GILOTRIF is a 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.

Non-Small Cell Lung Cancer: EGFR Mutation Positive…(eg, exon 19 deletion or L858R)…Afatinib...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-)...

As expected, TTSP/PFS were longer for pts with ECOG PS 0/1 vs 2, and for pts with Del 19 or L858R mutations, vs those with uncommon mutations, which may be due to the high prevalence (44%) of pts with exon 20 insertions included in this study. Considered table data too.

Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three)....First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC.

...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 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) ...

...- Evidence of common EGFR activating mutations (Del 19 and/or L858R)...

...Documented EGFR mutation (L858R and/or Deletion 19) with...

...Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6....

...L858R, exon 19 deletions, exon 20 insertions, T790M, list is...

...Documented activating EGFR mutation (Del 19 and/or L858R) determined in tumour tissues ? ...

...1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery....

...Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues....

...Documented EGFR mutation(s)-positive NSCLC (common mutations: Del19 and L858R) from tumour biopsy material....

...- Evidence of common EGFR mutation (Del 19 and/or L858R)...

...Patients with common EGFR mutations (Del19, L858R) 6....

...- The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment...

The presence of common baseline EGFR mutations (Del19, L858R) was associated with significantly prolonged median OS (49.6 vs. 30.1 months; P=0.017)….Afatinib was effective in Korean patients with EGFR mutation-positive NSCLC with median OS over 4 years.

In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53).

The median TTF was longer in patients with common EGFR mutation subgroup (Del19 and L858R) versus uncommon mutation subgroup (17.5 vs 13.8 months, p=0.045) and without versus with brain metastases at baseline (17.5 vs 15.1 months, p=0.049)….Afatinib showed promising clinically meaningful effectiveness and was well-tolerated in Vietnamese EGFR-mutant NSCLC patients.

Patients (pts) with EGFRm (Del19 or L858R) after failure of osimertinib treatment were assigned to a regimen of afatinib 20mg daily combined with carboplatin AUC5 mg/ml/min and pemetrexed 500mg/m2 every 3 weeks...By mutation type, ORR were similar for Del19 and L858R (46.7% and 50.0%, respectively)...

In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations...twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively....Patients with EGFRm + NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.

48 patients with EGFR-positive NSCLC were identified and divided into subgroups by mutation. Progression-free survival (PFS), overall survival (OS) and time to treatment failure (TTF) in those who were treated with Afatinib (Giotrif®) were evaluated….Patients with common mutations, deletion in exon 19 and L85R, had median OS of 31 months (95% CI: 22-51) and 23 months (95% CI: 6-33) and a median PFS of 16 months (95% CI: 9-33) and 10 months (95% CI: 6-22), respectively.

Del-19 mutations were identified in 52 patients and L858R in 67. The starting dose of afatinib was as follows: 20mg/30mg/40mg in 14 (12%)/ 42 (35%)/ 63 (53%), respectively….The ORR in all patients was 67% (95%CI: 57-75%), and disease control rate (DCR) 96% (95%CI: 90-99%). The median PFS (mPFS) was 18.4 (95% CI, 13.2-23.7) months (58 censored cases). ORR/mPFS were 67%/18.4 months in Del-19, and 61%/15.8 months in L858R.

...all patients with metastatic NSCLC harboring common EGFR mutations (exon 19 deletion or exon 21 L858R substitution) fulfilling the above criteria in Queen Mary Hospital in Hong Kong were included….Patients treated with afatinib in the first-line setting had significantly longer OS compared with those on gefitinib or erlotinib with median OS of being 44.6 months for patients on gefitinib and 48.6 months for patients on erlotinib, and 59.2 months for patients on afatinib....The results are in favor of afatinib (Figure 1). With multivariate analysis adjusted for age, gender, smoking status and the initial EGFR mutation, the result was statistically significant with HR of 0.373 (95% CI: 0.152–0.911, p = 0.031) for afatinib over gefitinib.

CONTRADICTING EVIDENCE: EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; p=0.016) and type I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; p=4.3x10-5 )....Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib….Median OS was 36.5 months (95% CI: 32.9–41.8; Fig. 1B, Table 3)....The ORR with afatinib was 73.6% (Table 3); median duration of response (DoR) was 9 months (IQR: 3–17). The disease control rate (DCR) was 100%. Of 178 evaluable patients, 3 (1.7%) had a complete response (CR), 128 (71.9%) had a partial response (PR) and 47 (26.4%) had stable disease (SD). In patient subgroups the ORR ranged between 67.3% (non-Asian patients) and 91.3% (brain metastases present; Table 3).

In this non-interventional, global, multi-center study (NCT04179890), existing medical or electronic health records were identified for consecutive EGFR TKI-naïve patients with EGFRm+ NSCLC (Del19 or L858R) treated in regular clinical practice with first-line afatinib and, following the detection of T790M, second-line osimertinib. ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001).

This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib...ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%.

9 patients (14F/5M), median age 56 (range 34-75) were enrolled. 12 had EGFR del19, 7 L858R...The ORR after neoadjuvant afatinib was 11/19 (58%; 95% CI, 33-80%)….In stage III EGFRm NSCLC, 2 months of neoadjuvant afatinib is associated with an ORR comparable to that seen in advanced disease and does not impair receipt of SOC chemoradiotherapy ± surgery. PFS and OS are favorable in this single-arm study.

Patients with treatment-naive stage IV EGFR-mutated (L858R or del19) NSCLC were enrolled. Orally osimertinib 80 mg once a day for 8 weeks, followed by afatinib 20 mg once a day for 8 weeks, which was repeated alternately….The ORR and one-year survival rate were 69.6% (95% CI: 54.2%-82.3%) and 93.48% (95% CI: 81.13%-97.85%), respectively….Although current study didn’t meet the primary endpoint of one-year PFS rate, alteration therapy with osimertinib and afatinib demonstrated promising efficacy...

Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations...Uncommon mutations were classed as: de novo T790M; exon 20 insertions (Ins20); major uncommon mutations (G719X/L861Q/S768I)....Includes patients with MU + Del19/L858R compound mutations.

EGFR mutation subtypes included exon 19 deletion (56.6%) and L858R point mutation (43.4%). The median PFS, time to treatment failure and overall survival were 12.6 months (95% CI: 9.7–14.3), 18.6 months (95%CI: 16.0-21.2) and not reached. The PE was met. The objective response and the disease control were 66.6% (95% CI: 51.7-78.5) and 92.5% (95% CI: 81.8-97.9). Low dose afatinib would be considered as one of standard therapy for EGFR mutation-positive NSCLCs because of promising clinical eficacy...

...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.

This study was a multicenter, single-arm, open-label phase II trial. Treatment-naïve patients with advanced NSCLC positive for common EGFR mutations received afatinib in a dose of 20mg/day….EGFR mutation subtypes included exon 19 deletion (56.6%) and L858R point mutation (43.4%)...The objective response and the disease control was 66.6% (95% CI: 51.7-78.5) and 92.5% (95% CI: 81.8-97.9)....Low dose afatinib would be considered as one of standard therapy for EGFR mutation-positive NSCLCs because of promising clinical efficacy and good tolerability.

Data were collected between December 2017 and December 2019 for patients with EGFR mutation-positive (Del19 and L858R) NSCLC who had T790M-positive disease after first-line afatinib and subsequently received osimertinib...Overall median OS was 37.6 months (90% CI: 35.5–41.3) with a 2-year survival rate of 80% (Figure 2A). Median OS was 44.8 months (90% CI: 37.0–57.8) in Asian patients and 41.6 months (90% CI: 36.9–45.0) in patients with Del19-positive disease...

Previously untreated patients, aged ≥ 75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity….Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%....

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).

ORR for the total treated population was 73% with a DCR of 90 %....Afatinib is a standard therapy for patients with activating EGFR mutations in Germany. The first results of this prospective NIS confirm the robust clinical data for Afatinib in the clinical routine setting...

Ten (43%) pts have achieved confirmed OR (complete/partial response: 1 [4%]/9 [39%]) and 10 (43%) pts have had stable disease....afatinib (30 mg/day) demonstrated a predictable safety profile in pts aged ≥70 yrs with Del19/L858R EGFRm+ NSCLC.

Neo-adjuvant afatinib achieves high ORR and major surgical path responses, and doesn’t impair receipt of SOC, curative CRT ± surgery in EGFR+ stage III NSCLC. Feasibility of NeoAfat exceeds AdjAfat in stage III setting. The prolonged PFS compares favorably to PACIFIC IO arm...

...study used medical records of TKI-naïve pts with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib...Median time on treatment and TTP was 18.7 mos and 20.8 mos respectively and was not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 and 25.9/20.0/29.0 mos for pts who started on ≤30 mg/reduced to <40 mg/remained on ≥40 mg)...Time on treatment/TTP were similar regardless of dose adjustment or reduced starting dose, confirming the efficacy of this regimen.

Sixty-six patients had more than one EGFR mutation, including those coexisting with exon 19 deletion or L858R mutation. In treatment-naïve patients with advanced stages (n = 72), the objective response rate was 35.8% for gefitinib/erlotinib group and 60.6% for afatinib group (p = 0.036)....For patients with NSCLC harbouring non-resistant uncommon EGFR mutations, afatinib use as the first-line therapy may provide a better treatment response but no survival benefit, as compared with gefitinib or erlotinib.

We thus evaluated the efficacy and tolerability of low-dose afatinib maintenance treatment among patients with NSCLC harboring EGFR mutations who had not been previously treated....Among 30 patients, 93% had adenocarcinoma, 53% had exon 19 deletion, 37% had L858R, and 10% had minor mutations. The 1-year PFS rate was 50% (95% confidence interval [CI], 31.3-66.1) and the median PFS was 11.8 months (95% CI, 7.1-21.4).

Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator....Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile.

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....Overall, patients with tumors harboring mutations in exon 20 (alone or as a compound mutation) had a lower ORR [26.7% (1 CR and 3 PRs among 15 patients)] compared with those with tumors harboring mutations in exons 18, 19, and 21 only (Figure 1). Afatinib showed strong activity against compound mutations, including an ORR of 100% in four patients with tumors harboring mutations in both exon 18 and 21 (Figure 1)...patients may appear in >1 category; specific mutations include: G719X (exon 18), Del19 (exon 19), S768I (exon 20), L858R and L861Q (exon 21).

129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations.

...we investigated the total TOT along with four treatment options starting from first-line afatinib treatment to various subsequent treatments, including osimertinib and cytotoxic chemotherapy....Regarding the subtype of EGFR mutations, the median total TOTs were 26.40 months (95% CI: 24.08–29.34 months), 20.60 months (95% CI: 19.91–26.45 months), 11.40 months (95% CI: 8.61–16.33 months), and 15.40 months (95% CI: 5.22–18.00 months) for Del19, L858R, uncommon mutations, and compound mutations, respectively (P<0.001).

The tumor was diagnosed as non-small cell carcinoma, favor adenocarcinoma and tested positive for the epidermal growth factor receptor (EGFR) mutation exon21 L858R….She was treated with afatinib. The tumor shrank markedly, and the left lower robe atelectasis also improved 3 months after the initiation of afatinib treatment...

...our report of a LFS patient with advanced lung adenocarcinoma containing EGFR L858R, ERBB2 S310F, and TP53 germ-line mutations, demonstrating a complete and durable response to afatinib, is the first case of its kind. The patient responded to afatinib completely after failure of multiple lines of chemotherapy.