Background
Phase IIb/III RCT; N=585; stage IIIB/IV lung adenocarcinoma progressing after 1-2 chemotherapy lines and >=12 weeks of erlotinib or gefitinib; randomized 2:1.
Interventions and follow up
Arm A: Afatinib 50 mg PO daily
Arm B: Placebo
Primary endpoint: OS
Arm B: Placebo
Primary endpoint: OS
Results
mOS: 10.8 mo vs 12.0 mo; HR 1.08 (95%CI 0.86–1.35); P=.74
mPFS: 3.3 mo vs 1.1 mo; HR 0.38 (95%CI 0.31–0.48); P<.0001
ORR (PR only, no CR): 7% vs 0.5%
mPFS: 3.3 mo vs 1.1 mo; HR 0.38 (95%CI 0.31–0.48); P<.0001
ORR (PR only, no CR): 7% vs 0.5%
Adverse events
GI: diarrhea 87% vs 9% (grade ≥3 17% vs 0%)
Skin: rash 78% vs 15% (grade ≥3 14% vs 0%)
Serious AEs: drug-related serious AEs 10% vs <1%; treatment-related deaths n=2 vs 0
Skin: rash 78% vs 15% (grade ≥3 14% vs 0%)
Serious AEs: drug-related serious AEs 10% vs <1%; treatment-related deaths n=2 vs 0
Conclusions
Afatinib improved PFS and ORR but not OS in patients progressing after chemotherapy and a first-generation EGFR TKI; the primary OS endpoint was not met.
Key Limitations
Primary OS endpoint negative; pre-osimertinib era with no T790M testing; subsequent therapies (including crossover at progression) may have diluted OS; toxicity at 50 mg dose notable.
Clinical Context
Did not establish afatinib in the post-TKI-progression setting. Modern practice uses T790M-directed osimertinib (AURA3) or, at osimertinib progression, platinum chemotherapy and emerging agents (e.g., amivantamab-based regimens, MARIPOSA-2).