Quantitatively Modeling Factors that Influence the Therapeutic Doses of Antibodies

Tang, Yu; Li, Xiaobing; Cao, Yanguang

doi:10.1101/2020.05.08.084095

Cited by 1 publication

(1 citation statement)

References 32 publications

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“…There was no apparent relationship between GSK2849330 dose (or PK exposure) and observed AEs, recognizing that therapeutic mAbs pose challenges in discerning dose-toxicity relationships in first-in-human trials owing to their unique pharmacological properties. These include target selectivity with limited off-target activity, longer half-lives, and rare/delayed toxicities, which preclude determination of DLTs and MTD [25,26].…”

Section: Discussionmentioning

confidence: 99%

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors

et al. 2021

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Background. GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/NRG1 signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. Patients and Methods. Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the doseexpansion phase, patients received 30 mg/kg GSK2849330 IV weekly. Results. Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n=18, dose expansion: n=11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1rearranged non-small cell lung cancer. Conclusion. GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited anti-tumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. The Oncologist 2021;9999:• • Implications for Practice: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this ADCC-and CDC-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich for potential responders to anti-HER3 agents in ongoing trials.

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Section: Discussionmentioning

confidence: 99%