LBA49 - Associations of ctDNA clearance (CL) during neoadjuvant Tx with pathological response and event-free survival (EFS) in pts with resectable NSCLC (R-NSCLC): Expanded analyses from AEGEAN

Background

In the phase 3 AEGEAN trial, perioperative durvalumab (D) + neoadj CT significantly improved the primary endpoints of EFS and pathological complete response (pCR) vs neoadj CT alone in pts with R-NSCLC. Using data from an expanded cohort of all biomarker-evaluable pts at the second interim EFS analysis, we report exploratory analyses for associations of ctDNA CL during neoadj Tx with pCR, major pathological response (MPR) and, for the first time, EFS.

Methods

AEGEAN is a double-blind PBO-controlled study (NCT03800134). Adults with Tx-naïve R-NSCLC (stage II–IIIB[N2]) and ECOG PS 0/1 were randomised (1:1) to receive neoadj platinum-based CT + D or PBO IV (Q3W, 4 cycles) before surgery (Sx) followed by D or PBO IV (Q4W, 12 cycles) after Sx. Efficacy was assessed in the mITT population, which excluded pts with known EGFR/ALK mutations. EFS was evaluated by BICR (RECIST v1.1) and pCR/MPR were evaluated centrally (IASLC). ctDNA analysis was performed on plasma collected before each neoadj Tx cycle and before Sx using pt-specific tumour-informed assays.

Results

ctDNA was evaluated in 1268 samples from 283 mITT pts (D arm, n=142; PBO arm, n=141). Among ctDNA+ pts at baseline (89.6%), all pts who achieved pCR and >93% who achieved MPR had ctDNA CL at C4D1. In both arms, lack of early ctDNA CL identified pts who had a low probability of achieving pCR (negative predictive value [NPV] ≥89% at C2D1). At pre-Sx, pts with vs without ctDNA CL had better EFS outcomes (D arm: HR, 0.26; 95% CI, 0.13–0.54; PBO arm: HR, 0.47; 95% CI, 0.26–0.84), and pts in the D vs PBO arm had trends for longer EFS regardless of ctDNA CL (ctDNA CL[+]: HR, 0.50; 95% CI, 0.24–1.05; ctDNA CL[-]: HR, 0.84; 95% CI, 0.47–1.48). Furthermore, pts with ctDNA CL had longer EFS regardless of pCR status compared to pts without either ctDNA CL or pCR who had the worst EFS outcomes (D arm: ctDNA CL[+], pCR[+]; HR, 0.14; 95% CI, 0.04–0.48; ctDNA CL[+], pCR[-]; HR, 0.35; 95% CI, 0.16–0.76; PBO arm: data to be presented). ctDNA CL identified more pts with improved EFS than pCR status.

Conclusions

Absence of early ctDNA CL may identify pts unlikely to achieve pCR. Pre-Sx ctDNA CL (alongside pCR) warrants further study as a surrogate endpoint of EFS.

Clinical trial identification

NCT03800134 (release date: January 11, 2019).

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Andrew Gannon, MS, MA (New York, NY, USA), of Ashfield MedComms, an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Reck: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, Mirati, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Regeneron, Samsung Bioepis; Financial Interests, Personal, Coordinating PI: AstraZeneca; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, Mirati, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Regeneron, Samsung Bioepis; Non-Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, Mirati, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Regeneron, Samsung Bioepis, Gilead; Other, Personal, Other: ESMO; Non-Financial Interests, Personal, Principal Investigator: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, Mirati, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Regeneron, Samsung Bioepis, Gilead; Financial Interests, Institutional, Research Funding: BMS, Boehringer Ingelheim, AstraZeneca; Financial Interests, Institutional, Research Grant: EU; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, Mirati, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Regeneron, Samsung Bioepis; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Amgen, Boehringer Ingelheim, BMS, Daiichi Sankyo, GSK, Lilly, MSD, Gilead, Roche, Regeneron, Seagen. D. Gale: Financial Interests, Personal and Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Personal and Institutional, Stocks/Shares: AstraZeneca, GSK; Non-Financial Interests, Institutional, Other, Patent pending: AstraZeneca. Z. Zhu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Other, Patent inventor (unrelated to work reported here): N/A. D. Harpole: Non-Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal and Institutional, Leadership Role: AstraZeneca; Non-Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca; Non-Financial Interests, Institutional, Research Funding: AstraZeneca; Non-Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca; Non-Financial Interests, Personal and Institutional, Steering Committee Member: AstraZeneca. J. Taube: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Regeneron, Elephas, Lunaphore, Roche, Moderna; Financial Interests, Institutional, Research Grant: BMA, Akoya, BioSciences. T. Mitsudomi: Financial Interests, Personal, Advisory Board: Regeneron, BMS, AstraZeneca, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Novartis, Amgen, MSD, Pfizer, Eli-Lilly, Merck Biopharma, Ono; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Taiho, Ono, MSD, Eli Lilly, Chugai, Bridge Bio; Non-Financial Interests, Personal, Steering Committee Member: AstraZeneca, BMS. M.J. Hochmair: Financial Interests, Personal, Invited Speaker: MSD, Roche, Lilly, AstraZeneca, Takeda; Financial Interests, Personal, Advisory Board: MSD, Roche, Lilly, AstraZeneca, Takeda. H. Akamatsu: Financial Interests, Personal, Advisory Board: Amgen Inc, Janssen Pharmaceutical K.K., Sandoz; Financial Interests, Institutional, Funding: Amgen Inc, Chugai Pharmaceutical Co. Ltd. and MSD K.K.; Financial Interests, Personal, Speaker’s Bureau: Amgen Inc, AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku. Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Inc, Takeda Pharmaceutical Co. Ltd. and Taiho Pharmaceutical Co. Ltd.. L. Antonuzzo: Financial Interests, Personal and Institutional, Invited Speaker: BMS, Amgen, Roche, AstraZeneca, Pfizer; Financial Interests, Institutional, Research Grant: Merck. Z. Szalai: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GSK. R. Stewart: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z. Lai: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Member: AACR, ASCO; Financial Interests, Personal, Stocks or ownership: AstraZeneca. D. Hodgson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G. Doherty: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.V. Heymach: Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Advisory Role: AstraZeneca; BerGenBio; Boehringer Ingelheim; Bristol Myers Squibb; DAVA Pharmaceuticals; EMD Serono; Genentech/Roche; GSK; Hengrui Pharmaceutical; Janssen; Jazz Pharmaceuticals; Jazz Pharmaceuticals; Lilly (Inst); Mirati Therapeutics; Nexus H, Pneuma Respiratory; Regeneron; Sanofi/Aventis; Spectrum Pharmaceuticals; Takeda; Financial Interests, Personal, Speaker’s Bureau: Dava Pharmaceuticals; IDEOlogy Health; MJH Life Sciences; Financial Interests, Personal and Institutional, Research Funding: AstraZeneca; Boehringer Ingelheim; Mirati Therapeutics; Spectrum Pharmaceuticals; Takeda; Financial Interests, Personal and Institutional, Other, Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations: Spectrum and MD Anderson. All other authors have declared no conflicts of interest.