David Allen Barbie, MD, on Clinical and Molecular Features of Participants in the ADRIATIC Trial

I'm going to discuss a presentation I gave on the ADRIATIC trial, which was presented last year at ASCO and has really changed the standard of care for limited stage small cell lung cancer, whereby following initial chemoradiotherapy for limited stage small cell lung cancer, durvalumab consolidation therapy has now become the standard of care based on a very significant improvement in overall survival. My presentation is to discuss the clinical characteristics as well as the molecular characteristics of the long-term durable responders or progressors who progressed after 12 months on therapy versus the early progressors as defined by early progression less than six months of therapy. With regards to the clinical characteristics, there were several features that were present in the long-term progressors irrespective of treatment, both in the durvalumab versus the control placebo condition and these characteristics included an earlier stage, stage zero or one, having prior hyperfractionated radiotherapy and also prior PCI therapy. What I think was particularly interesting were the molecular characteristics. This was performed in the tissue that was available, so not in all patients, but this was conducted via RNA sequencing analysis in a smaller fraction of patients as well as immunohistochemistry analysis in about 40 plus percent of patients. What was analyzed was PD-L1, which is one of the standard biomarkers using a Ventana assay as well as MHC Class 1 and CD8 expression, a marker on cytotoxic T cells. On using the RNA sequencing analysis, one could also look at specific gene signatures of a T-cell inflamed signature as well as STING pathway expression, which is a marker of innate immunity and sensitivity to DNA sensing. What was discovered and in these were all trends because of the power that that that while the overall study was powered. These are subgroup analyses based on what was available for having tissue. But the PD-L1 levels were not predictive of anything in terms of long-term progression or early progression regardless of treatment. However, the CD8 T-cell both by gene expression and by immunohistochemistry as well as the MHC Class 1 did trend towards being more being higher in the long-term progressors relative to the early progressors in both arms irrespective of treatment. However, when one looked at these gene expression signatures of a T-cell inflamed signature or STING pathway expression. In this case, there was a trend towards improved outcomes or higher levels in the long-term progressors relative to the early progressors specifically in the durvalumab arm. And so the conclusions from this while needing further evaluation is that potentially pre-chemoradiotherapy that there are certain features of small cell lung cancers, an inflamed subtype that's been described by multiple groups including our own could be the ones that particularly benefit. But of course this needs to be followed up in the larger, more powered study and for the biomarker analysis, such as more complicated multiplexed analysis and spatial analysis may be needed to develop an even more robust biomarker.