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Safety, pharmacokinetics (PK), pharmacodynamics (Pd), and antitumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies.
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2016
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Anti-erbb3 Antibody Ktn3379ImmunologyPathologyHuman Anti-erbb3 AntibodyImmunotherapeuticsImmunotherapyPd MarkersTumor BiologyOncologyMetronomic TherapyTumor ImmunityAnti-cancer AgentCancer ResearchMolecular OncologyPhase 1BTumor GrowthTargeted TherapiesCancer TreatmentPharmacologyImmune Checkpoint InhibitorMedicineCancer Growth
2501 Background: KTN3379 is a fully human anti-ErbB3 antibody with YTE half-life extension engineering that uniquely binds domain 3 locking ErbB3 in an inactive configuration. ErbB3 is implicated in tumor growth and treatment resistance. A phase 1b study of KTN3379 alone and in combination was undertaken to evaluate safety, PK, Pd, and efficacy (NCT02014909). Methods: Patients (pts) received KTN3379 alone at 5-20 mg/kg (N=21) or in combination at 15 or 20 mg/kg IV q3w with cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4) or trastuzumab (N=9). Safety monitoring and RECIST-based tumor assessments were conducted. PK was evaluated using a two-compartment pharmacokinetic model. Pd markers included serum ErbB3. Archival tumor was tested for neuregulin (NRG) and ErbB3. Results: 58 total pts were treated. No DLTs occurred in 21 pts receiving KTN3379 alone. DLTs of diarrhea, mucositis and rash were observed in 5 of 37 pts treated with combinations. The most common adverse events across all combinations were diarrhea, fatigue, nausea and rash. KTN3379 at or above 15 mg/kg was tolerated in all combination arms. Linear PK was observed at doses between 10 and 20 mg/kg and exceeded target concentration for antitumor activity. There was a trend toward slower clearance and longer half-life of KTN3379 compared to related compounds, consistent with the engineered YTE. Responses included 1 ongoing confirmed CR with cetuximab in a pt with HNSCC who had progressed on cetuximab alone, and 2 confirmed PRs with vemurafenib in pts with BRAF-mutant NSCLC, one of which previously progressed on dabrafenib (2 of 3 responders were NRG+). Analysis of Pd correlates is in progress and will be presented at ASCO. Conclusions: KTN3379 can be safely combined with standard doses of cetuximab, erlotinib, vemurafenib or trastuzumab at 15 to 20 mg/kg. Efficacy was observed including a CR in a pt with HNSCC with cetuximab and PRs in 2 pts with BRAF-mutant NSCLC in combination with vemurafenib. A phase 2 study of the combination of cetuximab and KTN3379 in HNSCC is planned, in addition to currently ongoing phase 1b studies in SCCHN and BRAF-mutant thyroid cancer. Clinical trial information: NCT02014909.