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A bispecific EGFR × HER3 antibody–drug conjugate for later-line recurrent or metastatic nasopharyngeal carcinoma: insights from BL-B01D1-303

Huaqiang Zhou, Jiayi Shen, Jiaqing Liu, Li Zhang and Yunpeng Yang
Cancer Biology & Medicine September 2026, 20260336; DOI: https://doi.org/10.20892/j.issn.2095-3941.2026.0336

Article Figures & Data

Figures

  • Treatment for recurrent or metastatic nasopharyngeal carcinoma. This timeline summarizes three successive treatment waves in R/M NPC. First-wave: chemotherapy. The timeline begins in 2016, when gemcitabine plus cisplatin was established as standard first-line treatment for R/M NPC, with an ORR of 64%, mPFS of 7.0 months, and mOS of 22.1 months in NCT01528618. Second-wave: ICIs have landed. From 2021 to 2025, chemoimmunotherapy was established as a first-line standard, with ORRs of 69.5%–87.3% and mPFS of 9.6–21.4 months across JUPITER-02, CAPTAIN-1ST, and RATIONALE-309. New-wave: arrival of the ADC era. From 2025 onwards, ADCs represented an emerging treatment backbone for NPC: BL-B01D1 showed later-line activity in the BL-B01D1-303 trial, with an ORR of 54.6% and mPFS of 8.38 months, and the MRG003 data provide additional evidence supporting the use of ADCs for NPC treatment. ADC, antibody–drug conjugate; ICI, immune checkpoint inhibitor; m, months; mOS, median overall survival; mPFS, median progression-free survival; NPC, nasopharyngeal carcinoma; ORR, objective response rate; R/M, recurrent or metastatic.
    Figure 1

    Treatment for recurrent or metastatic nasopharyngeal carcinoma. This timeline summarizes three successive treatment waves in R/M NPC. First-wave: chemotherapy. The timeline begins in 2016, when gemcitabine plus cisplatin was established as standard first-line treatment for R/M NPC, with an ORR of 64%, mPFS of 7.0 months, and mOS of 22.1 months in NCT01528618. Second-wave: ICIs have landed. From 2021 to 2025, chemoimmunotherapy was established as a first-line standard, with ORRs of 69.5%–87.3% and mPFS of 9.6–21.4 months across JUPITER-02, CAPTAIN-1ST, and RATIONALE-309. New-wave: arrival of the ADC era. From 2025 onwards, ADCs represented an emerging treatment backbone for NPC: BL-B01D1 showed later-line activity in the BL-B01D1-303 trial, with an ORR of 54.6% and mPFS of 8.38 months, and the MRG003 data provide additional evidence supporting the use of ADCs for NPC treatment. ADC, antibody–drug conjugate; ICI, immune checkpoint inhibitor; m, months; mOS, median overall survival; mPFS, median progression-free survival; NPC, nasopharyngeal carcinoma; ORR, objective response rate; R/M, recurrent or metastatic.

  • What BL-B01D1-303 established and what remains unresolved in later-line NPC. (1) Established evidence. In patients with R/M NPC previously treated with platinum-based chemotherapy and PD-1/PD-L1 blockade, iza-bren improved ORR, PFS, and DoR in comparison to physician’s choice of chemotherapy in a randomized phase 3 trial. (2) Unresolved questions. OS data remain immature. BL-B01D1-303 did not mandate prospective collection of tumor tissue for central testing of EGFR or HER3 expression. Therefore, correlations between baseline target expression and either response or survival outcomes cannot be assessed. Samples were also not prospectively collected for baseline or longitudinal assessment of plasma EBV DNA, leaving its value for response monitoring or prediction of ADC benefits unclear. The high incidence of grade ≥3 TRAEs and four treatment-related deaths necessitate careful patient selection, monitoring, supportive care, and dose modification. In addition, patients previously treated with an EGFR- or HER3-directed ADC or an ADC containing a TOP1 inhibitor payload were excluded. The trial therefore does not establish how iza-bren should be used after another ADC, whether the target or payload class should guide ADC sequencing, or which ADC should be selected first when multiple approved options are available. ADC, antibody–drug conjugate; DoR, duration of response; EBV, Epstein-Barr virus; EGFR: epidermal growth factor receptor; HER3: human epidermal growth factor receptor 3; NPC, nasopharyngeal carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R/M, recurrent or metastatic; TRAE, treatment-related adverse event.
    Figure 2

    What BL-B01D1-303 established and what remains unresolved in later-line NPC. (1) Established evidence. In patients with R/M NPC previously treated with platinum-based chemotherapy and PD-1/PD-L1 blockade, iza-bren improved ORR, PFS, and DoR in comparison to physician’s choice of chemotherapy in a randomized phase 3 trial. (2) Unresolved questions. OS data remain immature. BL-B01D1-303 did not mandate prospective collection of tumor tissue for central testing of EGFR or HER3 expression. Therefore, correlations between baseline target expression and either response or survival outcomes cannot be assessed. Samples were also not prospectively collected for baseline or longitudinal assessment of plasma EBV DNA, leaving its value for response monitoring or prediction of ADC benefits unclear. The high incidence of grade ≥3 TRAEs and four treatment-related deaths necessitate careful patient selection, monitoring, supportive care, and dose modification. In addition, patients previously treated with an EGFR- or HER3-directed ADC or an ADC containing a TOP1 inhibitor payload were excluded. The trial therefore does not establish how iza-bren should be used after another ADC, whether the target or payload class should guide ADC sequencing, or which ADC should be selected first when multiple approved options are available. ADC, antibody–drug conjugate; DoR, duration of response; EBV, Epstein-Barr virus; EGFR: epidermal growth factor receptor; HER3: human epidermal growth factor receptor 3; NPC, nasopharyngeal carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R/M, recurrent or metastatic; TRAE, treatment-related adverse event.

Tables

  • Table 1

    ADC landscape relevant to recurrent or metastatic nasopharyngeal carcinoma

    StudyTarget/payloadStagePopulation/settingKey dataSafety
    BL-B01D1-303 (iza-bren)7EGFR × HER3/TOP1 inhibitor payloadPublished randomised phase 3; approved in ChinaR/M NPC after at least 2 systemic lines including platinum and PD-1/PD-L1 inhibitorORR 54.6% vs. 27.0%; mPFS 8.38 vs. 4.34 months; median DoR 8.51 vs. 4.76 monthsGrade ≥3 TRAEs 80%; common grade ≥3 events were hematologic (anemia 50%, decrease in WBCs 43%, decrease in platelet count 43%, decrease in neutrophil count 38%); 4 treatment-related deaths
    MRG003 randomised trial (Magic-M001)11EGFR/MMAE payloadPhase 2b; approved in ChinaHeavily pretreated R/M NPC vs. capecitabine or docetaxelORR 30.2% vs. 11.5%; mPFS 5.8 vs. 2.8 months; interim mOS 17.1 vs. 12.0 monthsGrade ≥3 TRAEs 45.3% (decrease in WBC count 9.3%, decrease in neutrophil count 9.3%, hyponatremia 9.3%); 3 deaths due to AEs reported
    MRG003 phase 2a12EGFR/MMAE payloadPublished, phase 2aPreviously treated R/M NPC, including patients after PD-1/PD-L1 and multiple chemotherapy linesORR 42%; median DoR 8.0 months; mPFS 5.8 months; mOS 15.8 monthsGrade ≥3 TRAEs 39%; no treatment-related deaths reported
    YL201 phase 1/1b NPC cohort14B7-H3/TOP1 inhibitor payloadPublished, phase 1/1bHeavily pretreated advanced solid tumours; NPC subgroup had prior anti-PD-L1 and platinum, and 84.3% had at least 2 prior systemic linesORR 48.6%; DCR 92.9%Overall study grade ≥3 TRAEs included a decrease in neutrophil count (31.7%), decrease in WBC count (29.5%), and anemia (25.0%)
    YL201 (NCT06629597)B7-H3/TOP1 inhibitor payloadRecruiting, phase 3R/M NPC after prior PD-(L)1 inhibitor and at least 2 lines of chemotherapyN/AN/A
    MRG003 + pucotenlimab (Magic-C002, NCT06976190)EGFR ADC + PD-1 inhibitorRecruiting, phase 3R/M NPC after prior standard therapyN/AN/A
    MRG003 + pucotenlimab first-line study (NCT07381699)EGFR ADC + PD-1 inhibitorNot yet recruiting, phase 2First-line R/M NPCN/AN/A

    ADC, antibody–drug conjugate; DCR, disease control rate; DoR, duration of response; MMAE, monomethyl auristatin E; NPC, nasopharyngeal carcinoma; ORR, objective response rate; mOS, median overall survival; mPFS, median progression-free survival; R/M, recurrent or metastatic; TRAE, treatment-related adverse event; AE, adverse event; WBC, white blood cell; N/A, not applicable.

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