ERBB4 and glioblastoma: Afatinib is another potent, orally taken ATP-competitive inhibitor targeting EGFR, EGFRvIII, ERBB3 and ERBB4.57,58 Although it showed inhibitory efficacy against GBM cells harboring EGFRvIII and EGFR R108K mutations,57,59 results from completed phase I/II clinical trials showed that afatinib alone had limited activity with recurrent GBM patients, and the addition of temozolomide did not improve the PFS-6 rate or the median PFS (NCT00727506).60 Thus, the overall antitumor activities of second-generation EGFR inhibitors were comparable to those of the first generation.