Deciphering antitumour response and resistance with intratumour heterogeneity (DARWIN II)

TPS9099 Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study of patients with radically resected primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through genetic analysis of multi-region and longitudinal tumour sampling. DARWIN II is an investigator initiated study for patients who are enrolled within the TRACERx trial, or who have multi-region sequencing of their primary disease, but subsequently relapse with metastatic disease. This study will examine the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy. Methods: This multicentre non-randomised phase II molecularly stratified umbrella study will examine how clonal dominance and ITH influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between ITH and cfDNA/CTCs will also be explored in DARWIN II. The study arms: Arm 1: Patients either -1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy - Atezolizumab. Arm 2: BRAFV600 - Vemurafenib. Arm 3: ALK/RET gene rearrangement - Alectinib. Arm 4: Her2 Amplification - Trastuzumab Emtansine. Primary Outcome Measures: Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death will be assessed according to: Neo-antigen burden, mutational burden, ITH as assessed using an ITH ratio index and genomic instability as assessed using a weighted genome instability index (wGII). Trial Sponsor: University College London. Clinical trial information: NCT02314481.