It is the consensus opinion of the medical oncology reference committee that first-line treatment of metastatic non small cell lung cancer with EGFR mutations to be superseded as superior alternatives are available.
First-Line Setting
The evidence supporting the use of afatinib in the first-line setting is provided by two phase III multicentre international randomised trials (LUX-Lung-3 and LUX-Lung-6) in patients with stage IIIb or IV non small cell lung cancer and one phase II multicentre international randomised trial (LUX-Lung-7).
Lux-Lung-3r
Between August 2009 and February 2011, 230 were randomised to receive afatinib 40 mg once a day orally until disease progression, and 115 patients were randomised to receive intravenous cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) once every three weeks for a maximum of 6 cycles. Maintenance chemotherapy was not permitted. Treatment was continued until investigator assessed progression.
The primary end point was progression free survival (PFS) determined by independent blinded review) and secondary end points were objective response and disease control rates, patient-reported outcomes, treatment safety and adverse events profiles and pharmacokinetics of afatinib.
Lux-Lung-6r
Between 2010 and 2011, 242 Asian patients were randomised to receive afatinib until progression of death and 122 patients were randomised to receive cisplatin (75 mg/m2) and gemcitabine (1000 mg/m2) on days 1 and 8 on a three weekly cycle. A maximum of six cycles was given.
The primary end point was PFS by independent review. Secondary end points were overall response rate, disease control rate, overall survival, patient reported outcomes and pharmacokinetics of afatinib.
LUX- Lung 7r
Between 2011 and 2013, 379 patients with stage IIIb/IV EGFR mutant NSCLC were randomised to receive either afatinib 40 mg or gefitinib 250 mg daily.
The co-primary end points were progression-free survival (PFS) by independent central review, time-to-treatment failure (TTF), and overall survival (OS).
Second or Third Line Setting
LUX-Lung-2r
The evidence supporting the use of afatinib in the second line setting is provided by a phase II randomised open-label study. Between 2007 and 2009, 129 patients with EGFR mutations were treated with afatinib. 61 patients received afatinib as first line treatment whilst 68 patients received afatinib as second-line treatment (OR 0.71, 95% CI 0.35-1.44).
Efficacy
First Line Setting
LUX-Lung-3r
After a median follow up of 16.4 months, the median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (HR 0.58, 95% CI 0.43-0.78. P=0.001). Median PFS amongst those with exon 19 deletions and L858R EGFR mutations was 13.6 months for afatinib and 6.9 months for chemotherapy (HR= 0.47, 95% CI 0.34-0.65, P=0.001).
Kaplan Meier curve for progression free survival:r
© J Clin Oncol 2013
First line afatinib was associated with a significant delay in the pre-specified domains of time to deterioration of cough (HR 0.60; 95% CI, 0.41 to 0.87; P=0.007), and dyspnoea (HR 0.68, 95% CI 0.50-0.93, P=0.015) compared with chemotherapy.r Pain was not significantly different between treatment arms.
Lux-Lung-6r
After a median follow up of 16.6 months, the median PFS was 11.0 months for afatinib and 5.6 months for chemotherapy (HR 0.28, 95% CI 0.20-0.39, P<0.0001).r
Kaplan Meier curve for progression free survival:r
© Lancet Oncol 2014
LUX-Lung-7r
After a median follow up of 27.3 months, afatinib significantly improved PFS (HR=0.73; 95% CI, 0.57-0.95; p=0.017) compared with gefitinib. Median PFS was 11.0 months (95% CI 10.6-12.9) in the afatinib group and 10.9 months (95% CI 9.1-11.5) in the gefitinib group. TTF was also significantly improved, (HR=0.73; 95% CI, 0.58-0.92; p=0.0073). Median OS was 27.9 months (95% CI, 25.1-32.2) with afatinib versus 25.0 months (95%CI, 20.6-29.3) with gefitinib.
Kaplan Meier curve for progression free survival:r
© Lancet Oncol 2016
Toxicity
Lux-Lung-3r
Treatment related adverse events (AE) grade 3 or above occurred in 49% of patients receiving afatinib and 48% of patients receiving chemotherapy. Diarrhoea, rash, and dryness of the skin, mucosa and nails were the most common AEs related to afatinib. Most of these AEs were manageable with dose reductions and delays. 8% of patients receiving afatinib discontinued treatment due to AEs (diarrhoea 1.3% and paronychia 0.9%). Interstitial lung disease was a potential AE in 1% of patients.
© J Clin Oncol 2013
Lux-Lung-6r
Treatment-related AEs of grade 3 or above occurred in 6.4% of patients taking afatinib. The most common treatment-related AE's were rash or acne (14.6%), diarrhoea (5.4%) and stomatitis/mucositis (5.4%) Overall treatment-related serious events occurred in 6.3% of patients receiving afatinib.
Compared with chemotherapy a greater percentage of patients on afatinib experienced worsening of diarrhoea (83% vs 24%) sore mouth (815 vs 61%) and dysphagia (57% vs 38%). A > 10% change in each domain was considered clinically significant in the EORTC QLQ-C30 and QLQ-LC 13 modules.r
LUX-Lung-7r
Treatment-related AEs of grade 3 or above occurred in 57% of patient taking afatinib. The most common treatment-related AE's were diarrhoea 13%, rash or acne 9% (compared with 3% of those receiving gefitinib) and fatigue 6%. Serious treatment-related adverse events were reported in 11% of patients given afatinib and 4 % of patients given gefitinib, with diarrhoea being the most common (6% and 1% respectively). Interstitial lung disease occurred in 3% of patients receiving gefitinib and none of those receiving afatinib.
© Lancet Oncol 2016