AMG 925 In addition while a general biomarker hypothesis
In addition, while a general biomarker AMG 925 was stated in the protocol, the specific biomarker (i.e., HRG mRNA) and a description of the validated assay were defined only in the statistical analysis plan. An alternative approach would have been to amend the protocol once the preclinical data and assay became available and to formally elevate the single predictive biomarker hypothesis to a second primary end point (Beckman et al., 2011; Simon, 2005). As the HRG mRNA assay became available close to study completion, the protocol was not amended to specify the HRG subgroup analysis as the secondary primary end point due to the extra time and costs such an approach would have necessitated. However, this decision diminished the perceived credibility of the results in some instances, and the trade-off for omitting this administrative step may therefore have not been optimal, despite the development time it saved.
Due to the caveats in this prospective–retrospective approach and the potential for confounders in the observed effect size, a 2-part phase 3 study (HER3 Lung) will be conducted (NCT02134015) (Paz-Ares et al., 2014). Part A of the study will enroll patients with any level of HRG mRNA expression, and the statistical analysis will assess HRG-high and HRG-low biomarker groups for clinical benefit as measured by PFS to confirm the results of the HERALD study. The HRG cutoff will be further refined based on the clinical benefit observed in part A and in the HERALD study, using maximum likelihood methods (Altman et al., 1994; Jiang et al., 2007). This refined cutoff will then be applied in the pivotal part B, which will enroll HRG-high patients only, per revised criteria. Within part B, HRG-high patients will be further stratified into 2 levels of HRG mRNA expression. If part B is positive and the drug is registered, the information about Papovaviruses strata may be available to further inform physician and patient choices.
Conflicts of Interest