P-Loop/αC-Helix Compressing Mutations and Exon 20 Insertions in EGFR-Mutant NSCLC: A Rapidly Evolving Therapeutic Landscape.

PURPOSE: A structure-function classification has defined epidermal growth factor receptor (EGFR) P-loop/αC-helix compressing (PACC) mutations and exon 20 insertions (ex20ins) as distinct subsets of kinase domain EGFR alterations. Lung cancers harboring those mutations display reduced sensitivity to EGFR tyrosine kinase inhibitors (TKIs) currently approved for EGFR classical sensitizing mutations and have often been managed with chemotherapy. METHODS: This narrative review describes structural biology, clinical trial data, and real-world evidence on PACC and ex20ins EGFR-mutant non-small cell lung cancer, with a focus on current treatment options, emerging resistance mechanisms, and the potential treatment sequencing. RESULTS: For EGFR 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 EGFR 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 MET and other bypass track pathways. CONCLUSION: EGFR PACC and ex20ins are established subgroups of kinase domain mutations, distinct from classical mutations, due to structure and responsiveness to available TKIs.