What is the pivotal Phase III trial of gefitinib in epidermal growth factor receptor‑mutated non‑small‑cell lung cancer?

Pivotal Phase III Trials of Gefitinib in EGFR-Mutated NSCLC

The WJTOG3405 trial is the pivotal Phase III study demonstrating gefitinib's superiority over platinum-doublet chemotherapy in EGFR-mutated NSCLC, showing a median progression-free survival of 9.2 months versus 6.3 months with cisplatin plus docetaxel (HR 0.489, p<0.0001). 1

Key Pivotal Trials Establishing Gefitinib's Role

WJTOG3405 (Primary Pivotal Trial)

• Study design: Open-label, randomized Phase III trial conducted at 36 centers in Japan between March 2006 and June 2009 1
• Patient population: 177 chemotherapy-naive patients aged ≤75 years with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (exon 19 deletion or L858R point mutation) 1
• Treatment arms: Gefitinib 250 mg/day orally (n=88) versus cisplatin 80 mg/m² plus docetaxel 60 mg/m² every 21 days for 3-6 cycles (n=89) 1
• Primary endpoint results: Median PFS was 9.2 months (95% CI 8.0-13.9) with gefitinib versus 6.3 months (5.8-7.8) with chemotherapy (HR 0.489,95% CI 0.336-0.710, p<0.0001) 1
• Toxicity profile: Myelosuppression, alopecia, and fatigue were more frequent with chemotherapy, while skin toxicity, liver dysfunction, and diarrhea were more common with gefitinib 1
• Safety concern: Two patients (2.3%) developed interstitial lung disease on gefitinib, with one death 1

IPASS Trial (Supporting Pivotal Evidence)

• Clinical context: Large-scale randomized study comparing gefitinib monotherapy with carboplatin/paclitaxel in previously untreated patients with adenocarcinoma who were never- or light-smokers 2
• Key finding: Demonstrated improved progression-free survival in the gefitinib arm, particularly in patients with EGFR mutations 2
• Guideline impact: This trial, along with WJTOG3405, established gefitinib as first-line therapy for EGFR-mutated NSCLC 3

Guideline Recognition and Regulatory Approval

Current Guideline Recommendations

• NCCN Guidelines: Recommend gefitinib as first-line therapy (Category 1) for patients with metastatic nonsquamous NSCLC harboring sensitizing EGFR mutations 3
• Pan-Asian Guidelines: Designate gefitinib as standard-of-care first-line treatment for Asian patients with EGFR-mutated NSCLC [I, A] 3
• ESMO Guidelines: Recommend erlotinib, gefitinib, and afatinib as first-line therapy in patients with advanced NSCLC who have active sensitizing EGFR mutations, regardless of performance status [I, A], with no preference for any agent over the others 3

Regulatory Status

• European Medicines Agency: Granted marketing authorization in July 2009 for gefitinib for treatment of locally advanced or metastatic NSCLC with sensitizing EGFR mutations, across all lines of therapy 4

Supporting Phase III Evidence

WJTOG0203 Trial

• Design: Sequential therapy trial evaluating platinum-doublet chemotherapy for 3 cycles followed by gefitinib versus platinum-doublet chemotherapy for up to 6 cycles 5
• Results: Statistically significant improvement in progression-free survival with sequential gefitinib (HR 0.68,95% CI 0.57-0.80, p<0.001), though overall survival did not reach statistical significance (HR 0.86,95% CI 0.72-1.03, p=0.11) 5
• Subset analysis: Patients with adenocarcinoma receiving sequential gefitinib had significantly better overall survival (HR 0.79,95% CI 0.65-0.98, p=0.03) 5

Clinical Application Context

Patient Selection Criteria

• Mutation testing: EGFR mutation status is a long-established predictive marker, with Phase III trials demonstrating benefit specifically in patients with exon 19 deletions or L858R mutations 3, 1
• Histology consideration: ESMO Guidelines specify that only patients with nonsquamous NSCLC (e.g., adenocarcinoma) should be assessed for EGFR mutations, as patients with pure squamous cell carcinoma are unlikely to have sensitizing mutations 3

Comparative Efficacy with Other EGFR TKIs

• WJOG 5108L trial: Compared gefitinib versus erlotinib in previously treated patients, showing median PFS of 8.3 months for gefitinib versus 10.0 months for erlotinib in EGFR-mutated patients (HR 1.093,95% CI 0.879-1.358, p=0.424), indicating no significant difference 3
• Toxicity differences: Gefitinib had lower rates of grade 3-4 rash (2.2% vs 18.1%) but higher rates of ALT/AST elevations (6.1%/13.0% vs 2.2%/3.3%) compared to erlotinib 3

Important Caveats

Overall Survival Considerations

• Crossover effect: None of the Phase III trials comparing EGFR TKIs with platinum-based chemotherapy demonstrated overall survival benefit, likely due to high treatment crossover rates 3
• Clinical interpretation: Despite lack of OS benefit, the consistent PFS improvement, higher response rates, better tolerability, and improved quality of life support gefitinib as standard first-line therapy 3, 4

Current Treatment Landscape

• Third-generation TKIs: While WJTOG3405 established gefitinib's efficacy, osimertinib has now emerged as the preferred first-line option based on the FLAURA trial, showing superior PFS and overall survival 6
• Gefitinib's role: Remains an acceptable first-line alternative when osimertinib is unavailable or contraindicated, with median PFS of 9-13 months 6