The 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 receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen.

The NCCN NSCLC Panel recommends erlotinib and gefitinib as first-line therapy options in patients with metastatic nonsquamous NSCLC who have known active sensitizing EGFR mutation...The most commonly described mutations in EGFR (exon 19 deletions, p.L858R point mutation in exon 21) are associated with responsiveness to EGFR tyrosine kinase inhibitor (TKI) therapy...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-)

Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease…86 were randomly assigned to receive erlotinib...median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p<0·0001).

Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001).

...Inclusion Criteria of Target Disease: IIIA NSCLC patients according to TMN-staging of Lung Staging Standard version 7 2009, confirmed by histopathology or cytology after radical operation, and having EGFR exon 19 deletion mutation or exon 21 L858R single base substitution; Accept study adjuvant therapy within 4 weeks post radical operation; ECOP PS 0-1; Life expectancy >=12 weeks. ...

...- Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation...

...Progression-free Survival Per Investigator (PFS2)`Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R`Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R`Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)`Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R`Number of Participants With Adverse Events`Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)...

...EGFR exon 19 deletion or exon 21 L858R, which are positive by real-time PCR methods and negative by standard sequencing methods....

...- Confirmed with Exon 19 deletion or L858R EGFR mutation...

...Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3....

...- IIIA NSCLC patients according to TMN-staging of Lung Staging Standard version 7 2009, confirmed by histopathology or cytology after radical operation, and having EGFR exon 19 deletion mutation or exon 21 L858R single base substitution;...

...Number of participants with EGFR mutation (L858R/ exon 19 deletion) and who achieved clinical benefit status was reported. ...

...Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions)....

...A patients with EGFR mutation (including exon 19 deletion, L858R) 5....

...at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR...

...- Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1....

...- 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)...

...The tumor harbors an exon 19 deletion or exon 21 L858R mutation in EGFR, confirmed locally....

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

...- An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation....

...previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial)....

...If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution....

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

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

...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.

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). 

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.

Characteristics of patients sensitive to gefitinib (G) and erlotinib (E)….By contrast, the L858R mutant had an ≈10-fold greater sensitivity to both gefitinib (data not shown) and erlotinib…

We present a 52-year-old male patient with metastatic non-small-cell lung cancer (NSCLC). The patient was found to have L858R mutation in exon 21 of the EGFR gene….osimertinib (160 mg once daily) promptly induced clinical and radiological response that continued for five months. High dose pulsed erlotinib (1500 mg weekly) improved his quality of life and extended his survival for a further four months.

Consistent with previous reports, H3255 (EGFR L858R) and HCC827 (EGFR E746_A750del) were sensitive to erlotinib treatment ( 15, 16), with IC50 values of 0.031 and 0.003 μmol/L, respectively ( Fig. 1A).