Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer

Abstract

Purpose: We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods: Eligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS).

Results: Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months).

Conclusion: This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

Trial registration: ClinicalTrials.gov NCT00499109.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram.

Fig 2.

Patient survival. (A) Progression-free survival. (B) Progression-free survival between the experimental and control arms for patients with low ERCC1 and low RRM1 levels who received identical therapy (gemcitabine/carboplatin [GCb]). (C) Progression-free survival between the experimental and control arms for patients with high RRM1 and low ERCC1, low RRM1 and high ERCC1, and high RRM1 and high ERCC1 levels who received docetaxel/carboplatin (DCb), gemcitabine/docetaxel (GD), and docetaxel/vinorelbine (DV) therapy in the experimental arm and GCb in the control arm. (D) Overall survival.

Fig 3.

(A and B) ERCC1 and (C and D) RRM1 protein and mRNA expression.