Jivadco (trastuzumab duocarmazine) / Byondis, Medac - LARVOL DELTA

Overcoming Antibody-Drug Conjugate Resistance in HER2-Positive Breast Cancer: Insights into Molecular Mechanisms and Targeted Therapeutic Approaches (EACR 2025) - "Second-generation antibody-drug conjugates (ADC) trastuzumab deruxtecan (T-DXd; Enhertu®) and trastuzumab duocarmazine (SYD985) have shown effectiveness in HER2-positive and HER2-low metastatic breast cancer...BT-474 and MDA-MB-361 resistant cells retained sensitivity to the ADC trastuzumab emtansine and the tyrosine kinase inhibitors neratinib and lapatinib... Our study provides insight into the molecular basis of ADC resistance, identifying potential targets to overcome resistance and enhance ADC efficacy in HER2-positive breast cancer. The identification of RET downregulation in resistant cells and the observed synergy between T-DXd and selpercatinib highlight a potential strategy for limiting T-DXd resistance."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • IFNG

ADC efficacy and safety evaluation based on organoid models (AACR 2025) - "Responses to four groups of HER2-targeted ADC drugs were evaluated in these models by assessing cell viability, including Trastuzumab deruxtecan, Trastuzumab duocarmazine, Trastuzumab emtansine, Trastuzumab MMAE, and their corresponding payloads (with or without linker). The HER2 expression levels in the in vitro cultured PDXO models were almost consistent at both RNA and protein levels, and they accurately reflected the expression status of the original tissues. The ADC screening revealed a differential sensitivity of organoids based on HER2 expression levels, with high HER2 expression correlating with increased sensitivity to ADC treatment, while low expression indicated resistance. Interestingly, normal organoid models were insensitive to ADC treatment, suggesting a potential for minimal side effects."

Clinical • Oncology • HER-2

Systematic review of ADCs vs chemotherapy in 2L+ Her2+ mBC (SABCS 2024) - "TH3RESA and EMILIA assess T-DM1 (trastuzumab emtansine); DESTINY-Breast02 and DESTINY-Breast04 evaluate T-DXd (trastuzumab deruxtecan); and TULIP examines T-Duo (trastuzumab duocarmazine). Regardless of PIK3CA mutations and PTEN loss, which could be expected to drive Her2 pathway activation, T-DM1 and T-DXd are effective. While T-DM1 and T-DXd demonstrate enhanced benefit with relatively elevated Her2 mRNA levels, bot∫h remain effective even in cases of low Her2+ mBC."

Review • Breast Cancer • HER2 Positive Breast Cancer • HER-2 • PIK3CA • PTEN

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

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

Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2–Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP) (J Clin Oncol) - P3 | N=437 | TULIP (NCT03262935) | Sponsor: Byondis B.V. | "In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146)....The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points - clinical benefit rate, duration of response, and reduction in target lesion measurement - tended to favor T-Duo."

P3 data • HER2 Positive Breast Cancer

Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP). (PubMed, J Clin Oncol) - "Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1."

Journal • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Preclinical efficacy of the trastuzumab duocarmazine SYD985 as monotherapy or in combination with the PARP inhibitor niraparib in HER2-expressing endometrial cancer (ESMO 2024) - "This study highlights a potential impact of targeted-treatment against HER2 in combination with PARP inhibitor for patients with HER2-expressing EC."

Combination therapy • Monotherapy • Preclinical • Endometrial Cancer • Oncology • Solid Tumor • HER-2

Preclinical Efficacy Of The Trastuzumab Duocarmazine SYD985 As Monotherapy Or In Combination With The PARP Inhibitor Niraparib In HER2-Expressing Endometrial Cancer (ESGO 2024) - "Similarly, we observed an increased survival in animals treated with SYD985 alone or in combination with niraparib. Conclusion This study highlights a potential impact of targeted-treatment against HER2 in combination with PARP inhibitor for patients with HER2-expressing EC."

Combination therapy • Monotherapy • Preclinical • Endometrial Cancer • Oncology • Solid Tumor • HER-2

Evaluation of Safety and Efficacy of Sodium Thiosulfate (BYON5667) Eye Drops to Reduce Ocular Toxicity in Cancer Patients Treated With SYD985 (clinicaltrials.gov) - P1/2 | N=48 | Completed | Sponsor: Byondis B.V. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jun 2023 | Trial primary completion date: Dec 2023 ➔ Apr 2023

Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone (SABCS 2023) - "Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration."

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

Trastuzumab duocarmazine versus physician's choice therapy in pre-treated HER2-positive metastatic breast cancer: Final results of the phase III TULIP trial (ESMO 2023) - P3 | "Methods The TULIP trial randomly assigned patients with HER2-positive locally advanced or MBC with ≥2 previous HER2-targeting MBC regimens or pretreated with T-DM1, in a 2:1 ratio between T-Duo (1.2 mg/kg q3w) and PC. PC could be either trastuzumab combined with capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine...The final OS results confirm a trend towards a numerically prolonged OS (statistically non-significant) in the T-Duo group compared with PC group. Safety was aligned with the primary analysis, with no new signals identified."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Trastuzumab Duocarmazine Improves PFS in HER2+ Advanced Breast Cancer (Cancer Therapy Advisor) - P3 | N=437 | TULIP (NCT03262935) | Sponsor: Byondis B.V. | "Dr Aftimos presented these results, from the phase 3 TULIP trial...at the ESMO Congress 2023. TULIP enrolled 437 patients with HER2-positive, locally advanced or metastatic breast cancer....The median PFS, the study’s primary endpoint, was 7.0 months in the trastuzumab duocarmazine arm and 4.9 months in the chemotherapy arm (hazard ratio [HR], 0.64; 95% CI, 0.49-0.84; P =.002). The median OS was 21.0 months with trastuzumab duocarmazine and 19.5 months with chemotherapy (HR, 0.87; 95% CI, 0.68-1.12; P =.236). The estimated 1-year OS rates were 70% with trastuzumab duocarmazine and 68% with chemotherapy. The rate of treatment-emergent adverse events (TEAEs) was 96.5% in the trastuzumab duocarmazine arm and 96.4% in the chemotherapy arm."

P3 data • HER2 Positive Breast Cancer

#ESMO23 Aftimos presents final analysis of TULIP evaluating trastuzumab duocarmazine for HER2+ MBC. PFS benefit maintained. No OS benefit. High risk keratitis and some ILD. Doesn't seem that it can compete. @OncoAlert

Jivadco : Withdrawal of the marketing authorisation application (European Medicines Agency) - "Medac Gesellschaft für klinische Spezialpräparate mbH withdrew its application for a marketing authorisation of Jivadco for the treatment of HER2-positive breast cancer...The company withdrew the application on 12 September 2023....In its letter notifying the Agency of the withdrawal of the application, the company stated that it withdrew the application because it could not address EMA’s concerns within the required time limit."

European regulatory • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies. (PubMed, Cancers (Basel)) - "Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms."

IO biomarker • Journal • Metastases • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2

Phase I Study of SYD985 With Niraparib in Patients With Solid Tumors (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Byondis B.V. | Active, not recruiting ➔ Completed | N=120 ➔ 32

Combination therapy • Enrollment change • Metastases • Trial completion • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2

TULIP: SYD985 vs. Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P3 | N=436 | Completed | Sponsor: Byondis B.V. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Aug 2022

Metastases • Trial completion • Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

SYD985 in Patients With HER2-expressing Recurrent, Advanced or Metastatic Endometrial Carcinoma (clinicaltrials.gov) - P2 | N=64 | Completed | Sponsor: Byondis B.V. | Active, not recruiting ➔ Completed

Metastases • Trial completion • Endometrial Cancer • Oncology • Solid Tumor • HER-2

Phase I Study of SYD985 With Niraparib in Patients With Solid Tumors (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: Byondis B.V. | Trial completion date: Dec 2023 ➔ Jun 2023

Combination therapy • Metastases • Trial completion date • Breast Cancer • Endometrial Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2

U.S. Food and Drug Administration Issues Complete Response Letter for Byondis' [Vic-]Trastuzumab Duocarmazine (PRNewswire) - "Byondis B.V....announced that the U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) for the Biological License Application (BLA) for [vic-]trastuzumab duocarmazine (SYD985). With this BLA, Byondis sought approval for its anti-HER2 antibody-drug conjugate (ADC) in HER2-positive unresectable locally advanced or metastatic breast cancer (MBC), a disease with a high unmet medical need. According to the complete response letter, the FDA suspends the decision on the product's approvability. The agency requested additional information that requires time and resources that extend beyond the current evaluation period."

FDA event • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

The change of paradigm in the treatment of HER2-positive breast cancer with the development of new generation antibody-drug conjugates. (PubMed, Cancer Drug Resist) - "Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients. Trastuzumab emtansine, the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy. Despite the progress in treatment development, most patients develop resistance and eventually relapse. Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Emerging new treatments in HER2 positive breast cancer (SG-BCC 2023) - P1 | "Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026..."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Oncology • Solid Tumor • CDK4 • ER • HER-2 • KLRC1 • PD-L1 • PIK3CA

ISPY-P1.01:Evaluating the Safety of Weekly Paclitaxel With Trastuzumab Duocarmazine (SYD985) in Patients With Metastatic Cancer (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: QuantumLeap Healthcare Collaborative | N=27 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Metastases • Trial withdrawal • Bladder Cancer • Breast Cancer • Carcinoid Tumor • Endometrial Adenocarcinoma • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Estrogen Receptor Positive Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer