Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial

Summary

Background

An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer.

Methods

From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m², intravenously, every 21 days, or docetaxel 75 mg/m², intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690.

Findings

142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (p_interaction=0·017 when adjusted for stratification factors; p_interaction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08–2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77–1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group.

Interpretation

Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib.

Funding

Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

Introduction

The selection of patients with advanced non-small-cell lung cancer who would benefit more from treatment with EGFR tyrosine-kinase inhibitors such as gefitinib, erlotinib, and afatinib has improved substantially with the establishment of the important role of EGFR-sensitising mutations, particularly in first-line treatment.1, 2, 3 Although the use of EGFR tyrosine-kinase inhibitors in patients with an EGFR-activating mutation has become the standard of care, the role of EGFR tyrosine-kinase inhibitors in the second-line setting for patients with wild-type or unknown EGFR mutation status remains unclear.⁴ In second or higher lines, treatment options are single-agent chemotherapy, such as docetaxel or pemetrexed,5, 6 or an oral EGFR tyrosine-kinase inhibitor.7, 8 In the NCIC BR.21 study,⁹ the results of a subgroup analysis of erlotinib versus placebo in second and third lines showed that the EGFR tyrosine-kinase inhibitor is also active in patients with wild-type EGFR status and in those with advanced non-small-cell lung cancer with unknown EGFR status. The results of the INTEREST⁸ and TITAN¹⁰ trials suggested similar overall survival with EGFR tyrosine-kinase inhibitors and standard second-line monochemotherapy, whereas the findings of the TAILOR trial¹¹ in patients with wild-type EGFR status showed that docetaxel was superior to erlotinib for progression-free survival (PFS) and overall survival.

Taguchi and colleagues¹² have developed a test in which mass spectrometry is used for the analysis of serum to identify patients likely to have good or poor survival on EGFR tyrosine-kinase inhibitors. This test, which is commercially available as VeriStrat (Biodesix, Boulder, CO, USA), is used to assign one of two classifications—good or poor—by comparison of the intensity of eight regions in the mass spectra obtained from patients' pretreatment serum samples with the intensity of those of a reference set.¹² The results of retrospective studies have shown that patients with proteomic test classification of good have a significantly better outcome than do those classified as poor when treated with EGFR tyrosine-kinase inhibitors.12, 13, 14, 15, 16, 17 The test classification is a significant predictor of outcome independent of clinical and molecular characteristics such as performance status and EGFR and KRAS mutation status.15, 16 The results of a retrospective analysis of samples from the placebo group of the NCIC BR.21 trial showed that the proteomic test has a prognostic role,¹⁵ but no significant survival difference was noted between the two proteomic test classification groups when patients were given chemotherapy,¹² suggesting that the test might also be predictive of outcome between chemotherapy and EGFR tyrosine-kinase inhibitors. The predictive power of the test was reported in a study of elderly patients with non-small-cell lung cancer treated with erlotinib, erlotinib plus gemcitabine, and gemcitabine alone.¹³ The available data indicate poor outcomes for patients with a proteomic test classification of poor who were given erlotinib.

The primary aim of this phase 3 trial was to assess the predictive power of the proteomic test in the comparison of two approved treatments—erlotinib and chemotherapy—in patients with non-small-cell lung cancer.