IRESSA is a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

EGFR EXON 19 DELETION OR L858R MUTATIONS….Progression on erlotinib (± ramucirumab or bevacizumab), afatinib, gefitinib, or dacomitinib….SUBSEQUENT THERAPY...Continue erlotinib (± ramucirumab or bevacizumab) or afatinib or gefitinib or dacomitinib (if T790M-)

This was an open-label, parallel, phase 3 randomized clinical trial (GAP BRAIN) conducted in 6 centers in China. The main eligibility criteria included histologically or cytologically confirmed NSCLC with EGFR-sensitive mutation (exon 19 deletion or exon 21 L858R mutation)...In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases...

Pts with newly diagnosed stage III/IV/ recurrent NSCLC harboring an EGFR activating mutations (exon 19 deletion or exon 21 L858R) were randomized...GCP demonstrated significantly better PFS compared to G….Additional OS analysis (G:101 events vs GCP:83 events) revealed that median survival time of GCP was much longer than that of G (52.2 months vs 38.8 months, HR:0.695, p = 0.013).

First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy.

Pts with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (exon 19 deletion or exon 21 L858R) were randomized 1:1 to G 250 mg PO QD or GCP (G 250mg PO QD combined with carboplatin AUC 5 + pemetrexed 500mg/m2, every 3 weeks)....Although there was no difference in PFS2 between the arms, additional OS analysis (G 101 events vs GCP 83 events) revealed that median survival time of GCP was much longer than that of G (52.2 months vs 38.8 months, HR: 0.695, p = 0.013)....NEJ009 was the first phase III study which evaluated the efficacy of a combination of EGFR-TKI and platinum doublet chemotherapy in untreated advanced NSCLC pts with EGFR mutations.

...Locally identified EGFR exon 19 deletion or exon 21 p.L858R. ...

...Tumors with common EGFR mutations (19del or L858R) 3....

...Sensitive EGFR mutations (19del, 21L858R); 5....

...- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q)...

...- EGFR exon 19 deletion or exon 21 L858R....

...- Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations;...

...- Patients with tumor EGFR mutation positive (exon 19 deletion mutation or exon 21 L858R substitution mutation);...

...- History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21)...

...Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and 21 L858R). ...

...EGFR mutation, exon 19 Del or exon 21 L858R, must be confirmed before enrollment. ...

...EGFR exon 19 deletion (19del) or exon 21 mutation (L858R) has been confirmed....

...Harbouring activating EGFR mutations (either exon 19 deletion or L858R in exon 21); 4. ...

...to provide a testable specimen (tissue or cancerous pleural effusion) before the group to carry out genotyping, test results show EGFR-positive exon 19 deletion or exon 21 (L858R) mutation; 4) major organ function within 7 days prior to treatment, meeting the following criteria: (1) blood routine examination criteria (14 days without blood transfusion): hemoglobin (HB) ≥ 90g/L; neutrophil absolute (ANC) ≥ 1.5×10^9/L; platelet (PLT) ≥80×10^9/L; (2) biochemical tests to meet the following criteria: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase AST ≤ 2.5 ULN, Liver metastases, ALT and AST ≤ 5 ULN; serum creatinine (Cr) ≤ 1.5 ULN or creatinine clearance (CCr) ≥ 60ml / min; (3) Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥ normal low (50%). ...

...A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie, exon 19 deletion , L858R, L861Q, G719X etc.)....

...Patients with advanced non-small cell lung cancer (NSCLC) confirmed by histopathology or cytology, who can not be operated or have postoperative recurrence and metastasis [2009 IASLC international lung cancer staging (8th Edition) TNM stage III B-IV, see Appendix 2 of the trial protocol], according to the definition of the joint committee on cancer staging standards, they are not suitable for radical treatment; To confirm EGFR 19del or L858R mutation according to the detection method recommended by "expert consensus on detection of epidermal growth factor receptor gene mutation in Chinese patients with non-small cell lung cancer"; [Chinese Journal of Pathology, 2011,40 (10): 700-702] 2. ...

...- EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance...

...EGFR mutation (exon 19 deletion or exon 21 L858R) with Bim deletion or low abundance for EGFR mutation....

...EGFR exon 19 deletion or exon 21 L858R substitution mutation confirmed; 5....

...- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R)...

...- Target population is completely resected pathological stage IIIA-N2 NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation....

...Patients with deletion of exon 19 or mutation of L858R at exon 21 in EGFR gene 4....

...Detection of EGFR-positive exon 19 deletion or exon 21 (L858R) mutation was performed by providing a detectable specimen (tissue or cancerous pleural effusion) prior to enrollment; 5....

...to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M)....

This was an open-label, single arm, multi-center phase II trial that included patients aged 19 or older with sensitizing EGFR mutations and stage III NSCLC who had received platinum-based CCRT. Participants were treated with Gefitinib (250mg daily) up to 12 months....53.5% (8/15) of the patients had L858R point mutation and 40% (6/15) of the patients had 19 deletion….Overall response rate was 66.67% (10/15) and disease control rate was 93.33% (14/15).

In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial…use of Vβ20-1Jβ2-3 specifically for EGFR exon 19 del or Vβ9Jβ2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting...high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

Among the 60 patients, 52 patients (86.7%) had exon 19 deletion or L858R mutation, with 49 patients (81.7%) receiving gefitinib as the first-line EGFR TKI. The median PFS and OS from the initiation of EGFR TKI were 10.4 months (95% confidence interval [CI], 7.4–13.2) and 21.3 months (95% CI, 13.4–28.8), respectively.

Patients with advanced EGFR-mutant NSCLC were given concurrent gefitinib (250 mg orally daily) and 3-week cycle of carboplatin plus pemetrexed for 4 to 6 cycles, followed by gefitinib maintenance until disease progression or unacceptable toxicity….Of the 21 patients enrolled in this study, a 76.2% ORR and 100% DCR were observed and a higher ORR was seen in patients with EGFR 21L858R mutations than in those with 19del mutations (P = 0.012).

...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.

7/7 patients had adenocarcinoma, 5 with EGFR exon 19 and 2 with EGFR L858R. Patients received erlotinib (n=2) or gefitinib (n=5) for 10 days followed by TKI in combination with chemotherapy (docetaxel/cisplatin (n=4), paclitaxel/carboplatin (n=3)) for 3 cycles. Median OS of the 7 patients was 51 months and median PFS was 17 months. In conclusion 1st generation TKI-chemotherapy induction in EGFR mt+ NSCLC is feasible...

...patients with operable stage II-IIIA NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation were enrolled.... ORR, the primary endpoint, was 54.5% (95% confidence interval [CI], 37.7-70.7), and the rate of MPR was 24.2% (95% CI, 11.9-40.4)....Neoadjuvant therapy with gefitinib in patients with stage II-IIIA NSCLC is safe and may be a viable treatment for patients whose tumors have EGFR mutations.

A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib....Figure 2. Mutations in the EGFR Gene in Gefitinib-Responsive Tumors...

A total of 375 patients with recurrent or metastatic stage IIIB/IV NSCLC, who had either exon 19 deletion or the L858R mutation in exon 21, and had received either gefitinib (n = 228) or erlotinib (n = 147), were included in the study...The median PFS from EGFR TKI treatment in the gefitinib and erlotinib group was 11.7 months (95% CI, 9.4–13.9) and 9.6 months (95% CI 8.1–11.1), respectively (Fig. 1)....In conclusion, the present study demonstrated that both gefitinib and erlotinib are well tolerated and have similar effectiveness in NSCLC patients harboring EGFR mutation.

All patients had activating EGFR mutations; 20 (54%) had an exon 19 deletion mutation and 15 (41%) had the exon 21 point mutation L858R. All patients had responded clinically to either gefitinib (n=5) or erlotinib (n=32). 

Predefined subgroup analysis showed that PC-G produced favorable HR (0.20, 95% CI 0.05–0.75; P = 0.017) for patients with EGFR mutations (exons 19/21) compared with PC with regard to PFS...In patients with EGFR mutations (exons 19/21), the ORR was 76.9% for the PC-G arm and 50% for the PC arm (P = 0.13)....The EGFR mutation was defined by the presence of deletions on exon 19 or L858R mutations on exon 21.

In different EGFR variant-expressing 32D cells, only cells harboring L858R, E746-A750 deletion, and G719S mutants were clearly more sensitive to gefitinib than wild-type EGFR-expressing cells.