Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2–Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP)

Article

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

PURPOSEHuman 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.METHODSIn 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). CONCLUSIONTreatment 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.

2022-03-01·Cancer Treatment Reviews1区 · 医学

The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives

1区 · 医学

Review

作者: Patelli, Giorgio ; Siena, Salvatore ; Tosi, Federica ; Ghezzi, Silvia ; Spina, Francesco ; Righetti, Elena ; Sartore-Bianchi, Andrea ; Stabile, Stefano ; Amatu, Alessio ; Zeppellini, Annalisa

PURPOSEHER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively.METHODSThis is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches.RESULTS36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines.CONCLUSIONSERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

2020-09-16·Bioconjugate Chemistry2区 · 化学

A Platform for the Generation of Site-Specific Antibody–Drug Conjugates That Allows for Selective Reduction of Engineered Cysteines

2区 · 化学

Article

作者: Groothuis, Patrick G. ; Coumans, Ruud G. E. ; van der Lee, Miranda M. C. ; Spijker, Henri J. ; Blomenröhr, Marion ; Dokter, Wim H. A. ; Kokke, Bas P. A. ; Timmers, C. Marco ; Schouten, Jan ; Beusker, Patrick H. ; Ariaans, Gerry J. A. ; Ubink, Ruud ; Renart Verkerk, Pascal

Engineering cysteines at specific sites in antibodies to create well-defined ADCs for the treatment of cancer is a promising approach to increase the therapeutic index and helps to streamline the manufacturing process. Here, we report the development of an in silico screening procedure to select for optimal sites in an antibody to which a hydrophobic linker-drug can be conjugated. Sites were identified inside the cavity that is naturally present in the Fab part of the antibody. Conjugating a linker-drug to these sites demonstrated the ability of the antibody to shield the hydrophobic character of the linker-drug while resulting ADCs maintained their cytotoxic potency in vitro. Comparison of site-specific ADCs versus randomly conjugated ADCs in an in vivo xenograft model revealed improved efficacy and exposure. We also report a selective reducing agent that is able to reduce the engineered cysteines while leaving the interchain disulfides in the oxidized state. This enables us to manufacture site-specific ADCs without introducing impurities associated with the conventional reduction/oxidation procedure for site-specific conjugation.

项与 Duocarmazine 相关的新闻（医药）

2025-03-21

·Endpoints

Akeso shares new data for bispecific in cervical cancer; Pulmatrix to divest assets

+Plus, news about Autolus, MacroGenics and BlissBio: Akeso bispecific looks promising in cervical cancer: The China-based biotech said Friday that all patients in a Phase 3 cervical cancer trial responded to treatment with a bispecific antibody called cadonilimab. The addition of the PD-1xCTLA-4 bispecific on top of chemoradiotherapy in the COMPASSION-18 study generated complete and partial response rates of 84.8% and 15.2%, respectively. Median PFS was not reached, but the 12-month PFS rate was 74.9%. Cadonilimab is already approved in China for patients with recurrent or metastatic cervical cancer who have not responded to platinum-based chemotherapy. — Elizabeth Cairns Pulmatrix to divest assets ahead of merger: The biotech will seek buyers for three of its pipeline programs as well as its iSPERSE platform technology. Pulmatrix in November agreed to a reverse merger with Cullgen, which was expected to close this month but is now set to close in the first half of 2025. — Max Gelman BioNTech’s option for Autolus CAR-T fizzles out: The German biotech allowed its option to lapse for AUTO1/22, a CAR-T cell therapy in Phase 1 trials for childhood acute lymphoblastic leukemia. Back in February 2024 , BioNTech paid $50 million in cash and bought $200 million of Autolus’ shares in a deal that granted it access to AUTO1/22. The deal also covered AUTO6NG, a programmed T-cell therapy in early trials in neuroblastoma, and Aucatzyl, which has since been approved for an aggressive form of leukemia. BioNTech declined to exercise its time-limited option to AUTO1/22 because of a pipeline prioritization , and it lapsed Feb. 8. — Elizabeth Cairns MacroGenics shelves prostate cancer ADC: The company had to stop dosing prostate cancer patients in a Phase 2 trial of its antibody-drug conjugate, called vobramitamab duocarmazine, in July . On Thursday , it said it would shut down all development and seek a partner for the product, which targets the tumor antigen B7-H3 and delivers a cytotoxic duocarmycin payload. MacroGenics said the results of the trial do not justify any more investment; in the patients treated before dosing was halted, mature median radiographic progression-free survival was 9.5 months with the lower dose and 10 months with the higher. — Elizabeth Cairns BlissBio to proceed with ADC on its own: Eisai had signed an option deal in 2023 to advance a BlissBio program called BB-1701, but last month said in its third-quarter earnings that it would no longer do so. Instead, BlissBio will develop BB-1701 on its own. Eisai had been partnered with liquid biopsy company Angle on development plans, and now Angle is planning to work with BlissBio. — Max Gelman

临床结果免疫疗法细胞疗法临床2期上市批准

2025-03-21

·FierceBiotech

MacroGenics pulls plug on vobra duo ADC after seeing phase 2 prostate cancer data

Despite giving up on vobra duo, MacroGenics CEO Scott Koenig, M.D., Ph.D., said that the company still believes B7-H3 has “potential” as a target.\n MacroGenics has made the final decision to abandon work on one of its more advanced antibody-drug conjugates after taking a look at the latest phase 2 data.The biotech had already paused work on vobramitamab duocarmazine (vobra duo) back in November, explaining that it was awaiting progression-free survival (PFS) data from a phase 2 monotherapy prostate cancer trial. Vobra duo has a cleavable peptide linker designed to deliver a DNA-alkylating duocarmycin payload to solid tumors that express B7-H3.CEO Scott Koenig, M.D., Ph.D., explained to investors at the time that the company would make a call on whether to invest further in vobra duo after considering the final PFS data, the therapy’s safety profile and the competitive landscape in the context of the rest of its pipeline.The results are now in, and they show a median radiographic PFS of 9.5 months and 10 months for the 2-mg/kg and 2.7-mg/kg doses, respectively. Safety data “remained consistent with prior data disclosures,” MacroGenics said in its full-year earnings results March 20.“Based on its assessment of the vobra duo safety and efficacy profile and an internal resource and portfolio review, MacroGenics has decided not to pursue further internal development of vobra duo and will instead explore potential alternatives for partnering this program,” the company said in the release.Despite giving up on vobra duo, Koenig said the company still believes B7-H3 has “potential” as a target, adding that the biotech is “pleased with the progress being made with our alternate anti-B7-H3 ADC, MGC026.” MGC026, which is a TOP1i-based ADC, is undergoing a phase 1 dose-escalation study in patients with advanced solid tumors. The biotech also has another ADC in the clinic in the form of MGC028, a TOP1i-based ADC that targets ADAM9 and recently started a phase 1 study in solid tumors.MacroGenics is awaiting a readout later this year for lorigerlimab, a PD-1xCTLA-4 bispecific that the company is testing in a phase 2 prostate cancer trial in combination with docetaxel.“We concluded 2024 with the achievement of multiple clinical development milestones, including the completion of enrollment in the LORIKEET phase 2 study evaluating lorigerlimab in combination with docetaxel in patients with mCRPC,” Koenig said in yesterday\'s postmarket release.“We look forward to building upon this momentum in 2025 as we work to advance our novel pipeline of clinical product candidates, including lorigerlimab, MGC026 and MGC028,” the CEO added.MacroGenics entered the year with $201.7 million in the bank, which the company expects to last into the second half of 2026.

临床1期抗体药物偶联物临床2期

2025-03-21

·PipelineReview

MacroGenics Provides Update on Corporate Progress and 2024 Financial Results

ROCKVILLE, MD, USA I March 20, 2025 I MacroGenics, Inc. (NASDAQ: MGNX), a biopharmaceutical company focused on discovering, developing, manufacturing and commercializing innovative antibody-based therapeutics for the treatment of cancer, today provided an update on its recent corporate progress and reported financial results for the year ended December 31, 2024. “We concluded 2024 with the achievement of multiple clinical development milestones, including the completion of enrollment in the LORIKEET Phase 2 study evaluating lorigerlimab in combination with docetaxel in patients with mCRPC. We look forward to building upon this momentum in 2025 as we work to advance our novel pipeline of clinical product candidates, including lorigerlimab, MGC026 and MGC028,” said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. “Finally, we have determined that the results of the TAMARACK Phase 2 study of vobra duo in mCRPC do not support additional financial investment by MacroGenics. We believe the B7-H3 target continues to have potential and are pleased with the progress being made with our alternate anti-B7-H3 ADC, MGC026.” Updates on Proprietary Investigational Programs Lorigerlimab is a bispecific, tetravalent PD-1 × CTLA-4 DART ® molecule designed to enhance CTLA-4 blockade on dual-expressing, tumor-infiltrating lymphocytes compared to a PD-1/CTLA-4 monoclonal antibody (mAb) combination therapy, while maintaining maximal PD-1 blockade on all PD-1-expressing cells. Emerging ADC Pipeline. MacroGenics is developing two clinical and one preclinical antibody-drug conjugate (ADC) molecules that each incorporate a novel, glycan-linked topoisomerase I inhibitor (TOP1i)-based payload developed by the Company’s collaboration partner, Synaffix (a Lonza company). These three candidates are described below. Updates on Selected Partnered Programs Update on Vobramitamab Duocarmazine Vobramitamab duocarmazine (vobra duo) is an ADC with a cleavable peptide linker designed to deliver a DNA-alkylating duocarmycin payload to solid tumors that express B7-H3. 2024 Financial Results Conference Call Information To participate via telephone, please register in advance at this link . Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. The listen-only webcast of the conference call can be accessed under “Events & Presentations” in the Investor Relations section of MacroGenics’ website at https://ir.macrogenics.com/events-and-presentations/events . A recorded replay of the webcast will be available shortly after the conclusion of the call and archived on MacroGenics’ website for 30 days following the call. About MacroGenics, Inc. MacroGenics (the Company) is a biopharmaceutical company focused on discovering, developing, manufacturing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer. The Company generates its pipeline of product candidates primarily from its proprietary suite of next-generation antibody-based technology platforms, which have applicability across broad therapeutic domains. The combination of MacroGenics’ technology platforms and protein engineering expertise has allowed the Company to generate promising product candidates and enter into several strategic collaborations with global pharmaceutical and biotechnology companies. For more information, please see the Company’s website at www.macrogenics.com . MacroGenics, the MacroGenics logo and DART are trademarks or registered trademarks of MacroGenics, Inc. SOURCE: MacroGenics

抗体药物偶联物财报临床2期临床1期

100 项与 Duocarmazine 相关的药物交易

登录后查看更多信息