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InOncology.com

Uncommon EGFR Mutations

Efficacy of afatinib in patients with uncommon EGFR mutations in LUX-Lung 2, 3 and 6

Of 600 patients treated with afatinib* in the LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 non-small cell lung cancer (NSCLC) trials, 75 (12%) patients had uncommon epidermal growth factor receptor (EGFR) mutations (i.e. not del19 or L858R).1 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). Overall, afatinib treatment was associated with decreases in tumour size that were associated with an increase in progression-free survival (PFS). Afatinib had clinical activity in tumours that harboured uncommon EGFR mutations, including G719X, L861Q and S768I mutations (Group 1). In patients receiving afatinib, median PFS and median overall survival (OS) were highest for patients in Group 1; in particular, median PFS was longest in eight patients with S768I mutations (14.7 months). However, afatinib had little clinical activity in patients with de novo T790M and exon 20 insertion mutations.

Tumour shrinkage and PFS in patients with uncommon EGFR mutations

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

PFS, progression-free survival.

Efficacy of afatinib in patients with specific uncommon EGFR mutations

Figure for efficacy of afatinib in patients with uncommon EGFR mutations

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

Efficacy of afatinib in patients with uncommon EGFR mutations in an ongoing Phase IIIb clinical trial

In an ongoing Phase IIIb open-label, single-arm study of afatinib in Asian patients with advanced EGFR mutation-positive NSCLC who had not been previously treated with an EGFR tyrosine kinase inhibitor, 55 of 479 patients had uncommon EGFR mutations.2,3 In an interim analysis of this trial in patients with point mutations or duplications in exons 18–21, median PFS was 9.5 months and median time to symptomatic progression was not estimable.3

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

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

NE, non-estimable; TTSP; time to symptomatic progression.

Real-world evidence of the efficacy 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.4 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).4

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

PFS in relation to EGFR mutation type in Taiwanese patients

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

In another retrospective Taiwanese study in patients with advanced EGFR mutation-positive NSCLC, 104 out of 422 patients received afatinib as first-line treatment.5 Of these patients, 56% had exon 19 deletions, 22% had L858R mutations and 22% had uncommon EGFR mutations. In patients who received afatinib, median PFS was 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.5

Afatinib compared with gefitinib or erlotinib in Korean patients with uncommon EGFR mutations

A retrospective study was carried out in 467 Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC who received first-line afatinib (n=165), gefitinib (n=230) or erlotinib (n=72).6 In patients with uncommon EGFR mutations, median PFS was longer with afatinib (median PFS had not been reached at the data cut-off) versus gefitinib (5.0 months) or erlotinib (6.1 months). However, the difference between groups did not reach statistical significance in this small sample (p=0.06; n=31; median follow-up for the overall patient population: 17.7 months).6 In patients with tumours that had uncommon EGFR mutations other than T790M, an objective response was seen in eight of 10 patients in the afatinib group, four of nine patients in the gefitinib group and one of five patients in the erlotinib group. 6 None of the patients whose tumours developed a de novo T790M mutation had an objective response (afatinib: n=4; gefitinib: n=3).6

PFS with afatinib, gefitinib and erlotinib in Korean patients with uncommon EGFR mutations

PFS in Korean patients with uncommon EGFR mutations

NR, not reached; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

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References

1

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

2

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

3

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

4

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

5

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

6

Kim Y, et al. Cancer Res Treat 2018 Jun 13. doi: 10.4143/crt.2018.117. [E-pub ahead of print].

*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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Last updated: August 2018