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…

Patient had tumors harboring at least one uncommon mutation (exon 20 insertions [Ins20]: n = 70; T790M: n = 20; G719X: n = 41; L861Q: n = 47; S768I: n = 20; other: n = 25. Of note, 35% of pts had Ins20 mutations, a heterogeneous group generally resistant to EGFR TKIs). In those pts with uncommon mutations and brain metastases, median TTSP and PFS were 7.6 mos (95% CI 4.6–10.1) and 7.4 mos (95% CI 4.6–9.1)....Clinical activity in pts with uncommon mutations was greatest against tumors harboring G719X, L861Q or S768I. Some pts with Ins20 or T790M mutations appeared to benefit from treatment.

...1.Non-squamous NSCLC patients confirmed by imaging and histopathology as III B to IV stage; 2.Positive EGFR gene mutation (including 19DEL, 21L858R, G719A, G719C, G719S, L861Q, V689M, N700D, E709K/Q, S720P, L858R, N826S, A839T, K846R, G863D, G719X, S768I complex mutation, G719X complex mutation, etc.); 3.Has not received any previous systemic anti-tumor therapy; 4.No brain metastases, or asymptomatic brain metastases, or symptomatic brain metastases are treated and stable....

...7) Gene test from tumor tissues confirmed EGFR sensitive mutation positive (including classical mutation and non-classical mutation :19del, L858R, L861Q, G719X, S768I); 8) No brain metastasis, or accompanied by asymptomatic brain metastasis, or symptomatic brain metastasis after treatment which change to stable; 9) Adequate hematological function: neutrophil absolute count >=1.5x10^9/L, platelet count >= 100x10^9/L exclusion, hemoglobin >= 90 g/L; 10) Adequate liver function: all patients whose total bilirubin level is <= 1.5 times the normal upper limit, and the level of aspartate aminotransferase and aspartate aminotransferase is <=2.5 times the normal upper limit; 11) Adequate renal function: creatinine clearance rate >= 50ml/min (Cockcroft-Gault formula); 12) Adequate coagulation function: international standardized ratio (INR) or prothrombin time (PT) <=1.5 times the normal upper limit. ...

This is a multi-center observational study. Data of patients with major uncommon (G719X, L681Q, S786I) EGFR-mutated NSCLC who initiated first-line afatinib...ORR and DCR were 79% and 92%, respectively. Of 16 patients with measurable and non-radiated brain metastases, intracranial ORR and DCR were 56% and 100%, respectively. On mutation types, afatinib demonstrated activity against G719X (median TTF = 13.5 months; 95% CI: 8.0-19.0; ORR = 81.0%), L861Q (median TTF = 12.8 months; 95% CI: 6.5-19.1; ORR = 55%), S768I (median TTF = 10.5 months; 95% CI: 5.5-28.4; ORR = 50%), and compound mutations (median TTF = 17.5 months; 95% CI: 13.5-21.5; ORR = 87%)....Afatinib was a treatment of choice for Vietnamese patients with NSCLC harboring major uncommon mutations, demonstrating an encouraging survival outcome, high response rate, and manageable tolerability profile.

This study aimed to evaluate the efficacy of EGFR-TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations….Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124)....Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations....Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations....Tumors containing the L861Q, G719X, or S768I mutations were classified as “major uncommon mutations.”

In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), ‘other’ mutations (median TTF: 10.7 months; ORR: 63.9%)….High response rates were observed in patients with the specific uncommon mutations, G719X (61.3%), L861Q (57.7%), S768I (71.4%)...

We retrospectively evaluated survival characteristics of 125 patients with EGFR exon 18 and exon 20 mutated NSCLC...the second most common mutation was S768I, which was usually positive alone. Nine patients with this mutation received erlotinib and 6 received afatinib (Table 2)….In this patient group, especially patients with complex mutations are as sensitive to EGFR TKI treatment as classical mutations, and in patients with rare exon 18 and exon 20 mutations, both first- and second-generation TKIs should be considered.

...TTF was 15.0, 11.7, and 16.6 months in patients with G719X, S768I, and L861Q mutations, respectively. In patients with the rare uncommon mutation, median TTF was 10.0 months and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case of TTF > 1 year.

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.

Advanced NSCLC patients harboring uncommon (other than L858R and exon 19 deletion) EGFR mutations at baseline tissue biopsy were selected...Clinical activity of afatinib in patients with non-resistant uncommon mutations was consistent according to the different alterations (L861Q ORR 63% and DCR 75%; G719X ORR 44% and DCR 89%; and S768I ORR 50% and DCR 50%; p=0.81 and 0.17, respectively)…

Clinical activity (Asian/non-Asian) was observed against major uncommon mutations (ORR: 66/59%; median DoR: 14.7/15.9 mos; G719X: 62/65%; L861Q: 60/50%; S768I: 80/25%), compound mutations (ORR: 81/100%; median DoR: 11.5/18.6 mos) and other uncommon mutations (ORR: 79/60%; median DoR: 9.0/10.7 mos). Some pts with Ins20 responded (21/23%). TTF was longest in pts with compound mutations, particularly non-Asian pts (median 18.5 mos). Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations...

...the analysis showed that both Asian and non-Asian patients with NSCLC whose tumors harbor G719X/L861Q/S768I non-resistant EGFR mutations responded to afatinib.

This pooled analysis assessed afatinib activity in Asian/non-Asian, EGFR TKI-naïve pts with NSCLC and uncommon EGFR mutations, treated in RCTs and real-world studies. Uncommon mutations were classed as: de novo T790M; exon 20 insertions (Ins20); major uncommon mutations (G719X/L861Q/S768I)...Afatinib is effective in pts with NSCLC harboring major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations, unaffected by ethnicity.

Patients had uncommon EGFR mutations, which were categorized as follows...“major” uncommon mutations (G719X, L861Q, and S768I)….In EGFR TKI–naive patients (n = 315), afatinib demonstrated activity against major uncommon mutations (median TTF = 10.8 mo; 95% confidence interval [CI]: 8.1–16.6; ORR = 60.0%), compound mutations (median TTF = 14.7 mo; 95% CI: 6.8–18.5; ORR = 77.1%)....Afatinib has clinical activity in NSCLC against major uncommon and compound EGFR mutations.

Afatinib was well tolerated with no new safety signals, and efficacy was encouraging in Korean patients with EGFRm+ NSCLC, including those with baseline brain metastases and/or uncommon EGFR mutations....Patients with the major uncommon mutation S768I (n=7) had an ORR of 42.9%.

Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations)....In patients with uncommon EGFR mutations (group 1), median PFS (mPFS) was significantly longer when patients were treated with EGFR-TKI in 1L compared to chemotherapy (HR 0.53; 95% CI 0.30-0.93, P = 0.028….Afatinib was the most frequently applied EGFR-TKI in this group (36/79 treatments, 46%), followed by erlotinib (22/79 treatments, 28%), gefitinib (13/79 treatments, 16%) and osimertinib (8/79 treatments, 10%) (Figure 3A).

Clinical activity (Asian/non-Asian) was observed against major uncommon mutations (ORR: 66/59%; median DoR: 14.7/15.9 mos; G719X: 62/65%; L861Q: 60/50%; S768I: 80/25%), compound mutations (ORR: 81/100%; median DoR: 11.5/18.6 mos) and other uncommon mutations (ORR: 79/60%; median DoR: 9.0/10.7 mos). Some pts with Ins20 responded (21/23%)…Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations, unaffected by ethnicity.

...we initiated a real-world study to investigate the distribution and therapeutic responses in advanced NSCLC patients harboring uncommon EGFR alterations...EGFR uncommon alterations included single uncommon mutation (e.g., exon 18 p. G719X, exon 20 p. S768I, and exon 21 p. L861Q)...patients harboring compound EGFR uncommon mutations achieved significantly longer mPFS compared with single EGFR uncommon mutations (12.6 months, 95% CI: 9.4–15.9 months vs. 7.6 months, 95%CI: 6.8–8.4 months, p = 0.017) (Figure 2B)...this study indicated that the combination of 1G EGFR-TKIs with chemotherapy or afatinib monotherapy was associated with a favorable response and promising PFS benefit for NSCLC patients with uncommon EGFR alterations.