Case Series: EGFR exon 19–24 large deletion in histologically diverse solid tumors

Background Epidermal growth factor receptor ( EGFR ) alterations are well-characterized oncogenic drivers, with therapeutic targeting being based on an intact tyrosine kinase domain (TKD). Large EGFR deletions spanning exons 19–24, which remove the majority of the TKD, have not been systematically described. Methods We retrospectively reviewed the City of Hope molecular results database for patients with solid tumors harboring an EGFR exon 19–24 deletion detected by a combined DNA and RNA sequencing comprehensive genomic profiling. Clinical, pathologic, and genomic data were extracted from electronic medical records. Results Eight patients were identified (a median age 47 years, range 23–55; 5 male) with glioblastoma (n=4), non-small cell lung cancer (NSCLC, n=2), papillary thyroid carcinoma (n=1), and spindle cell sarcoma (n=1). EGFR amplification co-occurred in five cases (62.5%) and TERT promoter mutations in four GBM cases. Two patients received EGFR -directed therapy. One with glioblastoma, whose tumor harbored concurrent EGFR amplification and EGFR vIII, received off-label osimertinib from month 28 through 33.5 months (approximately 5.5 months on treatment). One with stage IV NSCLC remained on osimertinib for approximately 7 months, with SBRT delivered near the end of this interval before transitioning to amivantamab plus lazertinib. Conclusions The EGFR exon 19–24 deletion is a rare, structurally distinct alteration that removes most of the TKD and frequently co-occurs with EGFR amplification, raising the possibility that it arises as a secondary rearrangement, though this cannot be confirmed. Because the predicted deletion product lacks an intact ATP-binding pocket, any observed tyrosine kinase inhibitor activity likely reflects inhibition of co-existing kinase-competent EGFR alleles rather than the deletion itself. It is therefore best regarded as a variant of uncertain functional and therapeutic significance and should prompt molecular tumor board review.