Uncommon EGFR Mutations

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.

Find out more about use of afatinib* in patients with non-small cell lung cancer (NSCLC) and uncommon EGFR mutations below. Additionally, you can visit uncommonEGFRmutations.com to search our database of published clinical outcomes with afatanib in patients with advanced NSCLC harboring uncommon EGFR mutations. The database features outcomes data from >800 patients with >100 different mutations, including individual mutations and complex mutations in TKI-naïve and TKI-pretreated patients. In addition, a pooled statistical analysis of the activity of afatinib in 693 of these patients has been published (Yang JC-H, et al. J Thoracic Oncol. 2020).4 

 

 

Database of outcomes in patients with uncommon EGFR mutations

Uncommon mutations database

Visit uncommonEGFRmutations.com to search the database for mutations and associated clinical outcomes.

Uncommon EGFR mutations and their prevalence

Uncommon EGFR mutations in NSCLC are highly heterogeneous, with approximately 600 variants identified.4  Exon 18 G719X and Exon 21 L861Q mutations are among the most prevalent, reported in 11‒28% and 16–35% of patients with uncommon EGFR mutations, respectively.5-7 The exon 20 S768I mutation is less frequent, accounting for an estimated 5% of uncommon EGFR mutations.6,7 Up to 25% of cases exhibit compound mutations, defined by the presence of multiple uncommon (and/or common) EGFR mutations within the same tumor.4 The detection of uncommon EGFR mutations in NSCLC is expected to rise as sequencing techniques increase in sensitivity.4

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.8  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 tumors with more than 100 different uncommon EGFR mutations, including compound mutations.8 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

Evidence of EGFR TKI treatment response in patients with uncommon EGFR mutations

No clinical trials have specifically prospectively evaluated the efficacy of first-generation EGFR TKIs in patients with uncommon EGFR mutations, although such patients were eligible for inclusion in the NEJ0029 and IPASS10 studies.

The NEJ002 trial compared gefitinib with carboplatin-paclitaxel as first-line therapy in patients with EGFR-mutant NSCLC.11 Outcomes were compared for patients with uncommon (G719X or L861Q) vs common EGFR mutations in a post-hoc analysis.11 Overall survival (OS) was significantly shorter for patients with uncommon EGFR mutations treated with gefitinib, but was similar for those treated with chemotherapy.11

Real-world evidence studies also suggest that patients with uncommon EGFR mutations have worse outcomes than those with common mutations when treated with first-line, first-generation EGFR TKIs.7

 

 

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).12 These patients were divided into three subgroups depending on the type of mutation: those with point mutations or duplications in exons 18–21 (n=38); those with de novo T790M mutations alone or in combination with other mutations (n=14); and those with exon 20 insertions (n=23).12 Overall, afatinib treatment was associated with decreases in tumor size and increased progression-free survival (PFS). The clinical activity of afatanib in tumors that harbored major uncommon EGFR mutations (including G719X, L861Q and S768I) was similar to that in the overall population.12 Clinical activity in patients with de novo T790M mutations or exon 20 insertions was limited.12

Tumor shrinkage and PFS in patients with uncommon EGFR mutations in LUX-Lung 2, 3 and 612

Figure for tumor shrinkage and PFS in patients with uncommon EGFR mutations

PFS, progression-free survival.

Efficacy of afatinib in patients with specific uncommon EGFR mutations in LUX-Lung 2, 3 and 612

Efficacy of afatinib in patients with uncommon EGFR mutations

*Unconfirmed responses.

CI, confidence interval; NE, non-estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Clinical trial of afatinib in patients with uncommon EGFR mutations

In a 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.13-15 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.14

PFS in patients with point mutations or duplications in exons 18–2114

PFS in patients with point mutations or duplications in exons 18–21

PFS, progression-free survival.

Time to symptomatic progression in patients with point mutations or duplications in exons 18–2114

TTSP in patients with point mutations or duplications in exons 18–21

TTSP, time to symptomatic progression.

Real-world data on afatinib in patients with uncommon EGFR mutations

Afatinib in patients with NSCLC harboring uncommon EGFR mutations: a pooled analysis database of 693 cases

A pooled analysis was conducted to investigate the activity of afatinib in 693 patients with NSCLC harboring uncommon EGFR mutations. Efficacy and safety data were collected prospectively from patients treated with afatinib in randomized clinical trials, compassionate-use and expanded-access programs, Phase IIIb trials and non-interventional trials, as well as a systematic literature review of published case series/studies.4 The database can be explored in detail at uncommonEGFRmutations.com.

In EGFR TKI naïve patients (n=315), afatinib demonstrated activity against major uncommon EGFR mutations (G719X, L861Q, S768I), with a median time to treatment failure (TTF) of 10.8 months (95% confidence interval [CI]: 8.1–16.6). Median TTF in patients with compound mutations was 14.7 months (95% CI: 6.8–18.5). Activity was also observed in patients with other uncommon mutations (median TTF 4.5 months; 95% CI: 2.9–9.7) and some exon 20 insertions (median TTF 4.2 months; 95% CI: 2.8–5.3).4 

View the full online publication here (Yang JC-H, et al. J Thoracic Oncol. 2020).4 In addition, you can visit uncommonEGFRmutations.com to explore our database of published clinical outcomes with afatinib in patients with advanced NSCLC harboring uncommon EGFR mutations.

Time to treatment failure in EGFR TKI-naïve patients with NSCLC harboring uncommon EGFR mutations

TTF in patients with uncommon EGFR mutations (EGFR TKI naïve vs pretreated)

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Pooled analysis of three large Phase IIIb studies of afatinib in patients with EGFR mutation-positive NSCLC

A pooled analysis of three large Phase IIIb studies of afatinib in patients with advanced, TKI-naïve EGFR mutation-positive NSCLC (total N=1,108) was performed.16 Overall, 198/1,108 (17.9%) patients harbored uncommon EGFR mutations (Ex20 ins, L861Q, G719A/S/C, T790M, S768I). Median PFS in this group was 7.4 months, and time to symptomatic progression was 8.3 months.16

PFS in patients with common and uncommon EGFR mutations

PFS in patients with common and uncommon EGFR mutations

PFS, progression-free survival.

Real-world data on efficacy of afatinib in Taiwanese patients with advanced lung adenocarcinoma and uncommon EGFR mutations

A retrospective, observational study using medical records from Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma (N=140) evaluated whether EGFR mutation type affected clinical efficacy.17 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=0.85; 95% CI: 0.47–1.53; p>0.05).17

PFS in relation to EGFR mutation type in Taiwanese patients (excluding patients with exon 20 insertions)17

PFS in relation to EGFR mutation type in Taiwanese patients

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

Of 104 patients who received first-line afatinib in a separate retrospective 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.18Afatinib 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.18

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 a retrospective study using medical record data from 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.19 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).19 In patients with tumors 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.19 None of the patients whose tumors developed a de novo T790M mutation had an objective response (afatinib: n=4; gefitinib: n=3).19

PFS with afatinib compared with first-generation EGFR TKIs in Korean patients with uncommon EGFR mutations19

PFS 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 retrospective study using medical records from Taiwanese patients with advanced NSCLC and uncommon EGFR mutations (N=56).20 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).20 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).20 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) versus 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).20

A significant prolongation of PFS with afatinib compared with first-generation EGFR TKIs was also observed in a small retrospective study using clinical data from a Japanese center.21 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).21

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Krawczyk P, et al. Ann Oncol 2016;27(2):358‒9.

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 Kohsaka S, et al. Sci Transl Med 2017;9(416):pii:eaan6566.

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Mok TS, et al. N Engl J Med 2009; 361(10):947‒57.

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Watanabe S, et al. J Thorac Oncol 2014;9:189–94.

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Yang JC, et al. Lancet Oncol 2015;16(7):830–8.

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Wu Y-L, et al. Poster presented at WCLC 2017 (Poster P3.01-036).

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Märten A, et al. Poster presented at ELCC 2018 (Poster 158P).

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Wu Y, et al. J Thorac Oncol 2019;14:S679–80.

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Passaro A, et al. Ann Oncol 2019;30:503P.

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Liang S-K, et al. Oncotarget 2017;8(52):90430–43.

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Tu C-Y, et al. Oncotarget 2018;9(36):24237–47.

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Kim Y, et al. Cancer Res Treat 2019;51(2):502‒9.

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Shen Y-C, et al. Lung Cancer 2017;110:56‒62.

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Tanaka I, et al. Lung Cancer 2019;127:169‒71.

*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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Page last updated: November 2020