Hello, I'm Elsan Agnostou from Johns Hopkins, and on behalf of the study investigators, it is a great pleasure to present our trial in progress, a biomarker directed multi-center phase two study of molecular response adaptive immunochemotherapy in lung cancer. These are my disclosures. Liquid biopsy approaches are gaining momentum in immuno-oncology as they can be utilized to rapidly and accurately determine clinical responses that may otherwise be underestimated by conventional imaging. Our group has employed ultra-sensitive next-generation sequencing methods to analyze circulating cell-free tumor DNA, or ctDNA, in serial blood samples from lung cancer patients during treatment with immune checkpoint blockade. These analysis revealed distinct patterns of ctDNA-based molecular response that were reflective of patients' clinical outcome. Patients with a ctDNA molecular response had a dramatic reduction in ctDNA to undetectable levels which was reflective of long-term clinical benefit. In contrast, for patients with primary resistance to immune checkpoint blockade, ctDNA levels had limited fluctuations or displayed a rise after therapy initiation. We and others have shown that the quantitative variation in ctDNA levels is linked with therapeutic outcome such that patients with ctDNA molecular response have a longer progression-free and overall survival on immunotherapy. This clinical trial is conducted in two stages, as shown in the schematic here, a lead-in initial stage, shown on the left, and the ctDNA-driven randomized stage of the trial shown on the right. The question we are asking here is, which treatment-naive PD-L1-positive metastatic NMC patients can be treated with Pembrolizumab alone versus Pembrolizumab in chemotherapy? The first stage of the trial, which is what we're reporting here, will enroll 50 metastatic NMC patients eligible to receive first-line treatment with Pembrolizumab to solidify the liquid biopsy approach that will be utilized in the interventional second stage of the trial. Serial liquid biopsies will be performed utilizing the PGDX ileoplasma resolve assay, which is an ultra-sensitive, CLIA-grade, next-generation sequencing assay developed by Personal Genome Diagnostics. Through collection and comparative analysis of ctDNA levels in serial plasma samples, we will determine the optimal time point for molecular response, which is essential to establish the optimal design of the randomized portion of the study. In the second stage of the trial, treatment-naive NMC patients will start with single-agent Pembrolizumab and either continue on Pembrolizumab or escalate to Pembrolizumab and chemotherapy based on ctDNA molecular response. The key eligibility criteria include age off or above 18 years, ECOG performance status of 0 or 1, a diagnosis of stage 4 NMC that is confirmed EGFR and ALK alteration negative, with a PDL1 tumor proportion score of equal or more than 1%, and no prior systemic or immune-targeted therapy for metastatic NMC. The primary endpoints focus on determining the optimal time point for ctDNA molecular response, validation of the concordance of ctDNA response with radiologic response, and these will ultimately be used to establish the design for the randomized second stage portion of the study. Secondary endpoints include investigating the association of ctDNA molecular response with progression-free and overall survival, and tertiary endpoints include additional nuanced analysis of ctDNA features in longitudinal plasma samples. And this is our progress thus far. There are five active sites in Canada and one in the United States. The first patient was enrolled in April 2020, and we have enrolled 34 out of 50 planned patients and successfully collected and banked blood-derived biospecimens. And here's a preview of the leukobiopsy analysis. Again, for patients enrolled in the trial, serial blood samples are obtained every three weeks. With each cycle of first-line pembrolizoma, ctDNA is deeply sequenced, analyzed with matched leukocyte DNA to filter out clonal hematopoiesis variants, and dynamic changes in ctDNA levels will ultimately be linked to clinical outcome. And I'm showing here on the left a patient with ctDNA dynamics indicative of molecular response. You can appreciate here the clearance of tumor-derived mutations compared to a patient with persistence of ctDNA levels suggestive of molecular progression. Liquid biopsy analysis are performed in a blind manner with respect to clinical outcomes. In summary, our efforts are tuned towards implementation of liquid biopsies in clinical cancer care. Liquid biopsies can be incorporated in intensification immunotherapy treatment strategies when the initial immune-targeted agents fail, and a molecular response adaptive design allows for rapid identification of patients less likely to respond, who can then receive potentially more efficacious therapies. We envision that ctDNA interventional trials will further advance precision immuno-oncology by more reliably, rapidly, and cost-effectively tailoring therapies for the increasing number of patients treated with immunotherapy. This trial is run by the Canadian Cancer Trials Group and sponsored by the Cancer Research Institute, the Mark Foundation, and Personal Genome Diagnostics. I would like to thank all the study investigators and our sponsors, and of course our patients and their families that made this study possible. Thank you for your attention.

biomarker-directed immunochemotherapy

liquid biopsy

ctDNA levels

immune checkpoint blockade treatment

molecular response