Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer

Abstract

Background: 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). 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.

Methods: 55 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.

Results: 43 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.

Conclusions: Absence 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 registration: ClinicalTrials.gov NCT00203931.

Figure 1

Progression-free and overall survival by study arm (a,c) and by serum assay classifier (b,d).

Figure 2

Comparison of worst rash scores per patient by EIR and CTCAE scales.

Figure 3

Change in tumor size by arm (a) and serum proteomic classifier (b). The log of the ratio of the tumor size at the first evaluation on treatment (T1) to the baseline tumor size (T0) is plotted for each subject. The top red dashed line marks RECIST criteria for progressive disease at the time of the first CT scan, any values at or below the bottom dashed red line meet RECIST criteria for response, and those meeting criteria for stable disease lie in between the two dashed lines. Circles represent actual measured values, while triangle symbols indicate those subjects with brain MRIs confirming new metastases at the first evaluation and therefore equated with the change in tumor size of the worst progressor. The early death in Arm B was assigned a T1/T0 value of 2.5 (log(T1/T0) = 0.92).

Figure 4

Change in tumor size vs. change in EIR rash score. This is a plot of each individual, evaluable patient from this trial. The x-axis represents the change in EIR from baseline to C1D8. The y-axis represents the change in tumor size by log ratio of tumor burden at week 8 to baseline. Each patient is further represented by which arm to which they were randomized (red for Arm A, blue for Arm B) and serum predictor (x for poor, circle for good). The plot reveals potentially informative trends: 1) the top 5 tumor responses (the most negative log ratios) were among subjects randomized to Arm B, all of whom had “good” predictor status, but had rash changes on the EIR of 0, 1, 2, 4, and 5; 2) Of the early progressors (11 subjects with log ratio > 0.18 at or before the first imaging session), 8 had some evidence of rash and 5 had among the most severe rashes with an EIR rating change of 4 or 5; 3) No patient with a “poor” serum proteome predictor had any tumor shrinkage at all, but only 2 of these subjects were randomized to receive pemetrexed at the end of the 2-week run-in.