Purpose: Izalontamab (SI-B001) is a novel EGFR×HER3 bispecific antibody. This first-in-human phase I study presents the safety and pharmacokinetics of izalontamab. Patients and Methods: Previously treated patients with locally advanced or metastatic epithelial tumors were enrolled in the dose-escalation or dose-expansion phases. The dose-escalation phase consisted of an accelerated titration and a "3+3" design with 9 dose levels from 0.4 to 28.0 mg/kg. The dose-expansion phase included 5 dose levels from 6.0 to 21.0 mg/kg. Izalontamab was administered intravenously weekly(QW) or every two weeks(Q2W) in a four-week cycle. Available pre-treatment specimens were obtained to explore the relationship between EGFR/HER3 expression and efficacy. Results: 60 patients were enrolled. Among the 60 enrolled patients, 49 had non-small cell lung cancer(NSCLC), 6 had nasopharyngeal cancer, 3 had head and neck cancer(HNSCC), and 2 had other types of cancer. The most common treatment-related adverse events were rash (42%), paronychia (25%) and infusion-related reactions (23%). No drug-related death occurred. Izalontamab displayed non-linear pharmacokinetic behavior and clearance at steady state appeared to be approaching a dose-independent value at 6 mg/kg and above. The best response included 2 confirmed partial responses in NSCLC and HNSCC patients; 18 patients had stable disease, including NSCLC(n = 17) and colorectal cancer(n=1). The recommended phase 2 dose for izalontamab was determined as 9-16mg/kg QW weekly. Conclusions: Izalontamab was well tolerated and demonstrated preliminary antitumor activity in patients with locally advanced or metastatic epithelial tumors, supporting it as a promising therapeutic candidate for combination therapies, with a phase 3 study currently underway.

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First page of Izalontamab (SI-B001), a novel EGFRxHER3 bispecific antibody in patients with Locally Advanced or Metastatic Epithelial Tumor: Results from first-in-human phase I/Ib study<alt-title alt-title-type="left-running">Phase I study of izalontamab in advanced epithelial tumor</alt-title>

Supplementary data

Supplementary Methods S1

Supplementary Text. Inclusion and exclusion criteria

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Supplementary Figure S1

Supplementary Fig. S1 Pharmacokinetics of Izalontamab

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Supplementary Figure S2

Supplementary Fig. S2 Swimmer plots of responses to treatment and the duration of treatment in efficacy analysis set.

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Supplementary Figure S3

Supplementary Fig. S3 The waterfall plot depicts the best objective responses concerning the tumor size in the efficacy analysis set.

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Supplementary Figure S4

Supplementary Fig. S4 The relationship between baseline EGFR/HER3 expression and best response in patients

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Supplementary Table S1

Supplementary Table S1. Baseline clinical characteristics in different dose groups

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Supplementary Table S2

Supplementary Table S2. Representativeness of Study Participants

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Supplementary Table S3

Supplementary Table S3. Adverse events in different dose groups

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Supplementary Table S4

Supplementary Table S4. Treatment-emergent adverse events of Izalontamab

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Supplementary Table S5

Supplementary Table S5. Pharmacokinetic Parameter Summary of Izalontamab (Visit C1D22)

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Supplementary Table S6

Supplementary Table S6. Summary of anti-drug antibody

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Supplementary Table S7

Supplementary Table S7. Details of Rash and Paronychia at different doses

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