Randomized phase III trial of erlotinib (E) versus docetaxel (D) as second- or third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA).

Abstract

8006 Background: E and D are standard cares for previously treated patients with advanced NSCLC. Although E shows significant clinical benefits over best supportive care in the EGFR wild type tumors, it remains unknown whether E or D is more active against the disease. Methods: This is an open-label, multi-center phase III study, sponsored by the Japanese National Hospital Organization. Patients were randomized to E (150 mg, daily), or D (60 mg/m2, q3w) by the minimization method according to gender, performance status, histology, and institution. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), response rate, safety, and analyses on EGFR wild type tumors. Eligible patients were those with pathologically proven NSCLC with stage IIIB or IV (AJCC version 6) previously treated with one or two chemotherapy regimens including at least one platinum agent, evaluable or measurable disease, and ECOG PS 0-2. Target sample size was calculated to be 280 based on the assumption that E was superior to D in PFS (3.5 months [m] v 2.5 m, α =0.05 [two sided], β =0.80). Results: From August 2009 to July 2012, 301 patients were accrued from 41 institutions. In the ITT population, 150 and 151 patients were randomly assigned to E and D, respectively, including respective 109 (73%, E) and 89 (59%, D) with EGFR wild type tumors. Median PFS and OS for E v D were 2.0 m (95% CI: 1.3-2.8) v 3.2 m (2.8-4.0, log-rank p=0.092; HR=1.22, 95% CI: 0.97-1.55), and 14.8 m (9.0-19.4) v 12.2 m (9.0-15.5, p=0.527; HR=0.91, 95% CI: 0.68-1.22), respectively. In the EGFR wild type tumors, PFS and OS for E v D were 1.3 m v 2.9 m (p=0.013; HR =1.44, 95% CI: 1.08-1.92), and 9.0 m v 9.2 m (p=0.914; HR =0.98, 95% CI: 0.69-1.39), respectively. Main grade 3/4 toxicities were rash (13.3% [E] v 0.7% [D]) and leukopenia (5.4% [E] v 62.9% [D]). Conclusions: E failed to show better PFS over D. While PFS was significantly longer in D than E in EGFR wild type tumors, the difference did not translate into OS in this pragmatic trial. Clinical trial information: 000002314.

A randomized phase 2 trial of erlotinib versus pemetrexed as second‐line therapy in the treatment of patients with advanced EGFR wild‐type and EGFR FISH‐positive lung adenocarcinoma

“…The OS reported among patients in the erlotinib arm (median OS, 11.7 months) in the current study was in keeping with that demonstrated in previous studies, which reported an OS of 5.3 months to 14.8 months for patients treated with TKIs. [7][8][9]11,16,[22][23][24][25] However, the interpretation of the OS results of the current study might be confounded by the imbalance of crossover. In the current study, 61% of the patients in whom second-line pemetrexed failed crossed over to erlotinib therapy, but only 23% of the patients in whom second-line erlotinib failed crossed over to pemetrexed therapy.…”

“…14 The results of the current study demonstrated that erlotinib had efficacy similar to that of chemotherapy. In view of the evidence of the superiority of chemotherapy for patients with EGFR wild-type NSCLC, [23][24][25] the current study results indicate that EGFR TKIs should still be considered as an effective option for patients with EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. The PFS noted among patients in the erlotinib arm (median PFS, 4.1 months) in the current study was notably longer than those in previous, unselected, populationbased studies or studies targeting wild-type EGFR, which reported PFS of 1.5 months to 3.6 months for patients on the TKI arm.…”

“…23 In a recent phase 3 trial, a comparison of docetaxel with erlotinib as second-line or third-line treatment in patients with advanced NSCLC who had wild-type EGFR indicated that PFS was significantly improved with docetaxel (HR, 0.69; 95% CI, 0.52-0.93 [P 5 .013]). 24 In another recent phase 2 study in patients with advanced, nonsquamous NSCLC who had wild-type EGFR, second-line treatment with pemetrexed was found to confer a significantly longer PFS than gefitinib (HR, 0.51; 95% CI, 0.36-0.73 [P < .001]). 25 These findings suggest that for patients presented with EGFR wild-type NSCLC, chemotherapy is superior to an EGFR TKI.…”

“…The PFS noted among patients in the erlotinib arm (median PFS, 4.1 months) in the current study was notably longer than those in previous, unselected, populationbased studies or studies targeting wild-type EGFR, which reported PFS of 1.5 months to 3.6 months for patients on the TKI arm. [7][8][9]11,16,[22][23][24][25] Reasons for the longer PFS may largely relate to the 100% second-line setting and the 100% EGFR FISH-positive adenocarcinoma study design. Most previous studies were designed for previously treated patients with NSCLC who had failed of 1 or 2 prior chemotherapy regimens.…”

“…Most previous studies were designed for previously treated patients with NSCLC who had failed of 1 or 2 prior chemotherapy regimens. [7][8][9]11,22,24 In the 100% second-line setting TITAN (Tarceva In Treatment of Advanced NSCLC) trial, all the enrolled patients were those with poor prognosis (developed disease progression during 4 cycles of first-line chemotherapy). 16 Another reason might be the selection of erlotinib instead of gefitinib as second-line treatment.…”