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

Abstract

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