Gefitinib (IRESSA) versus vinorelbine in chemonaive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized Phase II study: B3-04

Background:

This Phase II, open-label, parallel-group study (INVITE [IRESSA in NSCLC vs Vinorelbine Investigation in The Elderly]) compared gefitinib (IRESSA) with vinorelbine in chemonaïve elderly patients with locally advanced or metastatic non small-cell lung cancer.

Methods:

Patients (?70 years; performance status ?2) were randomized to gefitinib (250 mg/day orally) or vinorelbine (30 mg/m² infusion on Days 1 and 8 of a 21 day cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR; assessed by RECIST), quality of life (QoL; assessed by Functional Assessment of Cancer Therapy Lung [FACT-L] and improvement in the physical aspects of QoL as measured by the trial outcome index [TOI]), pulmonary symptom improvement (PSI; assessed by the 4 pulmonary items of the lung cancer symptoms subscale [LCS] of the FACT-L) and adverse event (AE) profile. Exploratory analysis included EGFR gene copy number by fluorescence in situ hybridization (FISH), EGFR protein expression and EGFR mutation analysis.

Results:

196 patients (75.5% male, 85.7% regular/ex smokers, 40.3% adenocarcinoma) from a total of 10 countries were randomized to gefitinib (n=97) or vinorelbine (n=99). Hazard ratios (HR) for PFS and OS were 1.19 (95% CI 0.85, 1.65) and 0.98 (95% CI 0.66, 1.47), respectively, for gefitinib vs vinorelbine. ORR and disease control rates were 3.1% and 43.3% (gefitinib) and 5.1% and 53.5% (vinorelbine), respectively. FACT-L QoL improvement rates were higher with gefitinib vs vinorelbine (24.3% vs 10.9%, respectively) as was the TOI (22.9% vs 6.3%, respectively). Symptom improvement rates appeared similar with gefitinib vs vinorelbine: 36.6% vs 31.0% for PSI and 42.9% vs 39.1% on the LCS. In the EGFR FISH-positive subgroup (n=54), HRs for gefitinib vs vinorelbine were 3.13 (95% CI 1.45, 6.76) for PFS and 2.88 (95% CI 1.21, 6.83) for OS. In the EGFR FISH-negative subgroup (n=104), HRs for gefitinib vs vinorelbine were 0.93 (95% CI 0.59, 1.46) for PFS and 0.79 (95% CI 0.46, 1.37) for OS. Few patients had tumor samples that were EGFR protein expression negative (13/157 [8.3%] patients) or EGFR mutation-positive (7/65 [10.8%] patients), precluding further analysis of these data. The gefitinib arm had fewer treatment-related grade 3-5 AEs compared with vinorelbine (12.8% vs 41.7%). The most common AEs were rash and diarrhea for gefitinib, and constipation, fatigue and neutropenia for vinorelbine. There were three treatment-related deaths in the vinorelbine arm, and none in the gefitinib arm.

Conclusions:

Although the primary endpoint of demonstrating superior PFS for gefitinib relative to vinorelbine was not met, gefitinib was broadly similar to vinorelbine in terms of PFS, OS and ORR in this first-line study in elderly patients. Gefitinib was better tolerated than vinorelbine. Overall QoL improvement, including TOI, was increased with gefitinib compared with vinorelbine, while PSI and LCS was similar in both arms. The difference between gefitinib and vinorelbine in the small exploratory analyses of FISH positive patients requires further investigation.

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