Background
Phase III first-line RCTs of afatinib vs platinum-pemetrexed/gemcitabine. LUX-Lung 3: N=345 stage IIIB/IV lung adenocarcinoma with EGFR mutation. LUX-Lung 6: N=364 treatment-naive Asian patients with EGFR-mutated stage IIIB/IV NSCLC.
Interventions and follow up
Arm A: Afatinib 40 mg PO daily
Arm B: LUX-Lung 3: cisplatin + pemetrexed up to 6 cycles; LUX-Lung 6: cisplatin + gemcitabine q3wk up to 6 cycles
Primary endpoint: PFS
Arm B: LUX-Lung 3: cisplatin + pemetrexed up to 6 cycles; LUX-Lung 6: cisplatin + gemcitabine q3wk up to 6 cycles
Primary endpoint: PFS
Results
LUX-Lung 3 mPFS (overall): 11.1 mo vs 6.9 mo; HR 0.58 (95%CI 0.43–0.78); P=.001
LUX-Lung 3 mPFS (common mutations): 13.6 mo vs 6.9 mo; HR 0.47 (95%CI 0.34–0.65); P=.001
LUX-Lung 3 mOS: 28.2 mo vs 28.2 mo; HR 0.88 (95%CI 0.66–1.17); P=.385
LUX-Lung 6 mPFS: 11.0 mo vs 5.6 mo; HR 0.28 (95%CI 0.20–0.39); P<.0001
LUX-Lung 6 mOS: 23.1 mo vs 23.5 mo; HR 0.904 (95%CI 0.72–1.14); P=.401
LUX-Lung 3 mPFS (common mutations): 13.6 mo vs 6.9 mo; HR 0.47 (95%CI 0.34–0.65); P=.001
LUX-Lung 3 mOS: 28.2 mo vs 28.2 mo; HR 0.88 (95%CI 0.66–1.17); P=.385
LUX-Lung 6 mPFS: 11.0 mo vs 5.6 mo; HR 0.28 (95%CI 0.20–0.39); P<.0001
LUX-Lung 6 mOS: 23.1 mo vs 23.5 mo; HR 0.904 (95%CI 0.72–1.14); P=.401
Adverse events
Skin/nail: acneiform rash, nail changes
GI: diarrhea
Constitutional: fatigue
Lab changes: transient LFT elevation
Pulmonary: cough, dyspnea (ILD)
Ocular: keratitis, light sensitivity
Mechanism/PK: irreversible pan-ErbB (EGFR/HER2/HER4) inhibitor; resistance via KRAS/BRAF/ErbB-kinase mutations; CYP3A4 metabolism, mainly hepatic elimination
GI: diarrhea
Constitutional: fatigue
Lab changes: transient LFT elevation
Pulmonary: cough, dyspnea (ILD)
Ocular: keratitis, light sensitivity
Mechanism/PK: irreversible pan-ErbB (EGFR/HER2/HER4) inhibitor; resistance via KRAS/BRAF/ErbB-kinase mutations; CYP3A4 metabolism, mainly hepatic elimination
Conclusions
Afatinib significantly improved PFS over chemotherapy in EGFR-mutated advanced NSCLC, with OS benefit in the ex19del subgroup; historical first-line evidence.
Key Limitations
Higher rate of skin/GI toxicity than first-generation TKIs; OS benefit limited to ex19del subgroup; superseded by osimertinib first-line; LUX-Lung 6 Asian-only.
Clinical Context
Afatinib FDA approved first-line for EGFR ex19del/L858R (2013) and for selected uncommon EGFR mutations (G719X, L861Q, S768I). ESMO/ASCO prefer osimertinib first-line; afatinib remains an option, notably for some uncommon mutations.