Dataset Information

Phase 1 and dose-finding study of patritumab (U3-1287), a human monoclonal antibody targeting HER3, in Japanese patients with advanced solid tumors.

ABSTRACT:

Purpose

Patritumab (U3-1287) is a human epidermal growth factor receptor-3 (HER3)-targeted antibody that blocks ligand-associated activation of HER3. This open-label, phase 1 and dose-finding study (ClinicalTrials.jp Identifier: JapicCTI-101262) aimed to assess the safety, pharmacokinetics, incidence of anti-patritumab antibody, recommended dose for subsequent clinical studies, preliminary efficacy, and patritumab-related biomarkers in Japanese patients with advanced solid tumors.

Methods

Patients received patritumab 9 or 18 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity occurred. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Dose-limiting toxicities (DLTs) were evaluated from the initial dose to Cycle 1 Day 21. Tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).

Results

Nine patients received patritumab 9 mg/kg (n = 3) or 18 mg/kg (n = 6). Five patients were male, all patients had Eastern Cooperative Oncology Group performance status (PS) ≤ 1, and median (range) age of 67 (50-69) years. No DLTs were reported. Patritumab-related AEs reported in ≥2 patients were ALT increase (three patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash maculo-papular and AST increase (two each). Pharmacokinetics profile was similar to the preceding US phase 1 study. Soluble HER3 concentration in serum unexpectedly increased in all patients. These changes did not correlate with clinical response. Four patients had a best response of stable disease. All patients tested had negative for anti-patritumab antibody formation.

Conclusions

Patritumab was well tolerated up to 18 mg/kg without DLTs in Japanese patients with advanced solid tumors. Soluble HER3 increased in all patients.

SUBMITTER: Wakui H

PROVIDER: S-EPMC3931937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (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 methodsPatients 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 dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly.ResultsTwenty-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-NRG1-rearranged non-small cell lung cancer (NSCLC).ConclusionGSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor 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.Implications for practiceThis 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 antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-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 potential responders to anti-HER3 agents in ongoing trials.