...- 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)....

...Group 4: Patient has a documented EGFR Exon20ins activating mutation....

...- An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any Clinical Laboratory Improvement Act (CLIA)-certified tissue assay -...

...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....

...Documented EGFR mutation in exon 18-21, except insertions in exon 20, based on tissue analysis....

...- 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)....

...Uncommon mutation of EGFR (exon 20 insertion excluded) 5....

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

...Presence of an EGFR exon 20, non-T790M, mutation, deletions and/or insertion only, 5. ...

...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).`...

...Patients with EGFR mutation(any form of EGFR mutation subtype except for EGFR exon 20 insertion mutation) detected by First generation sequencing(Sager sequencing) or next generation sequencing(NGS) from tissue sample includes fresh tissue or formalin-fixed paraffin-embedded(FFPE)sample or body fluid sample(blood, pleural effusion, cerebrospinal fluid ,etc.) 3....

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.

The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC….The ORR was 28% (95% CI, 12-49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7-27.6). The median PFS was 6.8 months (95% CI, 4.6-9.1) and the median OS was 15.2 months (95% CI, 14.3-16.0).

The POSITION20 study shows antitumor activity in EGFRex20+ NSCLC patients treated with 160mg osimertinib, with an ORR of 27%. The TRAEs are consistent with other reports.

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.

CONTRADICTING EVIDENCE: Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins.

...Among the 20 eligible pts, the best response was PR in 4 pts and CR in one pt, for a confirmed ORR of 25%; 12 (60%) pts had SD. The median PFS was 9.7 months (95% CI, 4.07, NA), median duration of response (DOR) was 5.7 months (95% CI, 4.73, NA.)...Osimertinib 160mg daily is well-tolerated and showed clinical activity in EGFR ins20-mutant NSCLC with a response rate of 25%, disease control rate of 85%, and mPFS of 9.7 months.

...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.

17 patients with advanced NSCLC harboring an EGFR exon 20 insertion were treated with osimertinib 80 mg...Median PFS was 3.7 months (95% CI: 2.3 – 5.4 months). Six of seventeen patients (35%) achieved DCR at five months.

EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%)...Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0-12.9 months; range 4.9-14.6 months).