A phase 1 study combining the HER3 antibody seriba

Authors: James M Cleary Autumn J McRee Geoffrey I Shapiro Sara M Tolaney Bert H O’Neil Jeffrey D Kearns Sara Mathews Rachel Nering Gavin MacBeath Akos Czibere Sunil Sharma W Michael Korn

Publish Date: 2016/11/16

Volume: 35, Issue: 1, Pages: 68-78

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Abstract

Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFRdirected therapies Methods This Phase 1 trial assessed the tolerability maximum tolerated dose MTD and pharmacokinetic PK properties of the HER3 antibody seribantumab in combination with cetuximab Part I or cetuximab and irinotecan Part II in patients with EGFRdependent cancers In Part I escalating doses of seribantumab and cetuximab were administered In Part II of the trial escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks Results 34 patients were enrolled in Part I seribantumab/cetuximab and 14 patients were enrolled in Part II seribantumab/cetuximab/irinotecan Common toxicities of seribantumab/cetuximab included acneiform rash diarrhea stomatitis and paronychia The MTD of Part I was seribantumab 40 mg/kg bolus then 20 mg/kg weekly combined with cetuximab 400 mg/m2 bolus then 250 mg/m2 IV weekly Common toxicities reported in the seribantumab/cetuximab/irinotecan combination were similar to the Part I portion However toxicities were more frequent and severe with the triplet combination There was one treatmentrelated death in Part II secondary to Grade 4 neutropenia and grade 3 diarrhea Other doselimiting toxicities in Part II were Grade 3 mucositis and Grade 3 diarrhea A cholangiocarcinoma patient previously untreated with EGFRdirected therapy had a confirmed partial response PR One colorectal cancer patient previously treated with EGFRdirected therapy had an unconfirmed PR Conclusions Seribantumab/cetuximab was well tolerated and patients experienced toxicities typical to EGFR inhibition Unlike the seribantumab/cetuximab doublet seribantumab/cetuximab/irinotecan was difficult to tolerate in this heavily pretreated population There was limited efficacy of the combination therapyJC reports research funding to his institution from Merrimack Pharmaceuticals Taiho Oncology Merck Roche Abbvie Precision Biologics and Bristol Myers Squib He was a paid consultant with Agios Pharmaceuticals GI was a paid consultant for Lilly GI Therapeutics EMD Serono Chugai and Millennium He has also received research funding from Pfizer ST reports research funding to her institution from Genentech/Roche Merck Exelixis Pfizer Lilly and Novartis SM RN GM JK and AC are all employees of Merrimack Pharmaceuticals WMK is a paid consultant for Merrimack Pharmaceuticals AM BO and SS report no conflicts of interest

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