A Detouring Experience Not Recommended: Lessons Learned from PF00299804.

Patients with mutant EGFR positive non-small cell lung cancer (NSCLC) benefit from tyrosine kinase inhibitor (TKI) treatment. However, all patients ultimately develop acquired resistance, half of which are attributed to the EGFR exon 20 T790M mutation. A landmark publication in Cancer Research in 2007 demonstrated improved drug potency and pan-human EGFR (HER) inhibition with PF00299804, a second-generation EGFR TKI. Compared with first-generation EGFR TKI, PF00299804 showed the ability to overcome T790M mutation in vitro and had the potential to improve treatment outcomes of patients with mutant EGFR-positive NSCLC. Here we review the preclinical and clinical development of PF00299804 and reflect on the lessons learned from this detouring experience. See related article by Engelman and colleagues, Cancer Res 2007;67:11924-32.