This exploratory randomized phase II trial with a 2-week run-in of cetuximab monotherapy could inform future development of predictive biomarkers for EGFRi therapy in NSCLC. The biomarker development concepts implemented included: 1) piloting a modified version of the validated rosacea scale for EIR-rating, 2) use of modified quantitative assessment of tumor size changes to assess marker relationships, and 3) concomitant assessment of candidate markers, rash and serum proteomic profiling in the same patients. The EIR scale distributed rash ratings across a larger ordinal range than the conventional CTCAE rash scale; however this scaling did not strengthen the association with treatment outcomes beyond that of the categorical “rash vs. no rash” approach employed by Gatzemeier, et al. . The serum proteomic predictor was associated with treatment outcomes in this study of cetuximab and pemetrexed in the second-line treatment of NSCLC, although this finding might be due to confounding with treatment arm.
As a small trial, not meeting its intended accrual goals, there are clear limitations to this study. The setting of advanced NSCLC meant many patients deteriorated during or immediately after investigational treatment. As the value of information was not clear at the time of conducting the trial, we did not assess candidate molecular markers on patients’ tumors and we did not stratify the randomization by tumor histology. We had competing trials at that time that required information on tissue type for enrollment and a PS of only 0 or 1. This study unintentionally enrolled a typically more ill population with few never smokers (10%), fewer than usual women (under 40%), and many patients with non-adenocarcinoma or unknown histology (70%). The actual sample size meant only large effects, such as the benefit of immediate initiation of pemetrexed, could be detected with conventional measures such as progression-free and overall survival. The randomization did not effectively free the assessment from bias. This is highlighted by the unusually poor median-survival time in Arm A, 3.5 months is even low for a best-supportive care only trial. Arm A had fewer women, had patients with a higher median age, and more patients with serum proteome-profile-predicted “poor” outcomes with cetuximab monotherapy. It is therefore unclear the extent to which the treatment assignment versus the small sample size have biased the outcomes of this trial by study arm. The results are consistent with prior evidence of the value of timely treatment with pemetrexed in second-line treatment of NSCLC [29, 30]. Despite not reaching original accrual goals for the study, Arm B subjects, treated concurrently with pemetrexed and cetuximab, had better progression free and overall survival than Arm A subjects treated with sequential cetuximab followed by pemetrexed, reaching statistical significance for the latter. Notably, of the 20 evaluable patients who were randomized to Arm A, 10 did not maintain sufficiently good performance status to receive the pemetrexed after progression.
The EIR scale distributed ratings more broadly than CTCAE, but there is no evidence that this broader distribution will improve upon use of rash severity as a predictive marker for cetuximab efficacy in NSCLC. Serial skin biopsies were performed on a subset of patients in this study, but the heterogeneity of the specimens in terms of estimated volume, estimated total number of cells, enumerated EGFR-expressing cells and ratio of EGFR-expressing to total cells, as well as relative mRNA expression of candidate normalization molecules (data not shown) made semi-quantitative and correlative analyses impossible. Dose-to-rash studies with EGFRi have not revealed a significant benefit for increasing the severity of rash [31, 32]. Our data are consistent with the observations of others in larger trials, that incidence and not relative severity of EIR appears to be the pharmacodynamically relevant biomarker [7, 10].
Cetuximab monotherapy has no evident value in the treatment in unselected NSCLC patients in the second-line setting. Some could argue that cetuximab therefore has limited if any role in combination therapy. However, the data from Gatzemeier, et al. , suggest that a biomarker-based selection of patients who should receive cetuximab added to standard chemotherapy could yield improved outcomes over those reported for the cetuximab arm in the FLEX trial. This circumstance is increasingly common in oncology therapeutics, an agent that has limited but evident benefit in combination cannot be used ethically as monotherapy. Therefore, the early development monotherapy trials become an important opportunity with which to characterize candidate biomarkers and conduct preliminary validation and comparative estimate studies. In this “pure” setting, investigators can determine the typical time course, intensity, and interindividual variance in candidate markers. In a single disease, investigators can conduct preliminary comparisons to make estimates regarding which markers represent the best opportunities for future validation and qualification studies in large trials, including combination therapy trials.
For future qualification of candidate markers of EGFRi in the treatment of NSCLC, we propose that either the serum proteomic assay or incidence of rash be further evaluated as a means to exclude patients from receipt of cetuximab therapy. In patients who have the “poor” proteomic profile and those who fail to develop rash by 21 days of cetuximab therapy the likelihood of benefitting from cetuximab therapy appears low. In NSCLC, these markers, similar to the use of KRAS mutations in colorectal cancer, have reproducibly associated with absence of benefit from EGFRi therapy –[16, 33]. Our findings suggest future strategies to qualify these biomarkers for clinical use would be to demonstrate prospectively in a randomized trial that either or both markers effectively reduces the unnecessary, toxic, ineffective, and expensive use of cetuximab . Ideally, this study should help to identify safe and more effective alternatives for the patients who will not benefit from cetuximab therapy.