Compound EGFR Mutations Are Predominantly P-Loop and Alpha-C Helix Compressing Mutations With Increased...

EGFR kinase domain mutations in NSCLC can be classified into four subgroups (classical-like, exon 20 loop insertions, P-loop and αC-helix compressing [PACC], and T790M-like) to effectively predict the response to tyrosine kinase inhibitors (TKIs). These mutations can occur individually or as compound mutations. The frequency, drug sensitivity, and clinical outcomes of compound EGFR mutations, particularly those involving PACC and classical co-mutations, remain incompletely defined.

We characterized the landscape of single and compound EGFR mutations in 15,851 EGFR-mutant NSCLC samples tested by cell-free DNA. Drug sensitivity was assessed using in vitro Ba/F3 models. Clinical outcomes were retrospectively evaluated from the MD Anderson Cancer Center real-world cohort, the Guardant Health real-world cohort, and a literature review, totaling 1542 patients.

Among all EGFR mutations, PACC mutations were found in 9% (1421/15,851) of samples and occurred predominantly as in cis compound mutations (66.2%, 941/1421). Conversely, 84.3% (9576/11,365) of classical mutations and 88.6% (848/957) of exon 20 insertions were mainly single mutations, respectively (p < 0.0001). In vitro testing revealed that compound PACC mutations, including PACC plus PACC and PACC plus classical mutations, exhibited sensitivity profiles similar to those of single PACC mutations, with enhanced sensitivity to second- versus first- or third-generation TKIs. Analysis of retrospective data supported the finding that patients with NSCLC harboring single or compound PACC mutations had improved outcomes with second-generation TKIs compared with first- or third-generation TKIs.

EGFR PACC mutations primarily occur as in cis compound mutations. Compound PACC mutations exhibit similar patterns of drug sensitivity to those of single PACC mutations.