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Glioblastoma is an aggressive form of central nervous system tumor. Recurrence rates following primary therapy are high, and few second-line treatment options provide durable clinical benefit. Aberrations of the epidermal growth factor receptor ( EGFR ) gene are observed in up to 57% of glioblastoma cases and EGFR overexpression has been identified in approximately 60% of primary glioblastomas. In preclinical studies, afatinib, a second-generation ErbB blocker, inhibited cell proliferation in cells harboring mutations commonly found in glioblastoma. In two previous Phase I/II studies of afatinib plus temozolomide in patients with glioblastoma, limited efficacy was observed; however, there was notable benefit in patients with the EGFR variant III ( EGFRvIII) mutation, EGFR amplification, and those with loss of phosphatase and tensin homolog (PTEN). This case series report details treatment histories of three long-term responders from these trials. Next-generation sequencing of tumor samples identified alterations in a number of cancer-related genes, including mutations in, and amplification of, EGFR . Tumor samples from all three patients shared favorable prognostic factors, eg O 6 -methylguanine-DNA methyl-transferase ( MGMT ) gene promoter methylation; however, negative prognostic factors were also observed, suggesting that these shared genetic features did not completely account for the favorable responses. The genetic profile of the tumor from Patient 1 showed clear differences from the other two tumors: lack of involvement of EGFR aberrations but with a mutation occurring in PTPN11 . Preclinical studies showed that single-agent afatinib and temozolomide both separately inhibit the growth of tumors with a C-terminal EGFR truncation, thus providing further rationale for combining these two agents in the treatment of glioblastomas harboring EGFR aberrations. These findings suggest that afatinib may provide treatment benefit in patients with glioblastomas that harbor ErbB family aberrations and, potentially, other genetic aberrations. Further studies are needed to establish which patients with newly diagnosed/recurrent glioblastomas may potentially benefit from treatment with afatinib., Competing Interests: Scott Owen reports being part of an advisory council or committee for Bayer, Bristol-Myers Squibb, Merck, Pfizer; and receiving honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, Pfizer, and Roche. David A Reardon reports research support (paid to Dana-Farber Cancer Institute) from Acerta Pharmaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Omniox, Tragara; advisory/consultation (paid to Dr. Reardon) from AbbVie, Advantagene, Agenus, Agios, Amgen, AnHeart Therapeutics, Bayer, Boston Biomedical, Boehringer Ingelheim, Bristol-Myers Squibb, Celldex, Deciphera, Del Mar Pharma, DNAtrix, Ellipses Pharma, EMD Serono, Genenta, Genentech/Roche, Hoffman-LaRoche, Ltd, Imvax, Inovio, Kintara, Kiyatec, Medicenna Biopharma, Inc., Merck, Merck KGaA, Monteris, Neuvogen, Novartis, Novocure, Oncorus, Oxigene, Regeneron, Stemline, Sumitomo Dainippon Pharma, Pyramid, Taiho Oncology, Inc., Y-mabs Therapeutics; honoraria (paid to Dr. Reardon) from AbbVie, Advantagene, Agenus, Agios, Amgen, Bayer, Boston Biomedical, Boehringer Ingelheim, Bristol-Myers Squibb, Celldex, Deciphera, DelMar, Ellipses Pharma, EMD Serono, Genenta, Genentech/Roche, Imvax, Inovio, Kintara, Kiyatec, Medicenna Biopharma, Inc., Merck, Merck KGaA, Monteris, Neuvogen, Novartis, Novocure, Oncorus, Oxigene, Regeneron, Stemline, Sumitomo Dainippon Pharma, Taiho Oncology, Inc. Neil Gibson is an employee of Boehringer-Ingelheim GmbH & Co. KG. Karine Pemberton declares being a Global project Manager working for Boehringer Ingelheim. Flavio Solca reports employment from Boehringer Ingelheim RCV, during the conduct of the study; In addition, Flavio Solca is a co-inventor on Patent WO 02/50043 A1 describing afatinib. Agnieszka Cseh was an employee of Boehringer Ingelheim International. Current affiliation for Frank Saran is at the Department of Radiation Oncology, Auckland District Health Board, Auckland, New Zealand. The remaining authors report no potential conflicts of interest in this work., (© 2022 Owen et al.)