Abstract
BackgroundCandidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival.Methods55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected.Results43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did.ConclusionsAbsence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.Trial registrationClinicaltrials.gov Identifier NCT00203931
Highlights
Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC)
These findings suggested that non-tumor biomarkers might predict subsets of patients likely to benefit from administration of EGFRis, including cetuximab
The need to collect material for markers prospectively, combined with the observation time required to accumulate outcome data with which to qualify biomarkers makes the process slow and expensive. In this manuscript we have examined the data from this trial with 3 goals: 1) to explore the use of quantitative changes in tumor burden at an early timepoint in a trial as a measure of drug effect, 2) to determine whether the prospectively collected biomarker data in this trial are consistent with retrospective analyses of larger clinical trials, and 3) to perform a preliminary estimate of the value of intensive, quantitative rash assessments as a candidate biomarker for future studies of EGFR inhibitors
Summary
Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). For the small molecule EGFR inhibitor (EGFRi) erlotinib in NSCLC, skin rash and serum proteomic assays were initially identified as candidate predictive biomarkers [8,9,10] These findings suggested that non-tumor biomarkers might predict subsets of patients likely to benefit from administration of EGFRis, including cetuximab. A retrospective landmark time-point analysis in the BMS099 trial [2] and a pre-specified subset analysis in the FLEX [7] trial demonstrated better outcomes for patients who developed rash by the end of cycle 1 with cetuximab added to front-line therapy These findings suggested that rash is a candidate predictive clinical biomarker for cetuximab in front-line NSCLC therapy but to validate the marker would require another large, randomized prospective study [11]
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