Epidermal growth factor receptor (EGFR) mutations occur most commonly as exon 19 deletions (Del19; approximately 45‒50% of cases) and as exon 21 point mutations at the L858R residue (approximately 35‒40% of cases).1‒3 While the efficacy of EGFR tyrosine kinase inhibitors (TKIs) is well established in patients with these common mutations, data are also available on EGFR TKI treatment outcomes in patients with less common EGFR mutations.
Uncommon EGFR mutations and their prevalence
Uncommon EGFR mutations in non-small cell lung cancer (NSCLC) comprise a heterogeneous group of genetic alterations. Exon 18 G719 and Exon 21 L861 mutations are among the most common, reported in 11‒28% and 16–35% of patients with uncommon EGFR mutations, respectively.4‒6 The exon 20 S768I mutation is less frequent, accounting for an estimated 5% of uncommon EGFR mutations.5,6
Preclinical evidence suggests uncommon EGFR mutations are associated with differential sensitivities to EGFR TKIs
The heterogeneity of EGFR mutations has potential clinical implications for EGFR-targeted TKIs, which have different activities against different mutations.7 Data from in vitro studies, for example, suggest that E709, G719 and Ins19 mutations may have greater sensitivity to afatinib* than to gefitinib or erlotinib.3
A recent preclinical study used a high-throughput assay to investigate the activity of different EGFR TKIs in more than 100 different uncommon EGFR mutations, including compound mutations.7 Afatinib demonstrated a broad inhibitory profile, with activity against almost all mutations tested and greater potency against many variants than either erlotinib or gefitinib.7 While the activity of gefitinib and erlotinib appeared to be reduced in certain compound mutations (e.g. L858R and E709A/G) the activity of afatinib against the L858R.E709 compound mutation was not remarkably different to that against the L858R mutation alone.7
Clinical trial evidence of EGFR TKI treatment response in patients with uncommon EGFR mutations
No clinical trials have specifically evaluated the efficacy of first-generation EGFR TKIs in uncommon EGFR mutations. Although patients with uncommon EGFR mutations were eligible for inclusion in the NEJ0028 and IPASS9 studies, no subgroup analysis by mutation type were published.
LUX-Lung clinical trials: efficacy of afatinib in patients with uncommon EGFR mutations
Of 600 patients treated with afatinib in the LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 NSCLC trials, 75 (12%) patients had uncommon EGFR mutations (i.e. not del19 or L858R).10 These patients were divided into three subgroups depending on the type of mutation: those with point mutations or duplications in exons 18–21 (Group 1; n=38); those with de novo T790M mutations alone or in combination with other mutations (Group 2; n=14); and those with exon 20 insertions (Group 3; n=23).10 Overall, afatinib treatment was associated with decreases in tumour size and increased progression-free survival (PFS). Afatinib had clinical activity in tumours that harboured uncommon EGFR mutations, including G719X, L861Q and S768I mutations (Group 1).10 Median PFS and median overall survival (OS) for afatinib treatment were highest for Group 1 patients. PFS was longest in eight patients with S768I mutations (median 14.7 months).10 However, afatinib had limited clinical activity in patients with de novo T790M and exon 20 insertion mutations.
Tumour shrinkage and PFS in patients with uncommon EGFR mutations in LUX-Lung 2, 3 and 6
PFS, progression-free survival.
Efficacy of afatinib in patients with specific uncommon EGFR mutations
CI, confidence interval; NE, non-estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
Ongoing trials of afatinib in patients with uncommon EGFR mutations
In an ongoing, Phase IIIb, open-label, single-arm study of afatinib in TKI-naïve Asian patients with advanced EGFR mutation-positive NSCLC (N=479), 55 patients (11.5%) had uncommon EGFR mutations.11,12 At interim analysis patients with uncommon point mutations or duplications in exons 18–21 had a median PFS of 9.5 months; time to symptomatic progression was not estimable.12
PFS in patients with point mutations or duplications in exons 18–21
NE, non-estimable; PFS, progression-free survival.
Time to symptomatic progression in patients with point mutations or duplications in exons 18–21
TTSP, time to symptomatic progression.
Real-world evidence for afatinib in patients with uncommon EGFR mutations
Real-world effectiveness of afatinib in Taiwanese patients with advanced lung adenocarcinoma and uncommon EGFR mutations
A retrospective, observational study evaluated whether EGFR mutation type affected clinical efficacy in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma (N=140).13 Twenty-three percent of patients in this study had complex or rare EGFR mutations. After excluding patients with exon 20 insertions from the analysis, there was no significant difference in median PFS between patients who had common EGFR mutations (del19/L858R; n=108) and those who had uncommon EGFR mutations (n=22; median PFS, 12.2 vs 11.5 months; hazard ratio [HR]=0.85; 95% confidence interval [CI]: 0.47–1.53; p>0.05).13
PFS in relation to EGFR mutation type in Taiwanese patients (excluding patients with exon 20 insertions)
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
Of 104 patients who received first-line afatinib in a separate Taiwanese study in patients with advanced EGFR mutation-positive NSCLC (N=422), 56% had exon 19 deletions, 22% had L858R mutations and 22% had uncommon EGFR mutations.14 Afatinib was associated with a median PFS of 12.2 months in the overall patient group, 12.2 months in patients with exon 19 mutations, 11.7 months in patients with L858R mutations and 19.7 months in patients with uncommon EGFR mutations.14
Comparative effectiveness of afatinib and first-generation EGFR TKIs in patients with uncommon EGFR mutations
The comparative effectiveness of afatinib and first-generation EGFR TKIs (gefitinib or erlotinib) has been evaluated in a number of retrospective studies involving Asian patient populations.
In Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC (N=467), treatment outcomes were compared for first-line afatinib (n=165), gefitinib (n=230) or erlotinib (n=72) and stratified by EGFR mutation type.15 In patients with uncommon EGFR mutations, median PFS was longer with afatinib (not reached at time of data cut-off) than for gefitinib and erlotinib (5.0 and 6.1 months, respectively). The difference between groups did not, however, reach statistical significance (p=0.06; n=31; median follow-up for the overall patient population: 17.7 months).15 In patients with tumours that had uncommon EGFR mutations (other than T790M), an objective response was seen in 80% of patients (eight of ten) in the afatinib group, 44% (four of nine) patients in the gefitinib group and 20% (one of five) patients in the erlotinib group. 15 None of the patients whose tumours developed a de novo T790M mutation had an objective response (afatinib: n=4; gefitinib: n=3).15
PFS with afatinib compared with first-generation EGFR TKIs in Korean patients with uncommon EGFR mutations
NR, not reached; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
The comparative effectiveness of afatinib and first-generation EGFR TKIs gefitinib and erlotinib was also evaluated in a Taiwanese population with advanced NSCLC and uncommon EGFR mutations (N=56).16 After excluding five patients with exon 20 insertions, median PFS with afatinib (n=21) was 11.0 (95% CI: 0‒22.8) months compared with 3.6 (95% CI: 0.1‒7.1) months with gefitinib or erlotinib (n=30) (p=0.03).16 In a subset of patients with uncommon EGFR mutations occurring together with common (del19/L858R) mutations, there was no difference in median PFS between the afatinib (n=8) and gefitinib/erlotinib (n=9) groups (11.0 [95% CI: 0‒26.1] vs 8.2 [95% CI: 2.1‒14.3] months; p=0.19).16 However, in patients with uncommon EGFR mutations occurring alone or in combination with other uncommon EGFR mutations, there was a numerical improvement in PFS with afatinib (n=13) vs gefitinib/erlotinib (n=21) that did not reach statistical significance (18.3 [95% CI: 3.2‒33.4] vs 2.8 [95% CI: 2.1‒3.4] months; p=0.07).16
A significant prolongation of PFS with afatinib compared with first-generation EGFR TKIs was also observed in a small retrospective Japanese study.17 Among 18 patients with advanced NSCLC and uncommon EGFR mutations, those who received first-line treatment with afatinib (n=8) had a PFS of 17.1 months compared with 5.5 months for those treated with first-line gefitinib or erlotinib (n=10) (p=0.0481).17
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*Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list, please click here. Registration conditions differ internationally; please refer to locally approved prescribing information.
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