Background
Group of phase III first-line RCTs of gefitinib vs platinum chemotherapy. IPASS: N=1217 East-Asian pulmonary adenocarcinoma (never/light smokers), response by EGFR status. NEJ002: N=230 EGFR-mutation-positive NSCLC. WJTOG3405: N=172 stage IIIB/IV EGFR-mutation-positive tumors.
Interventions and follow up
Arm A: Gefitinib 250 mg PO daily until progression
Arm B: Platinum doublet (IPASS: carboplatin + paclitaxel; NEJ002: carboplatin + paclitaxel; WJTOG3405: cisplatin + docetaxel x3-6)
Primary endpoint: PFS (IPASS noninferiority)
Arm B: Platinum doublet (IPASS: carboplatin + paclitaxel; NEJ002: carboplatin + paclitaxel; WJTOG3405: cisplatin + docetaxel x3-6)
Primary endpoint: PFS (IPASS noninferiority)
Results
IPASS 12-mo PFS (all): 25% vs 7%; HR 0.74
IPASS mPFS, EGFR+: 9.5 mo vs 6.3 mo; HR 0.48 (95%CI 0.34–0.67)
IPASS mPFS, EGFR-: 1.5 mo vs 6.5 mo; HR 3.85 (95%CI 2.09–7.09)
IPASS mOS (all): 18.8 mo vs 17.4 mo; HR 0.90 (95%CI 0.79–1.02)
IPASS OS, EGFR+: HR 1.00 (95%CI 0.76–1.33); P=.990
IPASS OS, EGFR-: HR 1.18 (95%CI 0.86–1.63); P=.309
NEJ002 mPFS: 10.8 mo vs 5.4 mo; HR 0.30 (95%CI 0.22–0.41)
WJTOG3405 mPFS: 9.2 mo vs 6.3 mo; HR 0.49 (95%CI 0.34–0.70)
IPASS mPFS, EGFR+: 9.5 mo vs 6.3 mo; HR 0.48 (95%CI 0.34–0.67)
IPASS mPFS, EGFR-: 1.5 mo vs 6.5 mo; HR 3.85 (95%CI 2.09–7.09)
IPASS mOS (all): 18.8 mo vs 17.4 mo; HR 0.90 (95%CI 0.79–1.02)
IPASS OS, EGFR+: HR 1.00 (95%CI 0.76–1.33); P=.990
IPASS OS, EGFR-: HR 1.18 (95%CI 0.86–1.63); P=.309
NEJ002 mPFS: 10.8 mo vs 5.4 mo; HR 0.30 (95%CI 0.22–0.41)
WJTOG3405 mPFS: 9.2 mo vs 6.3 mo; HR 0.49 (95%CI 0.34–0.70)
Adverse events
Skin: acneiform rash
Cardiovascular: hypertension
GI: decreased appetite, mild nausea/vomiting
Pulmonary: cough, dyspnea (ILD)
Ocular: keratoconjunctivitis
PK notes: hepatic CYP3A4 metabolism (increase dose with strong inducers e.g. phenytoin); raises INR with warfarin; take with/without food; avoid PPI/H2 or separate by 12 h (PPI)/6 h (H2)
Cardiovascular: hypertension
GI: decreased appetite, mild nausea/vomiting
Pulmonary: cough, dyspnea (ILD)
Ocular: keratoconjunctivitis
PK notes: hepatic CYP3A4 metabolism (increase dose with strong inducers e.g. phenytoin); raises INR with warfarin; take with/without food; avoid PPI/H2 or separate by 12 h (PPI)/6 h (H2)
Conclusions
Gefitinib improved PFS over chemotherapy in EGFR-mutated advanced NSCLC (and was harmful in EGFR-wild-type); historical evidence establishing biomarker-selected TKI therapy. OS not improved (crossover).
Key Limitations
OS confounded by crossover; predominantly East-Asian populations; IPASS enrolled by clinical phenotype with retrospective EGFR testing; superseded by osimertinib (FLAURA) with superior CNS activity/OS.
Clinical Context
Gefitinib FDA approved for first-line EGFR ex19del/L858R NSCLC (2015). ESMO/ASCO now prefer osimertinib first-line; gefitinib is an alternative when osimertinib is unavailable.