We performed a clinical trial in non-muscle invasive urothelial cancer (NMIUC) patients randomized (2:1) to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly x 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib. Thirty-seven volunteers (6 female/31 male, mean age 70, 35 white/2 non-white) with confirmed or suspected NMIUC were enrolled into either erlotinib (n=24; 900 mg-13, 600 mg-11) or placebo (n=13). Immunohistochemical assessment of phosphorylated and total EGFR in adjacent normal urothelium (20 erlotinib; 9 placebo) or tumor (21 erlotinib and 11 placebo subjects) at study end observed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, e-cadherin, p53 and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g. 38% experienced Grade 1 with rare grade 2 diarrhea and skin toxicity vs 8% in placebo. Clinically insignificant, but statistically significant (p=0.001) elevations in serum total bilirubin and creatinine were observed in erlotinib participants. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all erlotinib subjects and did not significantly differ between the 600 and 900 mg doses. Despite compelling pre-clinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib to prevent progression of NMI bladder cancer.
Cancer prevention research (Philadelphia, Pa.). 2024 Aug 27 [Epub ahead of print]
Tracy M Downs, Howard H Bailey, Taja Lozar, Natalie S Schmitz, Heather Green, Cameron O Scarlett, Thomas C Havighurst, Kyleigh Twaroski, Katina DeShong, Barbara Wollmer, Trinity J Bivalacqua, Daniel R Saltzstein, Neal Shore, KyungMann Kim, Wei Huang, William A Ricke, Lisa Barroilhet, Margaret House, Howard L Parnes, Edward Messing
University of Virginia, Charlottesville, VA, United States., UW Carbone Cancer Center, Madison, WI, United States., University of Wisconsin-Madison, Madison, WI, United States., UW Carbone Cancer Center, United States., University of Pennsylvania, Philadelphia, PA, United States., Urology San Antonio, San Antonio, TX, United States., Carolina Urologic Research Center, Myrtle Beach, SC, United States., National Cancer Institute, Rockville, MD, United States., National Cancer Institute, Bethesda, United States., University of Rochester, Rochester, NY, United States.