Abstract CT212: A ctDNA-directed, multi-center phase II study of molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer: Analysis of Stage 1 of CCTG BR.36
Authors: Anagnostou Valsamo K. , Ho Cheryl , Nicholas Garth , Juergens Rosalyn Anne , Sacher Adrian , Fung Andrea , Wheatley-Price Paul , Laurie Scott , Levy Benjamin , Brahmer Julie , Balan Archana , Niknafs Noushin , Avrutin Egor , Zhu Liting , Sausen Mark , Bradbury Penelope , O'Donnell-Tormey Jill , Gaudreau Pierre-Olivier , Ding Keyue , Dancey Janet 
Published: April 2023

Abstract
Introduction: Analyses of circulating tumor DNA (ctDNA) have shown promise in capturing tumor burden dynamics during immune checkpoint blockade (ICB), with the potential to allow patients with primary resistance to be rapidly identified and redirected to alternative therapies.
Methods: BR.36 is an international multicenter, open label, biomarker-directed, phase II trial of molecular response-adaptive immuno-chemotherapy for patients with treatment-naïve non-small cell lung cancer-NSCLC (NCT04093167). The trial consists of two stages; stage 1 was a single-arm study to validate the ctDNA approach, with stage 2 focusing on ctDNA guided treatment selection. Key eligibility criteria included EGFR and ALK mutation negative, ICB and chemotherapy-naïve metastatic NSCLC with PD-L1 expression ≥1%. Primary objectives were to ascertain ctDNA molecular response, determine its timing and concordance with radiologic RECIST/iRECIST response. Secondary objectives included the evaluation of time to ctDNA molecular response and its correlation with progression-free (PFS) and overall survival (OS). Liquid biopsy analyses utilized a validated tumor-agnostic white blood cell (WBC) DNA-informed 33-gene panel approach. Ultra-sensitive error-correction ctDNA next-generation sequencing (NGS) was performed at baseline/cycle 1 (C1D1), cycle 2 (C2D1) and cycle 3 (C3D1) of pembrolizumab (200mg IV q3 weeks). The maximum variant allele fraction (maxVAF) of tumor-derived variants was tracked from the pre-treatment to on-therapy timepoints.
Results: Activated October 17, 2019, stage 1 completed accrual of 50 patients on April 5, 2022; data lock date was September 20, 2022. Most patients were ever-smokers (98%), had no prior systemic therapy (92%), stage IV NSCLC (98%), adenocarcinoma (76%) with PD-L1 tumor proportion score of ≥ 50% (96%); cohort consisted of 82% white, 52% female, 56% age&gt;65 and 76% ECOG PS 1 participants. Median follow-up was 13.5 months (range 2.5-23.0). Best overall response rate (ORR) by RECIST was 32% with a median duration of 10.1 months. Matched WBC DNA analyses allowed for effective removal of germline and clonal hematopoiesis variants, followed by evaluation of ctDNA response. MaxVAF clearance signified molecular response (mR), while maxVAF persistence indicated molecular disease progression (mPD). Among 35 evaluable patients (77.8%), 15 were classified in the mR category, with an evaluable mR rate of 43% (90% CI: 0.29-0.58). The median time to molecular response was 2.1 months (90% CI: 1.5-2.6). The sensitivity of ctDNA molecular response for RECIST and iRECIST response was 82% (90% CI: 52%-97%) and 83% (90% CI: 56%-97%), with a specificity of 75% (90% CI: 56.5%-88.5%) and 78% (90% CI: 60%-91%) respectively. Patients with mR attained longer PFS (5.03 vs 2.6 months,) and OS (not reached vs 7.23 months); ctDNA response also provided prognostic information for patients with RECIST stable disease.
Conclusions: ctDNA molecular responses were concordant with radiologic response assessments, but importantly better predicted PFS and OS for patients with stable disease or better. These findings are now incorporated into the interventional second stage of the trial.
Citation Format: Valsamo K. Anagnostou, Cheryl Ho, Garth Nicholas, Rosalyn Anne Juergens, Adrian Sacher, Andrea Fung, Paul Wheatley-Price, Scott Laurie, Benjamin Levy, Julie Brahmer, Archana Balan, Noushin Niknafs, Egor Avrutin, Liting Zhu, Mark Sausen, Penelope Bradbury, Jill O'Donnell-Tormey, Pierre-Olivier Gaudreau, Keyue Ding, Janet Dancey. A ctDNA-directed, multi-center phase II study of molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer: Analysis of Stage 1 of CCTG BR.36 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT212.