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; Yunpeng Yang

doi:10.20892/j.issn.2095-3941.2026.0336

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Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: a multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023; 41: 1061–72.e4.
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6. Qu S,
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First-line tislelizumab plus chemotherapy for recurrent or metastatic nasopharyngeal cancer: three-year follow-up of the phase 3 RATIONALE-309 randomized clinical trial. JAMA Oncol. 2026; 12: 384–93.
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Izalontamab brengitecan, an EGFR and HER3 bispecific antibody-drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China. Lancet. 2025; 406: 2235–43.
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Efficacy and safety of PD-1 inhibitors in recurrent or metastatic nasopharyngeal carcinoma patients after failure of platinum-containing regimens: a systematic review and meta-analysis. BMC Cancer. 2023; 23: 1172.
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BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 2024; 25: 901–11.
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Becotatug vedotin for recurrent/metastatic nasopharyngeal carcinoma (Magic-M001): a multicenter, randomized trial. Ann Oncol. 2026: S0923-7534(26)00936-1
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2. Han F,
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Becotatug vedotin, MRG003, in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase IIa trial. Med. 2026; 7: 101029.
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A B7H3-targeting antibody–drug conjugate in advanced solid tumors: a phase 1/1b trial. Nat Med. 2025; 31: 1949–57.
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2. Fang B,
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4. Lu Y,
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EGFR- and HER3-targeted bispecific antibody-drug conjugate demonstrates antitumor activity in metastatic castration-resistant prostate cancer. J Clin Invest. 2026; 136: e201090.
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2. Wan W,
3. Zhao S,
4. Zhuo S,
5. Zhang Y,
6. Chen L,
7. Li G, et al.
Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation. Cancer Res. 2023; 83: 2642.
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2. Yonesaka K,
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HER3 augmentation via blockade of EGFR/AKT signaling enhances anticancer activity of HER3-targeting patritumab deruxtecan in EGFR-mutated non-small cell lung cancer. Clin Cancer Res. 2022; 28: 390–403.
OpenUrl Abstract/FREE Full Text
18.↵
2. Huang S,
3. Li C,
4. Armstrong EA,
5. Peet CR,
6. Saker J,
7. Amler LC, et al.
Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res. 2013; 73: 824–33.
OpenUrl Abstract/FREE Full Text
19.↵
2. Zhao Y,
3. Zhao H,
4. Wang Q,
5. Yang K,
6. Li Y,
7. Fu Z, et al.
Izalontamab brengitecan (iza-bren), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate in extensive-stage small cell lung cancer: results from a phase Ib study. J Clin Oncol. 2026: JCO2600243.
20.↵
2. Powell CA,
3. Modi S,
4. Iwata H,
5. Takahashi S,
6. Smit EF,
7. Siena S, et al.
Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022; 7: 100554.
21.↵
2. Haratani K,
3. Yonesaka K,
4. Takamura S,
5. Maenishi O,
6. Kato R,
7. Takegawa N, et al.
U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation. J Clin Invest. 2020; 130: 374–88.
OpenUrl CrossRef PubMed
22.
2. Iwata TN,
3. Ishii C,
4. Ishida S,
5. Ogitani Y,
6. Wada T,
7. Agatsuma T.
A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol Cancer Ther. 2018; 17: 1494–503.
OpenUrl Abstract/FREE Full Text
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2. Marinello J,
3. Arleo A,
4. Russo M,
5. Delcuratolo M,
6. Ciccarelli F,
7. Pommier Y, et al.
Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway. Br J Cancer. 2022; 127: 1214–25.
OpenUrl CrossRef PubMed
24.
2. Nakajima S,
3. Mimura K,
4. Matsumoto T,
5. Thar Min AK,
6. Ito M,
7. Nakano H, et al.
The effects of T-DXd on the expression of HLA class I and chemokines CXCL9/10/11 in HER2-overexpressing gastric cancer cells. Sci Rep. 2021; 11: 16891.
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2. Oh KS,
3. Nam AR,
4. Bang JH,
5. Jeong Y,
6. Choo SY,
7. Kim HJ, et al.
Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells. Cell Commun Signal. 2024; 22: 518.
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2. Hong X,
3. Wang G,
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5. Shi W,
6. Wang T,
7. Rong Z, et al.
Prognostic value of EGFR and p-EGFR in nasopharyngeal carcinoma: a systematic review and meta-analysis. Medicine (Baltimore). 2022; 101: e28507.
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2. Qiu MZ,
3. Zhang Y,
4. Guo Y,
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OpenUrl PubMed

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[1] 1.↵

Mai HQ,
Chen QY,
Chen D,
Hu C,
Yang K,
Wen J, et al.
Toripalimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: the JUPITER-02 randomized clinical trial. JAMA. 2023; 330: 1961–70.
OpenUrl CrossRef PubMed

[3] Mai HQ,

[4] Chen QY,

[5] Chen D,

[6] Hu C,

[7] Yang K,

[8] Wen J, et al.

[9] 2.

Yang Y,
Qu S,
Li J,
Hu C,
Xu M,
Li W, et al.
Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021; 22: 1162–74.
OpenUrl CrossRef PubMed

[11] Yang Y,

[12] Qu S,

[13] Li J,

[14] Hu C,

[15] Xu M,

[16] Li W, et al.

[17] 3.

Yang Y,
Pan J,
Wang H,
Zhao Y,
Qu S,
Chen N, et al.
Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: a multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023; 41: 1061–72.e4.
OpenUrl CrossRef PubMed

[19] Yang Y,

[20] Pan J,

[21] Wang H,

[22] Zhao Y,

[23] Qu S,

[24] Chen N, et al.

[25] 4.↵

Yang Y,
Yen CJ,
Pan J,
Wang H,
Qu S,
Chen N, et al.
First-line tislelizumab plus chemotherapy for recurrent or metastatic nasopharyngeal cancer: three-year follow-up of the phase 3 RATIONALE-309 randomized clinical trial. JAMA Oncol. 2026; 12: 384–93.
OpenUrl PubMed

[27] Yang Y,

[28] Yen CJ,

[29] Pan J,

[30] Wang H,

[31] Qu S,

[32] Chen N, et al.

[33] 5.↵

Rueda Domínguez A,
Cirauqui B,
García Castaño A,
Alvarez Cabellos R,
Carral Maseda A,
Castelo Fernández B, et al.
SEOM-TTCC clinical guideline for nasopharyngeal carcinoma (update 2025). Clin Transl Oncol. 2026; 28: 1151–64.
OpenUrl PubMed

[35] Rueda Domínguez A,

[36] Cirauqui B,

[37] García Castaño A,

[38] Alvarez Cabellos R,

[39] Carral Maseda A,

[40] Castelo Fernández B, et al.

[41] 6.↵

Liu X,
Shen H,
Zhang L,
Huang W,
Zhang S,
Zhang B.
Immunotherapy for recurrent or metastatic nasopharyngeal carcinoma. NPJ Precis Oncol. 2024; 8: 101.
OpenUrl PubMed

[43] Liu X,

[44] Shen H,

[45] Zhang L,

[46] Huang W,

[47] Zhang S,

[48] Zhang B.

[49] 7.↵

Yang Y,
Zhou H,
Tang L,
Qiu S,
Han Y,
Ji D, et al.
Izalontamab brengitecan, an EGFR and HER3 bispecific antibody-drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China. Lancet. 2025; 406: 2235–43.
OpenUrl PubMed

[51] Yang Y,

[52] Zhou H,

[53] Tang L,

[54] Qiu S,

[55] Han Y,

[56] Ji D, et al.

[57] 8.↵

Luo J,
Xiao W,
Hua F,
Cao Y,
Wang D,
Wang X.
Efficacy and safety of PD-1 inhibitors in recurrent or metastatic nasopharyngeal carcinoma patients after failure of platinum-containing regimens: a systematic review and meta-analysis. BMC Cancer. 2023; 23: 1172.
OpenUrl PubMed

[59] Luo J,

[60] Xiao W,

[61] Hua F,

[62] Cao Y,

[63] Wang D,

[64] Wang X.

[65] 9.↵

Chan ATC,
Hui EP,
Ma BBY.
The arrival of antibody drug conjugates in nasopharyngeal cancer. Lancet. 2025; 406: 2194–6.
OpenUrl PubMed

[67] Chan ATC,

[68] Hui EP,

[69] Ma BBY.

[70] 10.

Ma Y,
Huang Y,
Zhao Y,
Zhao S,
Xue J,
Yang Y, et al.
BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 2024; 25: 901–11.
OpenUrl CrossRef PubMed

[72] Ma Y,

[73] Huang Y,

[74] Zhao Y,

[75] Zhao S,

[76] Xue J,

[77] Yang Y, et al.

[78] 11.↵

Han F,
Xiang YQ,
Wang XH,
Qu S,
Tang LQ,
Shu XL, et al.
Becotatug vedotin for recurrent/metastatic nasopharyngeal carcinoma (Magic-M001): a multicenter, randomized trial. Ann Oncol. 2026: S0923-7534(26)00936-1

[80] Han F,

[81] Xiang YQ,

[82] Wang XH,

[83] Qu S,

[84] Tang LQ,

[85] Shu XL, et al.

[86] 12.↵

Han F,
Lv X,
Zhou YJ,
He Q,
Guo Y,
Xiang YQ, et al.
Becotatug vedotin, MRG003, in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase IIa trial. Med. 2026; 7: 101029.

[88] Han F,

[89] Lv X,

[90] Zhou YJ,

[91] He Q,

[92] Guo Y,

[93] Xiang YQ, et al.

[94] 13.↵

Blair HA.
Becotatug vedotin: first approval. Drugs. 2026; 86: 573–9.
OpenUrl PubMed

[96] Blair HA.

[97] 14.↵

Ma Y,
Yang Y,
Huang Y,
Fang W,
Xue J,
Meng X, et al.
A B7H3-targeting antibody–drug conjugate in advanced solid tumors: a phase 1/1b trial. Nat Med. 2025; 31: 1949–57.
OpenUrl PubMed

[99] Ma Y,

[100] Yang Y,

[101] Huang Y,

[102] Fang W,

[103] Xue J,

[104] Meng X, et al.

[105] 15.↵

Fang B,
Li X,
Lu Y,
Ma W,
Gan H,
Zhang T, et al.
EGFR- and HER3-targeted bispecific antibody-drug conjugate demonstrates antitumor activity in metastatic castration-resistant prostate cancer. J Clin Invest. 2026; 136: e201090.

[107] Fang B,

[108] Li X,

[109] Lu Y,

[110] Ma W,

[111] Gan H,

[112] Zhang T, et al.

[113] 16.↵

Wan W,
Zhao S,
Zhuo S,
Zhang Y,
Chen L,
Li G, et al.
Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation. Cancer Res. 2023; 83: 2642.
OpenUrl

[115] Wan W,

[116] Zhao S,

[117] Zhuo S,

[118] Zhang Y,

[119] Chen L,

[120] Li G, et al.

[121] 17.↵

Yonesaka K,
Tanizaki J,
Maenishi O,
Haratani K,
Kawakami H,
Tanaka K, et al.
HER3 augmentation via blockade of EGFR/AKT signaling enhances anticancer activity of HER3-targeting patritumab deruxtecan in EGFR-mutated non-small cell lung cancer. Clin Cancer Res. 2022; 28: 390–403.
OpenUrl Abstract/FREE Full Text

[123] Yonesaka K,

[124] Tanizaki J,

[125] Maenishi O,

[126] Haratani K,

[127] Kawakami H,

[128] Tanaka K, et al.

[129] 18.↵

Huang S,
Li C,
Armstrong EA,
Peet CR,
Saker J,
Amler LC, et al.
Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res. 2013; 73: 824–33.
OpenUrl Abstract/FREE Full Text

[131] Huang S,

[132] Li C,

[133] Armstrong EA,

[134] Peet CR,

[135] Saker J,

[136] Amler LC, et al.

[137] 19.↵

Zhao Y,
Zhao H,
Wang Q,
Yang K,
Li Y,
Fu Z, et al.
Izalontamab brengitecan (iza-bren), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate in extensive-stage small cell lung cancer: results from a phase Ib study. J Clin Oncol. 2026: JCO2600243.

[139] Zhao Y,

[140] Zhao H,

[141] Wang Q,

[142] Yang K,

[143] Li Y,

[144] Fu Z, et al.

[145] 20.↵

Powell CA,
Modi S,
Iwata H,
Takahashi S,
Smit EF,
Siena S, et al.
Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022; 7: 100554.

[147] Powell CA,

[148] Modi S,

[149] Iwata H,

[150] Takahashi S,

[151] Smit EF,

[152] Siena S, et al.

[153] 21.↵

Haratani K,
Yonesaka K,
Takamura S,
Maenishi O,
Kato R,
Takegawa N, et al.
U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation. J Clin Invest. 2020; 130: 374–88.
OpenUrl CrossRef PubMed

[155] Haratani K,

[156] Yonesaka K,

[157] Takamura S,

[158] Maenishi O,

[159] Kato R,

[160] Takegawa N, et al.

[161] 22.

Iwata TN,
Ishii C,
Ishida S,
Ogitani Y,
Wada T,
Agatsuma T.
A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol Cancer Ther. 2018; 17: 1494–503.
OpenUrl Abstract/FREE Full Text

[163] Iwata TN,

[164] Ishii C,

[165] Ishida S,

[166] Ogitani Y,

[167] Wada T,

[168] Agatsuma T.

[169] 23.

Marinello J,
Arleo A,
Russo M,
Delcuratolo M,
Ciccarelli F,
Pommier Y, et al.
Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway. Br J Cancer. 2022; 127: 1214–25.
OpenUrl CrossRef PubMed

[171] Marinello J,

[172] Arleo A,

[173] Russo M,

[174] Delcuratolo M,

[175] Ciccarelli F,

[176] Pommier Y, et al.

[177] 24.

Nakajima S,
Mimura K,
Matsumoto T,
Thar Min AK,
Ito M,
Nakano H, et al.
The effects of T-DXd on the expression of HLA class I and chemokines CXCL9/10/11 in HER2-overexpressing gastric cancer cells. Sci Rep. 2021; 11: 16891.

[179] Nakajima S,

[180] Mimura K,

[181] Matsumoto T,

[182] Thar Min AK,

[183] Ito M,

[184] Nakano H, et al.

[185] 25.↵

Oh KS,
Nam AR,
Bang JH,
Jeong Y,
Choo SY,
Kim HJ, et al.
Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells. Cell Commun Signal. 2024; 22: 518.
OpenUrl PubMed

[187] Oh KS,

[188] Nam AR,

[189] Bang JH,

[190] Jeong Y,

[191] Choo SY,

[192] Kim HJ, et al.

[193] 26.↵

Hong X,
Wang G,
Xu G,
Shi W,
Wang T,
Rong Z, et al.
Prognostic value of EGFR and p-EGFR in nasopharyngeal carcinoma: a systematic review and meta-analysis. Medicine (Baltimore). 2022; 101: e28507.

[195] Hong X,

[196] Wang G,

[197] Xu G,

[198] Shi W,

[199] Wang T,

[200] Rong Z, et al.

[201] 27.↵

Qiu MZ,
Zhang Y,
Guo Y,
Guo W,
Nian W,
Liao W, et al.
Evaluation of safety of treatment with anti–epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: a phase 1 nonrandomized clinical trial. JAMA Oncol. 2022; 8: 1042–6.
OpenUrl PubMed

[203] Qiu MZ,

[204] Zhang Y,

[205] Guo Y,

[206] Guo W,

[207] Nian W,

[208] Liao W, et al.

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