Abstract 582: Circulating tumor DNA (ctDNA) variant allele frequencies are reduced in responders to durvalumab and low baseline variant allele frequencies are associated with improved overall survival in NSCLC patients
Authors: Michael A. Kuziora, Brandon W. Higgs, Philip Brohawn, Rajiv Raja, Koustubh Ranade
Journal: Cancer Research (2017)

Abstract Mutations can influence patient responses to treatment in non-small cell lung cancer (NSCLC). Monitoring such mutations can be critical to guiding treatment decisions, however, accessing sufficient biopsy material for mutation analysis can be challenging. Circulating tumor DNA (ctDNA) in the plasma offers a robust and highly sensitive approach to identifying mutations. Further, variant allele frequencies (VAFs) in individual mutations represent the number of cancer clones harboring a mutation, thus providing an indicator of tumor burden. Here we evaluated baseline mutation spectrum in genes implicated in cancer for association with clinical outcomes to durvalumab, an anti-PDL1 molecule, and examined changes in VAFs, as a surrogate for tumor burden, after treatment with durvalumab in NSCLC patients. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab in patients with advanced NSCLC or other solid tumors. By 29APR2016, 304 NSCLC pts received 10 mg/kg Q2W of D ≤12 months with median 18.8 months follow up. A panel of 70 genes was assayed for nonsynonymous mutations and copy number (CN) variants using the Guardant360 cancer panel in plasma ctDNA from 115 NSCLC patients pre-treatment and 28 patients pre and 8 weeks post-treatment with durvalumab (Q2W). The mean VAF of all mutations harbored by a patient was correlated with clinical outcomes. Objective response rate (ORR) was calculated according to RECIST v1.1 and a Cox proportional hazards model was calculated adjusting for baseline ECOG, gender, age, smoking status, therapy lines, histology, and number of metastases. Partial responders (PRs) showed a significant decrease (Δ= -2.7%, p=0.005) in ctDNA mean VAF post-treatment with durvalumab (i.e. reduction in tumor burden) compared to an increase in mean VAF (i.e. increase in tumor burden) in progressive disease (PD) patients (Δ=+1.7%, p=0.17). This correlation was also observed in total mutation count in PR (Δ=-5.3, p=0.037) compared to PD patients (Δ=+2.7, p=0.003). In a PD patient, the VAF of T790M EGFR mutation doubled after 6 weeks of durvalumab treatment. Patients with VAFs below the median VAF or no CN gains had longer median overall survival (15.7 months, 95% CI=[11.2,not reached] ) compared to those with VAFs above the median or CN gains (5.1 months 95% CI=[3.8,9.4]; HR=0.29; p=0.0005), even after adjustment for clinical covariates. CtDNA VAFs were consistently reduced in responders but not non-responders after eight weeks of durvalumab. Below median pre-treatment VAFs or no CN gains in ctDNA correlated with longer overall survival in patients treated with durvalumab. Because we examined oncogenes and tumor suppressors, increased VAF in ctDNA of these genes may help to identify aggressive, and difficult to control tumors Note: This abstract was not presented at the meeting. Citation Format: Michael A. Kuziora, Brandon W. Higgs, Philip Brohawn, Rajiv Raja, Koustubh Ranade. Circulating tumor DNA (ctDNA) variant allele frequencies are reduced in responders to durvalumab and low baseline variant allele frequencies are associated with improved overall survival in NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 582. doi:10.1158/1538-7445.AM2017-582