{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:09:29Z","timestamp":1789416569234,"version":"build-2803163510"},"reference-count":71,"publisher":"American Society of Clinical Oncology (ASCO)","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["J Clin Oncol"],"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>\n                      A structure-function classification has defined epidermal growth factor receptor (\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      ) P-loop\/\u03b1C-helix compressing (PACC) mutations and exon 20 insertions (ex20ins) as distinct subsets of kinase domain\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      alterations. Lung cancers harboring those mutations display reduced sensitivity to EGFR tyrosine kinase inhibitors (TKIs) currently approved for\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      classical sensitizing mutations and have often been managed with chemotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      This narrative review describes structural biology, clinical trial data, and real-world evidence on PACC and ex20ins\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      -mutant non\u2013small cell lung cancer, with a focus on current treatment options, emerging resistance mechanisms, and the potential treatment sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      For\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      PACC variants such as G719X, S768I, E709X, and L747X, second-generation TKIs such as afatinib provide the most consistent activity, whereas common-plus-PACC compound mutations often derive greater benefit from third-generation TKIs, including osimertinib. Emerging mutant-selective inhibitors, including firmonertinib and enozertinib, are now being explored as dedicated options for PACC mutations. For\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      ex20ins, amivantamab and mutant-selective TKIs such as sunvozertinib, zipalertinib, and firmonertinib have demonstrated clinically meaningful activity, with WU-KONG28 establishing first-line superiority of sunvozertinib over platinum-pemetrexed. Across both these subsets, resistance remains heterogeneous, encompassing on-target mutations, including C797S and E709K, as well as\n                      <jats:italic toggle=\"yes\">MET<\/jats:italic>\n                      and other bypass track pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      PACC and ex20ins are established subgroups of kinase domain mutations, distinct from classical mutations, due to structure and responsiveness to available TKIs.\n                    <\/jats:p>\n                  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