LBA51 - Circulating tumor DNA (ctDNA) dynamics and treatment responses in chemotherapy-ineligible patients (pts) with unresectable stage III NSCLC from the phase II DUART trial

Background

In the phase 2, open-label, single-arm DUART trial, radiotherapy (RT) followed by durvalumab (D) showed promising results in chemotherapy-ineligible pts with unresectable stage III NSCLC. We report exploratory ctDNA analyses.

Methods

Pts without disease progression after standard (54–66 Gy) or palliative RT (40–<54 Gy) received D for up to 12 months. We analyzed ctDNA samples collected at protocol-specified timepoints (prior to D administration at cycle 1 [C1], C2, and C7) with a targeted methylation-based test (GRAIL); ctDNA detection, dynamics, and associations with progression-free survival (PFS) were assessed. Survival analyses used a Cox proportional hazards model, with p-values calculated via log-rank test.

Results

We collected 216 samples from 93 pts (standard RT: n=47; palliative RT: n=46) from the intent-to-treat (ITT) population. Baseline characteristics of pts in whom ctDNA was evaluated and the ITT population were similar. The proportion of evaluable pts with detectable ctDNA at C1 was 35% (32/91) and was numerically higher after palliative (20/45 [44%]) vs standard RT (12/46 [26%]). Detectable ctDNA at C1 was associated with a trend toward shorter PFS irrespective of RT dose (HR: 1.60; 95% CI: 0.89, 2.86; p=0.11); this trend in PFS was primarily due to the results from pts receiving standard RT (HR: 2.84; 95% CI: 1.16, 6.99; p=0.017). Among pts evaluable for ctDNA clearance (CL), the ctDNA CL rate in pts receiving palliative vs standard RT, respectively, was similar at C2 (4/21 [19%] vs 2/13 [15%]) and higher at C7 (6/14 [43%] vs 0/10 [0%]). Among pts with available samples at C7, estimated median PFS was 25.5 months for pts with undetectable ctDNA (n=26) vs 9.2 months for pts with detectable ctDNA (n=18), irrespective of RT dose (HR:4.43; 95% CI: 1.55, 12.72; p=0.0026).

Conclusions

The presence of ctDNA after RT alone does not clearly associate with prognosis among pts receiving consolidation D, but absence of detectable ctDNA later during consolidation is associated with prolonged PFS. RT followed by D can lead to complete molecular responses and improved PFS. ctDNA monitoring could help identify pts who may benefit from more intensive treatment in future trials.

Clinical trial identification

NCT04249362 (release date: January 30, 2020).

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Eric Exner, MD, PhD, of Ashfield MedComms (New York, NY, USA), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

A.R. Filippi: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Role: Radiomics (OncoRadiomics); Financial Interests, Personal, Coordinating PI: AstraZeneca; Other, Institutional, Funding: AstraZeneca, Roche, MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Institutional, Local PI: AstraZeneca, Roche, MSD; Non-Financial Interests, Personal, Membership or affiliation: ESMO, ESTRO, IASLC; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Takeda; Financial Interests, Personal, Steering Committee Member: AstraZeneca, EORTC. M.R. Garcia-Campelo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, F. Hoffmann-La Roche, Janssen, Lilly, MSD, Pfizer, Sanofi, Takeda, Pfizer; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, DaiichiSankyo, F. Hoffmann-La Roche, GSK, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Amgen, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, F. Hoffmann-La Roche, GSK, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Amgen, Pfizer. J. Paoli: Financial Interests, Personal, Research Funding: AstraZeneca, BMS, MSD, Pfizer. D.M. Kowalski: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, Pfizer, Takeda, Johnson & Johnson, AstraZeneca, Medison, Amgen; Financial Interests, Personal, Advisory Role: MSD, BMS, Roche, Pfizer, Takeda, Johnson & Johnson, AstraZeneca, Medison, Amgen; Financial Interests, Personal, Local PI: MSD, BMS, Roche, Pfizer, Takeda, Johnson & Johnson, AstraZeneca. C. Bennati: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Pfizer, Janssen; Financial Interests, Personal, Advisory Role: Daiichi. P. Borghetti: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Takeda; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, Roche, MSD; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Roche; Non-Financial Interests, Personal, Steering Committee Member: AstraZeneca. D.L. Cortinovis: Financial Interests, Personal, Advisory Board: Pfizer, MSD, BMS, Roche, AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, Takeda, BeiGene, Janssen; Financial Interests, Personal, Speaker’s Bureau: Pfizer, MSD, BMS, Roche, AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, Takeda, BeiGene, Janssen. A. Delmonte: Financial Interests, Personal, Advisory Board: Novartis, Takeda. C. Genova: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Novartis; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, MSD, Roche, Novartis. R.M. Mroz: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Roche; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, MSD, BMS, Roche; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, MSD, BMS, Roche; Financial Interests, Personal, Ownership Interest, Centrum Medycyny Oddechowej Mroz Spolka Jawna: AstraZeneca, MSD, BMS, Roche. G. Tonini: Financial Interests, Personal, Advisory Board: Molteni, Novartis, MSD, PharmaMar. R. Stewart: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z. Zhu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Advisory Board, Patent inventor (unrelated to work reported here): N/A. G. Wetherill: Financial Interests, Personal, Financially compensated role, Consultant statistician: AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultant statistician: AstraZeneca. N.E. Georgoulia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Financially compensated role: AstraZeneca; Financial Interests, Personal, Stocks or ownership: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I. Diaz Perez: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Dziadziuszko: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, BMS, Novartis, Amgen, Regeneron; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, BMS, Takeda, MSD, Novartis, Amgen, Regeneron, Pfizer; Financial Interests, Personal, Principal Investigator: AstraZeneca, Amgen, Roche, Ryvu Therapeutics, Takeda, MSD, Novartis, ThurningPoint Therapeutics, Pfizer; Financial Interests, Personal, Product Samples: Novartis, Pfizer. All other authors have declared no conflicts of interest.