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FDA approves antibody-drug conjugate Datroway

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On January 17, 2025, the Food and Drug Administration approved datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo, Inc.), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for adult patients with unresectable or metastatic, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. The recommended datopotamab deruxtecan-dlnk dose is 6 mg/kg (maximum of 540 mg for patients ≥90 kg), administered as an intravenous infusion, once every 3 weeks (21-day cycle), until disease progression or unacceptable toxicity.

Datopotamab deruxtecan is an anti- trophoblast cell-surface antigen 2 (TROP2) ADC in development as a treatment for breast and lung cancer. The payload, a topoisomerase I inhibitor, is conjugated to a humanized IgG1k antibody via a cleavable linker. Daiichi Sankyo maintains exclusive rights for this ADC in Japan but has an agreement with AstraZeneca to jointly develop and commercialize datopotamab deruxtecan in the rest of the world. DATROWAY® was first approved in December 2024 in Japan for the treatment of adult patients with hormone receptor (HR) positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) unresectable or recurrent breast cancer after prior chemotherapy.

Efficacy was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial.  A total of 732 patients were randomized (1:1) to datopotamab deruxtecan (n=365) or investigator’s choice of chemotherapy (n=367); eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%). The major efficacy outcome measures were progression-free survival (PFS), assessed by blinded independent central review (BICR), based on RECIST v1.1 and overall survival (OS). Additional efficacy outcomes included confirmed objective response rate (ORR) and duration of response (DOR) by BICR. Median PFS was 6.9 months (95% CI: 5.7, 7.4) in the datopotamab deruxtecan-dlnk arm and 4.9 months (95% CI: 4.2, 5.5) in the chemotherapy arm (Hazard ratio 0.63 [95% CI: 0.52, 0.76] two-sided p-value <0.0001). Median OS was 18.6 months (95% CI: 17.3, 20.1) in the datopotamab deruxtecan-dlnk arm and 18.3 months (95% CI: 17.3, 20.5) in the chemotherapy arm (Hazard ratio 1.01 [95% CI: 0.83, 1.22]; two-sided p-value was not statistically significant). Confirmed ORR was 36% (95% CI: 31, 42) and 23% (95% CI: 19, 28) and median DOR was 6.7 months (95% CI: 5.6, 9.8) and 5.7 months (95% CI: 4.9, 6.8) in the datopotamab deruxtecan-dlnk and chemotherapy arms, respectively.

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies!

FDA approves BIZENGRI® (zenocutuzumab-zbco)

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On December 4, 2024, Merus N.V. announced the FDA approved BIZENGRI® (zenocutuzumab-zbco) as a treatment indicated for adults with pancreatic adenocarcinoma or NSCLC that are advanced unresectable or metastatic and harbor a NRG1 gene fusion who have disease progression on or after prior systemic therapy.

Zenocutuzumab is a humanized, ADCC-enhanced, bispecific IgG1k antibody that simultaneously targets the growth factor receptors HER2 and HER3, thereby blocking signal transduction caused by the binding of HER3 with its ligand neuregulin 1 (NRG1) or NRG1-fusion proteins. The antibody is in development by Merus as a treatment for patients with solid tumors harboring NRG1 gene fusions (NRG1+ cancer), who typically have suboptimal responses to conventional systemic treatment. FDA granted Breakthrough Therapy Designation for zenocutuzumab for the treatment of patients with advanced unresectable or metastatic NRG1+ pancreatic cancer following progression with prior systemic therapy or who have no satisfactory alternative treatment options, as well as Fast Track Designation for the treatment of patients with metastatic NRG1+ cancer that have progressed on standard of care therapy and Orphan Drug Designation for the treatment of patients with pancreatic cancer.

FDA’s approval was based on data from the open-label Phase 1/2 eNRGy trial (NCT02912949), which evaluated the safety and anti-tumor activity of zenocutuzumab monotherapy in NRG1+ NSCLC, PDAC, and other solid tumors. The study consisted of three patient cohorts: 1) NRG1+ NSCLC, 2) NRG1+ PDAC, and 3) other NRG1+ solid tumors. In the dose expansion period of the eNRGy study, participants received IV infusions of 750 mg of zenocutuzumab Q2W. Response rates were measured using RECIST v1.1 as assessed by blinded ICR. The ORR was 33% (95% CI, 22%-46%) and 40% (95% CI, 23%-59%) in the NRG1+ NSCLC (n=64) and NRG1+ PDAC (n=30) cohorts, respectively, and the median DOR was 7.4 months (95% CI, 4.0-16.6) in the NRG1+ NSCLC cohort and ranged from 3.7 months to 16.6 months in the NRG1+ PDAC cohorts.

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies! 

FDA approves zanidatamab (Ziihera®)

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On November 20, 2024, Jazz Pharmaceuticals announced that FDA granted accelerated approval of Ziihera® (zanidatamab-hrii) 50mg/mL for injection for intravenous use for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.[28] A confirmatory, randomized Phase 3 trial (HERIZON-BTC-302; NCT06282575) evaluating zanidatamab in combination with standard-of-care therapy versus standard-of-care therapy alone in the first-line setting for patients with HER2-positive BTC initiated in July 2024 is currently recruiting patients.

Zanidatamab (ZW25) is a humanized, biparatopic, bispecific IgG assembled from half-antibodies (Fab-h-CH2-CH3 x scFv-h-CH2-CH3) that targets two non-overlapping epitopes of HER2. In 2022, Zymeworks licensed the development and commercialization rights across all indications in the United States, Europe, Japan and all other territories, except for those Asia/Pacific territories previously licensed by Zymeworks, to Jazz Pharmaceuticals. BeiGene acquired exclusive development and commercial rights to zanidatamab, in Asia (excluding Japan), Australia, and New Zealand in 2018. FDA granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified BTC, Fast Track designation for zanidatamab as a single agent for refractory BTC, and Orphan Drug designation for zanidatamab in refractory BTC.

The approval was based in part on the results of the single-arm, Phase 2b trial (HERIZON-BTC-01; NCT04466891) of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic BTC with disease progression on previous gemcitabine-based therapy. The efficacy of zanidatamab was evaluated in 62 patients with HER2-positive (IHC 3+ by central assessment) BTC in Cohort 1 of HERIZON-BTC-01, with major efficacy outcome measures of  objective response rate (ORR) and duration of response (DOR) as determined by independent central review according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1. The study demonstrated an ORR of 52% [95% confidence interval (CI): 39, 65)] with a Kaplan Meier estimated median DOR of 14.9 months [95% CI: 7.4-not estimable] by independent central review [1].

Marketing applications for zanidatamab as a treatment for BTC were also submitted in the European Union and China. Beigene anticipates approval by NMPA for zanidatamab as second-line treatment of HER2+ BTC in the second half of 2025.

[1] ZIIHERA (zanidatamab-hrii) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.

FDA approves Vyloy (zolbetuximab-clzb)

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On October 18, 2024, the US Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.) for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma who may be eligible for treatment with zolbetuximab.

The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m2 intravenously (IV) as the first dose, with subsequent dosages of 600 mg/m2 IV every 3 weeks, or 400 mg/m2 IV every 2 weeks.

Zolbetuximab is a chimeric IgG1 antibody targeting Claudin 18.2 (CLDN18.2) originally developed by Ganymed Pharmaceuticals AG, which was acquired by Astellas. Japan’s Ministry of Health, Labour and Welfare approved VYLOY™ for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer in March 2024 and zolbetuximab was subsequently approved for untreated CLDN18.2-positive, HER2-negative unresectable advanced G/GEJ adenocarcinoma in the United Kingdom and the European Union in August and September 2024, respectively.

The marketing approvals were based on data from the Phase 3 SPOTLIGHT (NCT03504397) and GLOW clinical trials (NCT03653507). Both were randomized (1:1), double-blind, multicenter trials that included patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic G/GEJ adenocarcinoma. The SPOTLIGHT trial included 565 patients randomized to receive either zolbetuximab (800 mg/m2 loading dose administered IV followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 chemotherapy (283 patients) or placebo plus mFOLFOX6 (282 patients). The GLOW study evaluated zolbetuximab plus capecitabine and oxaliplatin as first-line treatment in 507 patients.

In the SPOTLIGHT study, the median progression-free survival (PFS) was 10.6 months (95% CI: 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy arm and 8.7 months (95% CI: 8.2, 10.3) in the placebo/chemotherapy arm (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). Median overall survival (OS) was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively, (HR 0.750 [95% CI: 0.601, 0.936]; 1-sided p-value=0.0053).

In the GLOW study, the median PFS was 8.2 months (95% CI: 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy arm and 6.8 months (95% CI: 6.1, 8.1) in the placebo/chemotherapy arm (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). Median OS was 14.4 months (95% CI: 12.3, 16.5) and 12.2 months (95% CI: 10.3, 13.7), respectively (HR 0.771 [95% CI: 0.615, 0.965]; 1-sided p-value=0.0118).

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies! 

FDA approves HYMPAVZI™ (marstacimab-hncq)

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On October 11, 2024, Pfizer Inc. announced that the U.S. Food and Drug Administration approved HYMPAVZI™ (marstacimab-hncq) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) without factor VIII (FVIII) inhibitors, or hemophilia B (congenital factor IX deficiency) without factor IX (FIX) inhibitors. Marstacimab is an IgG1l monoclonal antibody targeting tissue factor pathway inhibitor, a single-chain polypeptide that can reversibly inhibit Factor Xa. The antibody’s Fc mutations (L234A, L235A, G237A) impair Fc effector functions.

HYMPAVZI  is the first hemophilia medicine approved in the U.S. to be administered via a pre-filled, auto-injector pen. The approval was based on results of the Phase 3 BASIS study (NCT03938792), which evaluated the efficacy and safety marstacimab in adult and teenage participants with severe hemophilia A or moderately severe to severe hemophilia B.  In the study, HYMPAVZI reduced the annualized bleeding rate (ABR) for treated bleeds by 35% and 92% after a 12-month active treatment period compared to routine prophylaxis and on-demand treatment, respectively, in patients with hemophilia A or B without inhibitors. The safety profile for HYMPAVZI was consistent with Phase 1/2 results.

In September 2024, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion for marstacimab for the routine prophylaxis of bleeding episodes in adults and adolescents 12 years and older with severe hemophilia A without FVIII inhibitors, or severe hemophilia B without FIX inhibitors. A decision by the European Commission is expected by the end of 2024.

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies!