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 mutations…

...- EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q....

...Staging will be according to the pTNM (pathologic tumour,node, metastasis) staging system for lung cancer 8) Confirmation by the local laboratory that the tumour harbours 1 of the following EGFRmutations:-1 of the 2 common EGFR mutations (Ex19del, L858R), either alone or incombination with other EGFR mutations including de novo T790M and excluding allexon 20 insertions (Common EGFRm Cohort); or - Uncommon EGFR mutations G719X, S768I, and L861Q, either alone, in combination with each other, or in combination with other uncommon EGFR mutations (excluding all exon 20 insertions) (Uncommon EGFRm Cohort).9) Complete surgical resection of the primary NSCLC is mandatory. ...

...The tumour harbors at least 1 of the 4 uncommon EGFR mutations (G719X/L861Q/S768I/T790M), either alone or in combination, which...

...Patients must fulfil one of the following:• Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)• OR• Must have experienced clinical benefit from EGFR-TKI, according to the Jackman criteri (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI7. ...

...- A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (eg., T790M, G719X, Exon20 insertions, S7681 and L861Q)....

...L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X....

...- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally....

...- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q)....

...Confirmation by the local laboratory that the tumour harbours one of the two common EGFR mutations (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo EGFR mutation resulting in substitution of threonine with methionine at amino acid position 790 in exon 20 of EGFR (T790M) or uncommon EGFR mutations G719X, S768I, and L861Q, either alone, in combination with each other, or in combination with other uncommon EGFR mutations (excluding all exon 20 insertions) (Uncommon EGFRm Cohort)....

...At least one documented uncommon EGFR mutation of G719X/L861Q/S768I/de novo T790M without EGFR Ex19del/L858R/exon 20 insertion as detected in tumour tissue, through real-time PCR or NGS analysis from accredited laboratories approved by the Chinese regulatory authority....

...EGFR activating mutations include exon19 deletion, T790M, L858R, G719X, L861Q, or S768I....

...Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy...

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)....

...- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6....

...For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.- Histologically or cytologically documented non-squamous NSCLC with completely resectable (Stage II - IIIB N2) disease (according to Version 8 of the IASLC Cancer Staging Manual [IASLC Staging Manual in Thoracic Oncology 2016]).- Complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a Mulit-disciplinary Team (MDT) evaluation (which should include a thoracic surgeon, specialised in oncologic procedures).- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.- A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q).`...

...According to the ARMS or Super-ARMS or NGS test results of tumor tissue or plasma from a certified laboratory approved by Chinese regulatory authorities, the tumor carries at least one of the 4 rare EGFR mutations (G719X/L861Q/S768I/T790M) (single mutation or compound mutation), but not other EGFR mutations (including ex19del/L858R). ...

...These include exon 19 deletions, L858R (exon 21), G719X (exon 18), L861Q (exon 21), S768I (exon 20) and T790M (exon 20). ...

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)....

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)....

...- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR...

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)....

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or T790M EGFR resistance mutation as assessed by local laboratory/or central laboratory via tissue/cytology or in plasma....

...- A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q)....

...Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test....

...Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)....

Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I....ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations.

The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting....Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations.

This is a multi-center, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC osimertinib-treated as first EGFR inhibitor....The largest subgroups were G719X (30%), L861Q (20%) and de novo T790M (15%)….For L861Q ORR was 80%, mPFS 16m and mDOR 16m….Osimertinib demonstrated activity in ucEGFRmut with high rate of disease control systemically and intracranially.

This is a multi-center, international, academic-initiated retrospective study of mNSCLC with ucEGFRmut treated with osimertinib prior to any other EGFRi….Median DOR was 17.4 months (95% CI 9.1-NA). RR for G719X was 43.8%, 33.3% for T790M, and 71.4% for L861Q....Median PFS was 9.1 months (95% CI 8.1–19.2). Median OS was 18.4 months (95% CI 13.5-NR)....Osimertinib showed activity in ucEGFRmut with 85% disease control rate and encouraging PFS and DOR. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRmut.

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.

...Fifty-one NSCLC pts with uncommon EGFR mutations...The most frequent mutations were L861Q (35.3%,N=18), G719X (27.5%, N=14), and Exon 20 ins (15.7%, N=8).Osi was used in the 1L setting in 39.2% (N=20).Median time on osi was 7.1 months (mo.) in the overall cohort (95% CI, 5.4 to 8.8 mo.) and 8.9 mo.(95% CI, 7.0 to 10.8 mo.) in pts receiving 1L osi.Patients harboring G719X (N=4) and L861Q (N=10) mutations had a median time on 1L osimertinib of 5.8 mo. and 19.3 mo.,respectively.One patient’s tumor had an EGFR exon 19 ins and was on 1L osi with a partial response for 16.8 months.Two patients with Exon 20 ins were on 1L osi for 9.3 mo. and 8 mo.,respectively....Patients with L861Q and Exon 19 insertion appeared to benefit the most from osi in this time on treatment retrospective analysis.

This difference in PFS was maintained even when we restricted our analysis to patients who first received afatinib or osimertinib (respectively, 7 vs. 15.5 months; P < .002; HR ¼ 0.81;...Median PFS across EGFR subtypes was as follows: exon 19 del (17 months), L858R (18 months), G719X/L861Q (7 months), and exon 20 insertion (5 months). Median OS across EGFR subtypes was as follows: exon 19 del (63 months), L858R (73 months), G719X/L861Q (30 months), and exon 20 insertion (16 months).

The most common mutations are G719A/C/D/S/X (19, 52.8%) followed by L861Q (9, 25%), S7681 (8, 22%), and others (4, 11%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10 (52.6%) with G719A/C/D/S/X mutation; three (37.5%) with S768I mutation....Osimertinib showed highly active and durable in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports.