Predictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs)

Background: Pseudo-progression associated with ICI has been well described. HP - characterized by paradoxically accelerated tumor growth rate (TGR) - while on ICI is increasingly being recognized. Preliminary data have reported murine double minute (MDM2/MDM4) amplification as a possible predictive biomarker for HP based on pre-treatment next generation sequencing (NGS) of tumor tissue. We sought to identify patients that hyper-progressed at our institution, characterize the SAs in those patients (pts) and conversely, estimate the incidence of HP in pts with such SAs. Methods: HP was defined as: 1. progression at first restaging on ICI 2. Increase in tumor size > 50%, 3. >2-fold increase in TGR. Data were obtained by interrogating our institutional electronic medical record and molecular database (MDB). Next Generation Sequencing (NGS -Foundation Medicine, Cambridge MA) was performed on pre-treatment tumor tissue; DNA was extracted, NGS was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: 5 pts met criteria for HP, NGS data was available on 4 (80%) pts. Most frequently encountered SAs were MDM2/MDM4 amplifications (amp -50%), EGFR amp (25%) and amp of several genes located on chromosome 11q13 -CCND1, FGF3, FGF4, FGF19 (75%). Tumor mutational burden ranged from 4-13/Mb for all pts with HP. Review of our MDB (N = 696) identified MDM2/MDM4, EGFR and 11q13 amp in 26 (4%), 26 (4%) and 25 (4%) pts respectively. Of the 70 patients with these SAs, 10 received ICI. The incidence of HP in pts with MDM2/MDM4, EGFR and 11q13 amp was 2 (66%), 1 (50%) and 3 (43%) respectively. Patient details are summarized below.Table1140PDAge - SexDisease# Prior lines of chemotherapyICITime to HP (months)NGS65 - Male (M)NSCLC2Nivolumab (N)2CCDN1, CDK4, FGF19, FGF4, MDM2, FGF3, FRS268 - MEsophageal Adeno Ca1Pembrolizumab (P)2CCND1, EGFR, FGFR19, FGF3, FGF4,77 - MEsophageal SCC3P3EPHA3, MDM4, CHEK2, EP300, NOTCH1, NOTCH3, SPOP, TP5359 - MLung Ca (neuroendocrine features)1N2CCND1, FGF19, FGF3, FGF4, KRAS, NFE2L2, TP5358 FRenal Cell Ca2N1NA Open table in a new tab Conclusions: A subset of pts treated with ICI develop HP. Copy number alterations in MDM2/MDM4, EGFR and several genes located on 11q13 are associated with HP. The role of these SAs as putative predictive biomarkers for HP needs further validation in larger cohorts of pts. Immune escape/editing, leading to HP needs mechanistic elucidation; prospective identification of pts at risk for HP is crucial and merits further investigation. Legal entity responsible for the study: Arun K Singavi, MD and Ben George, MD Funding: None Disclosure: S. Ali: Employee - Foundation Medicine, Cambridge, MA. B. George: Consultant for Celgene, Cook Medical, Merrimack, Foundation Medicine, Ipsen. All other authors have declared no conflicts of interest.