The NCCN NSCLC Panel has preference stratified the systemic therapy regimens and decided that afatinib or osimertinib are preferred options for patients with metastatic NSCLC and EGFR L861Q, G719X, and S768I mutation; other recommended options include erlotinib, gefitinib, dacomitinib.

...- Presence of one of the EGFR activating mutations in the tumor (exon 19 deletion or L858R, G719X or L861Q)...

...Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment)....

...- Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q)...

...- A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e. G719X, exon 19 deletion, L858R, L861Q)...

...- Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q)...

Progression-free survival and overall survival of 30 non-small cell lung cancer patients treated with erlotinib or afatinib due to single epidermal growth factor receptor L861Q positivity were compared retrospectively....Median progression-free survival was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups was 77.9 months and 30.3 months, respectively....Survival times of erlotinib and afatinib treatment are similar in patients with a single epidermal growth factor receptor L861Q mutation....In patients with rare mutation exon 21 L861Q positivity, both first-generation and second-generation tyrosine kinase inhibitors should be considered.

Uncommon mutation categories were: major uncommon (G719X, L861Q, S768I; 73%); compound (35%); ex20ins (12%); T790M (7%); other (9%). Most pts (n = 226; 92%) were treated in 1st-line with an EGFR TKI; 132 (54%), 70 (28%), 35 (14%) and 7 (3%) received afatinib, gefitinib, erlotinib and osimertinib....Overall median OS was 24.4 mos....ORR was 42% overall (major: 50%; compound: 49%; other: 44%; T790M: 20%; ex20ins: 17%); afatinib: 44% (DoR: 12.0 mos); 1st-gen TKIs: 44% (DoR: 11.0 mos)....Response was highest in pts with major uncommon, and/or compound mutations.

...EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy....The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively.

Among the 10 patients who received erlotinib, the ORR was 10% and the DCR was 50%. The DCR by a-EGFR mutation was as follows: G719X (2/4, 50%), L861Q (2/3, 66%), and exon 20 insertion (1/3, 33%).

Moreover, the PFS of patients with the G719X mutation (n = 12, median PFS: 32.9 months) was longer than that of patients with the L861Q mutation (n = 4, median PFS: 11.1) and compound mutations (n = 4, median PFS 7.3 months)….First and second generation EGFR-TKIs are effective treatments for patients with NSCLC with uncommon mutations. Notably, a greater favorable response was observed in patients with G719X mutations than those with L861Q and compound mutations.

Some of these include mutations known to be associated with sensitivity (L861Q) or resistance (exon 20 insertions) to EGFR-TKI. Other mutations or combinations of mutations, 

...recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%–50%

Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation...The median PFS for all 44 patients was 6.70 months [95% confidence interval (CI)=2.06-8.66 months], with a longer median PFS for those treated with erlotinib than gefitinib (7.50 versus 5.83 months; log-rank p=0.32) (Figure 2)….Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations.

The first case is a 65-year-old woman (P27), initially diagnosed with a localized form of NSCLC and treated by conventional chemotherapy and radiotherapy. After developing metastasis, she tested positive for the p.L861Q mutation and had received a 1-year long erlotinib therapy. Now she is in complete remission with an OS of 40 months...