patients have been enrolled and completed ≥ 6 months of follow-up. Clinical trial information: NCT06244485."

Metastases • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EZH2 • HER-2 • SLFN11

Opportunities for ADC Development in 2L NSCLC Leveraging Predictive Biomarkers (IASLC-WCLC 2024) - "In the P1b TROPION-LUNG02 trial, Dato-DXd combined with pembrolizumab proved effective regardless of PD-L1 expression. While T-DXd and HER3-DXd have been tested in HER2 and EGFR mutated cohorts, respectively, Dato-DXd use has not shown to be impacted by any specific biomarker. These results indicate the need to identify predictive biomarkers of response for improved patient population selection."

Biomarker • IO biomarker • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2 • PD-L1