Delving into the Latest Updates on Trastuzumab duocarmazine with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

(vic-)trastuzumab-duocarmazine, Anti-HER2 ADC(Byondis), Immunoglobulin g1-kappa, anti-(homo sapiens erbb2 (epidermal growth factor receptor 2, receptor tyrosineprotein kinase erbb-2, egfr2, her2, her-2, p185cerbb2, neu, cd340)), humanized monoclonal antibody conjugated to the pro-drug seco-duocarmycinhydroxyb

+ [6]

Target

DNA x HER2

Action

inhibitors, antagonists

Mechanism

DNA inhibitors(DNA inhibitors), HER2 antagonists(Receptor tyrosine-protein kinase erbB-2 antagonists), ADCC(Antibody-dependent cell-mediated cytotoxicity (ADCC) effects)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases+ [3]

Active Indication-

Inactive Indication

Bladder CancerEndometrial CarcinomaHER2 Positive Breast Cancer+ [17]

Originator Organization

Synthon BV

Active Organization-

Inactive Organization

Byondis BV

medac Gesellschaft für klinische Spezialpräparate mbH

License Organization

Quantumleap Healthcare Collaborative

Byondis BV

medac Gesellschaft für klinische Spezialpräparate mbH

Drug Highest PhaseDiscontinuedNDA/BLA

First Approval Date-

RegulationFast Track (United States)

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Structure/Sequence

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Sequence Code 18481L

Source: *****

Sequence Code 44772H

Source: *****

Author: Morales, Serafin ; Bordonaro, Roberto ; Ali, Haythem ; Si Jing, Joline Lim ; Chaudhry, Madhu ; Luporsi, Elisabeth ; Borms, Marleen ; Macpherson, Iain ; Cortes Castan, Javier ; Denys, Hannelore ; Taylor, Sara ; Helsten, Teresa ; Jerez Gilarranz, Yolanda ; Modiano, Manuel ; Marchetti, Paolo ; Meshad, Michael ; Bianchini, Giampaolo ; Crook, Timothy ; Palmieri, Carlo ; Danso, Michael A. ; Quenel-Tueux, Nathalie ; Bianchi, Giulia ; de Romani Muñoz, Santiago Escriva ; Doni, Laura ; Koper, Norbert ; Guarneri, Valentina ; Oesterholt, Mayke ; Papadimitriou, Konstantinos ; Klint, Leif ; Kaczmarek, Emilie ; Borley, Annabel ; Edlund, Per ; Armstrong, Anne ; Jerusalem, Guy ; Orfeuvre, Hubert ; Tan, Tira J. ; de Vries, Elisabeth G.E. ; Altena, Renske ; Lortholary, Alain ; Vega Alonso, Estela ; Petit, Thierry ; Ladoire, Sylvain ; Aftimos, Philippe ; Turner, Nicholas ; Teixeira, Luis ; O'Shaughnessy, Joyce ; Mowat, Rex ; Quenel Tueux, Nathalie ; Wedervang, Kim ; Song, Xinni ; Harroff, Allyson ; Colleoni, Marco ; Duhoux, François ; Rosenblatt, Paula ; Favret, Anne ; Cobleigh, Melody ; Jing Ying, Tira Tan ; Jensen, Jeanette Dupont ; Cognetti, Francesco ; Martinez, Maria ; Bonnin, Nathalie ; Piacentini, Federico ; Thirlwell, Michael ; Lim, Joline Si Jing ; Lindman, Henrik ; Ponce, Jose Juan ; Saura, Cristina ; Anton, Antonio ; Owera, Rami ; van den Tweel, Evelyn ; Abadie-Lacourtoisie, Sophie ; Joy, Anil ; Pluard, Timothy ; Cazzaniga, Marina ; Brufsky, Adam ; Dakhil, Shaker ; Jain, Sharad ; Zamagni, Claudio ; Adamo, Barbara ; Jeppesen, Nina ; Levitt, Nicola ; Escrivá-de-Romaní, Santiago ; Maiello, Evaristo ; Punie, Kevin ; Stradella, Agostina ; Menke-van der Houven van Oordt, Willemien ; Cairo, Michelina ; Christophe Thery, Jean ; Biganzoli, Laura ; Andersen, Jay ; Kuip, Evelien

PURPOSE:

Human epidermal growth factor receptor 2 (HER2)–targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer.

METHODS:

In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review.

RESULTS:

In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. 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. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC).

CONCLUSION:

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.

16 Dec 2022·Cancer research

Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Article

Author: Duro-Sánchez, Santiago ; Arenas, Enrique Javier ; Gandullo-Sánchez, Lucía ; Lalinde-Gutiérrez, Marta ; Dokter, Wim H.A. ; Pandiella, Atanasio ; Nadal-Serrano, Mercedes ; Pérez-Ramos, Sandra ; Rodilla, Verónica ; Escrivá-de-Romaní, Santiago ; Bernadó Morales, Cristina ; Morancho, Beatriz ; Escorihuela, Marta ; Esteve-Codina, Anna ; Arribas, Joaquín ; Cortés, Javier ; Dijcks, Fred A. ; Saura, Cristina

Abstract:

Antibody–drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression.

Significance::

Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.

02 Nov 2022·Expert review of clinical pharmacology

Interstitial lung disease associated with anti-HER2 anti-body drug conjugates: results from clinical trials and the WHO's pharmacovigilance database

Review

Author: An, Zhuoling ; Zhang, Yuhui ; Zhu, Min ; Ma, Zhuo ; Feng, Lin ; Zhang, Yi

BACKGROUND:

Interstitial lung disease (ILD) events associated with anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have aroused wide attention.

RESEARCH DESIGN AND METHODS:

In meta-analysis, we systematically reviewed literatures, and the outcomes were the proportion and risk of ILD related to anti-HER2 ADCs. A disproportionality analysis based on data from VigiBase was conducted to characterize the main features of anti-HER2 ADC-related ILD/pneumonitis.

RESULTS:

Two hundred and forty-five all-grade and 47 grade ≥ 3 ILD events with the proportion of 4.4% (95% confidence interval (CI) [2.0%, 6.8%]) and 0.5% (95% CI [0.3%, 0.8%]) were observed for anti-HER2 ADCs, respectively. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine significantly increased the risk of all-grade and grade ≥ 3 ILD events with Peto odd ratios of 2.62 (95% CI [1.71, 4.04], P < 0.0001) and 2.82 (95% CI [1.07, 7.42], P = 0.04), respectively. In VigiBase, 271 cases of ILD/pneumonitis related to trastuzumab emtansine and trastuzumab deruxtecan were extracted. The median time to the onset of event was 86 days and 54.95% of events occurred within 3 months.

CONCLUSIONS:

Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine increased the risk of ILD, which can lead to serious outcomes and tends to occur early.

17

News (Medical) associated with Trastuzumab duocarmazine

17 May 2023

·www.fiercebiotech.com

Byondis' breast cancer drug fails to bloom as FDA denies approval

Byondis' antibody-drug conjugate treatment was assessed in a phase 3 trial dubbed TULIP. Byondis' efforts to get an antibody-drug conjugate (ADC) treatment for HER-2 positive metastatic breast cancer approved have been pruned by the FDA. Last July, the federal agency accepted the Dutch company’s application for trastuzumab duocarmazine, also known as SYD985, an anti-HER2 ADC designed to treat HER2-positive unresectable locally advanced or metastatic breast cancer. The FDA set an expected decision date for May 12. Now, the agency has rejected the drug in a complete response letter, saying that further unspecified information is needed, according to the biotech's Monday release. Byondis said the request would require time and resources “that extend beyond the current evaluation period,” according to a company release. The biotech expressed disappointment but plans to continue seeking approval of the lead asset in the EU and the U.K. "We continue to believe that SYD985 can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer," Byondis CEO Marco Timmers, Ph.D., said in a May 15 release. "We appreciate the FDA's guidance and support and will carefully evaluate the complete response letter and consider potential next steps." SYD985 was assessed in a multicenter, open-label, randomized phase 3 trial dubbed TULIP. The study showed a statistically significant improvement over a physician's choice of treatment among 436 patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer, according to Byondis. The asset—which received fast-track designation from the FDA in 2018—contains the monoclonal antibody Herceptin and an investigational cleavable linker drug, which can help boost the success of ADC therapies by making tumor cells selectively release the toxin in the therapy. Byondis is trying to enter a tight market dominated by Big Pharma. In the physicians' choice trial, SYD985 was evaluated against GSK’s Tykerb, Genentech’s Xeloda, Eisai’s Halaven, Roche’s Herceptin and the chemotherapy Navelbine. The company is also testing out SYD985 in patients with endometrial cancer, efforts that are currently in phase 2 development.

Phase 2Phase 3ADCFast TrackClinical Result

16 May 2023

·www.pharmamanufacturing.com

FDA says no to Byondis breast cancer ADC

Dutch biopharma Byondis that the U.S. FDA issued a complete response letter for the company's lead asset, an anti-HER2 antibody-drug conjugate (ADC) for breast cancer treatment. With its BLA, Byondis sought approval for SYD985 in HER2-positive unresectable locally advanced or metastatic breast cancer — a disease with a high unmet medical need. According to Byondis, the agency requested additional information that "requires time and resources that extend beyond the current evaluation period." Byondis submitted its to the FDA back in July of last year, along with aMarketing Authorization Application to the . The EMA's decision is still pending, and is between April 2023 and October 2023. The BLA and MAA were supported by data from the phase 2 TULIP trial comparing SYD985 to physician’s choice (PC) treatment in patients with pre-treated HER2-positive unresectable breast cancer. The study met its primary endpoint of progression-free survival, demonstrating a statistically significant improvement of 2.1 months over PC. The trial also demonstrated supportive overall survival. Despite the CRL, Byondis remains optimistic about SYD985’s potential and is working with the FDA on next steps. “We continue to believe that SYD985 can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” said Byondis CEO Marco Timmers. HER2has become an increasingly popular target for drugmakers in the cancer space. Back in BioNTech signed a $1.5 billiondeal with China-based biotech DualityBio to co-develop and commercialize two cancer ADCs candidates, including DualityBio’s lead candidate, DB-1303, which is a topoisomerase-1 inhibitor-based ADC directed against HER2. Eisai and China-based Bliss Biopharmaceutical just a clinical trial collaboration agreement — with the option to license — for BlissBio's ADC candidate directed against HER2 for the treatment of cancers. SYD985 is also in for uterine cancer and solid tumors.

Clinical ResultADCLicense out/inPhase 2

15 May 2023

·byondis.com

U.S. Food and Drug Administration Issues Complete Response Letter for Byondis’ [Vic-]Trastuzumab Duocarmazine

Byondis B.V., an independent, Dutch clinical-stage biopharmaceutical company creating targeted medicines, today 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. While Byondis is disappointed with this outcome, the company remains optimistic about SYD985’s potential. “We continue to believe that SYD985 can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” said Byondis CEO Marco Timmers, Ph.D. “We appreciate the FDA’s guidance and support and will carefully evaluate the complete response letter and consider potential next steps.” Timmers added, “We will continue with the SYD985 applications in EU and UK and await the outcome of the review process.” [Vic-]Trastuzumab Duocarmazine Phase III TULIP® Study Results The BLA and MAA are supported by data from the pivotal Phase III TULIP multi-center, open-label, randomized clinical trial comparing SYD985 to physician’s choice (PC) treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer (SYD985.002/NCT03262935). The study, the results of which were presented at the 2021 ESMO Congress, met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement of 2.1 months over PC. TULIP also demonstrated supportive overall survival (OS) results.

Clinical ResultPhase 3ADC

100 Deals associated with Trastuzumab duocarmazine

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KEGG	Wiki	ATC	Drug Bank
D11375	-	-	DB16342

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
HER2 Positive Breast Cancer	NDA/BLA	European Union	Byondis BV	12 Jul 2022
HER2 Positive Breast Cancer	NDA/BLA	European Union	medac Gesellschaft für klinische Spezialpräparate mbH	12 Jul 2022
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	United States	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Belgium	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Canada	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Denmark	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	France	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Italy	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Netherlands	Byondis BV	15 Dec 2017
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	Singapore	Byondis BV	15 Dec 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03262935 (TULIP, Pubmed \| J Clin Oncol)	Phase 3	Metastatic human epidermal growth factor 2 positive carcinoma of breast HER2-positive	437	Trastuzumab Duocarmazine (T-Duo)	lijyfvhgav(qkpcvtbals) = wuiamwdffn yuntzqrttf (edwwgbighb, 5.4 - 7.2) View more	Positive	10 Feb 2025
				Trastuzumab Duocarmazine (Physician's Choice (PC))	lijyfvhgav(qkpcvtbals) = emvjeyhwpw yuntzqrttf (edwwgbighb, 4.0 - 5.5) View more
NCT04205630 (CTgov)	Phase 2	HER2-Expressing Endometrial Carcinoma	64	SYD985	ctjfimjxid = wgiyeieydy gvuncpptwj (cvjdbbllnr, uuppbngrjj - iagduwlfmr) View more	-	30 May 2024
EUCTR2017-001994-18-BE \| NCT03262935 (TULIP, ESMO 12023 \| ESMO 22023) Manual	Phase 3	HER2 Positive Breast Cancer HER2 Positive	437	Trastuzumab duocarmazineTrastuzumab duocarmazine 1.2 mg/kg q3w	atlkzeuxti(qdeqhcnjer) = huuppkxbpf snkaltvukv (nszjrsmmrf ) View more	Superior	22 Oct 2023
				physician's choice	atlkzeuxti(qdeqhcnjer) = lojmlcggzp snkaltvukv (nszjrsmmrf ) View more
NCT03262935 (NEPTUNE \| ASCENT-04 \| TULIP \| I-SPY2, CTgov)	Phase 3	Metastatic human epidermal growth factor 2 positive carcinoma of breast	437	(vic-)trastuzumab duocarmazine ((Vic-)Trastuzumab Duocarmazine)	rkpzxtuenm(mmkmtfqtwn) = bkpknfpsaq ftcpxjdkne (bramqxawmm, xpumrtyxkt - nijhlnkgax) View more	-	19 Oct 2023
				Trastuzumab+Eribulin+Lapatinib+Vinorelbine+Capecitabine (Physician's Choice)	rkpzxtuenm(mmkmtfqtwn) = nhnazqmdvk ftcpxjdkne (bramqxawmm, xmejztbane - zeqvvafytx) View more
NCT03262935 (TULIP, ESMO 12021 \| ESMO 22021) Manual	Phase 3	HER2 Positive Breast Cancer HER2 Positive	437	trastuzumab duocarmazine	gobcluekjh(aywgqrouca) = yamedncxfy kneeosqhns (wrijaeuclz, 5.4 - 7.2) View more	Superior	19 Sep 2021
				physician’s choice treatment	gobcluekjh(aywgqrouca) = mmntazmyea kneeosqhns (wrijaeuclz ) View more
NCT02277717 (Pubmed) Manual	Phase 1	Solid tumor \| HER2 Positive Breast Cancer HER2 Positive	185	Trastuzumab duocarmazine (dose-escalation)	trvbivzfbf(xfyzdvqkid) = igdtetokxl yxrazywebv (mnsdmakwyx )	Positive	01 Aug 2019
				Trastuzumab duocarmazine (dose-expansion)	yitqyorzea(epjyecynyd) = drxzrusbdr oalhaqwloj (iqsvrhrzhy, 20.4 - 48.4) View more
NCT02277717 (ASCO2018)	Phase 1	Metastatic human epidermal growth factor 2 positive carcinoma of breast	99	SYD985	haqozghwcn(zzoutxqrbu) = jstmfqjwcj vpvszmxgbd (euksyljvfu ) View more	Positive	01 Jun 2018
NCT02277717 (Phase I trial, SABCS2017)	Phase 1	Metastatic human epidermal growth factor 2 positive carcinoma of breast HER2-positive \| HER2-negative	-	SYD985	tbvirrqmus(dhhfqtnxzd) = conjunctivitis, stomatitis, fatigue, and decreased appetite usniitcyhs (jspdkehvld ) View more	Positive	15 Feb 2017
				Placebo

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Trastuzumab duocarmazine

Overview

Basic Info

Structure/Sequence

Related

External Link

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Biosimilar

Regulation