Clinical features and treatment outcome of non-small cell lung cancer (NSCLC) patients with uncommon or complex epidermal growth factor receptor (EGFR) mutations

Abstract

IntroductionTyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm.ResultsAmong 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm. Patients receiving first-line TKIs (N = 17) achieved median Progression Free Survival (PFS) and Overall Survival (OS) of 53 (IC 95%, 2–105) and 84 (CI 95%, 27–141) weeks respectively, without significant covariate impact. Response Rate and Disease Control Rate (DCR) were 47% and 65%, respectively. Uncommon exon 19 mutations achieved longer OS and PFS and higher DCR compared with exon 18 and 20 mutations. No additional gene mutation was discovered by MassARRAY analysis. TKIs were globally well tolerated.Materials and methodsA retrospective review of advanced non-squamous NSCLC harbouring rare/complex EGFRm referred to our Center between 2010 and 2015 was performed. Additional molecular pathways disregulation was explored in selected cases, through MassARRAY analysis.ConclusionsPeculiar clinical features and lower TKIs sensitivity of uncommon/complex compared with common EGFRm were shown. Exon 19 EGFRm achieved the best TKIs treatment outcome, while the optimal treatment of exon 18 and 20 mutations should be further clarified.

Epidermal Growth Factor Receptor Mutation Frequency in Squamous Cell Carcinoma and Its Diagnostic Performance in Cytological Samples: A Molecular and Immunohistochemical Study

“…Complex mutations with more than one type of EGFR mutations were found in 5/250 (2%) cases. Complex EGFR mutations have also been reported in the similar range (2-3.4%) in other studies [28, 41-43].…”

“…From the Asia-Pacific region, Taiwan shows highest EGFR mutation of 57% (range 36-76%), while Singapore shows the lowest frequency of 40% (range 39-43%). However, in the extreme south-east Australia lowest EGFR mutation frequency ranging between 7-36% [27, 28] was reported. The widest range of EGFR mutation in NSCLC has been reported from South America ranging between 9-67% with an overall frequency of 36% [2, 29, 30].…”

Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC

“…1B), all of which have been observed in patients with NSCLC (V769_D770insASV, D770delinsGY, H773_V774insH, Y764_V765insHH, and D770_N771ins-SVD; refs. 15,16). In Ba/F3 cells treated with amivantamab ranging from 0.05 to 1 mg/mL, a significant and dosedependent decrease in Ba/F3 cell viability (P < 0.0001) was observed in all five EGFR Exon20ins mutations (Fig.…”

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

“…Focusing on the most relevant of these mutations, we and others have reported outcomes in erlotinib- or gefitinib-treated NSCLC cases carrying at baseline the exon 18 G719X (G719C, G719S, G719A or G719D), exon 20 S768I, or exon 21 L861Q EGFR -mutations, which are present in 1–8% of EGFR M+ NSCLCs and often occur simultaneously as complex mutants (G719X+S768I/L861Q) [1,51,75,76,77,78,79,80]. Together with even more uncommon single or complex (≥2 different co-existing) mutations in exon 18, 20 or 21, the G719X, S768I, and L861Q mutants, although structurally considered TKI-sensitizing [76,81], have shown in several case reports and retrospective case series treated with erlotinib or gefitinib significantly lower RR, shorter PFS, and worse OS compared to exon 19dels or L858R [54,56,75,77,78,79,80,81,82,83,84,85,86,87]. The frequency of these different uncommon mutations and the reported associated values for RR and survival vary among different reports, which is likely related to the retrospective character of these studies and the heterogenous cohorts analyzed.…”