1264P - Early circulating tumour DNA (ctDNA) dynamics for predicting and monitoring response to immunotherapy (IO) vs chemotherapy (CT) in patients with 1L metastatic (m) NSCLC: Analyses from the phase III MYSTIC trial

Background

We have previously shown that ctDNA dynamics can identify pts as “molecular responders” (MRs) to IO who have improved OS compared with molecular non-responders (non-MRs). Larger randomized studies in specific clinical settings including 1L are needed to optimize use of ctDNA as a biomarker of response. We report analyses of ctDNA in pts with mNSCLC treated with 1L durvalumab (D), D + tremelimumab (T), or CT in the phase III MYSTIC trial (NCT02453282).

Methods

Plasma was collected at baseline and on-treatment (predose at Cycle 2 of D ± T/Cycle 3 of CT) and ctDNA was sequenced using the GuardantOMNI panel (500 genes). Mean variant allelic frequency (VAF) values of baseline variants with ≥0.3% VAF and the change between baseline and on-treatment were used to calculate delta VAF. MRs were defined as having a decrease of ≥50% from baseline mean VAF.

Results

Biomarker evaluable populations (BEPs) with variants ≥0.3% VAF were n=901 for baseline (BEP1) and n=713 for baseline + on-treatment (BEP2). Both BEPs were similar to the ITT population. Pts with baseline mean VAF 6 months) vs non-MRs with D (OR 4.4, 95% CI 2.1–9.4) and D + T (6.8, 3.2–15.2) with a weaker trend for CT (2.9, 0.91–12.5). Among pts with stable disease at wk 6, MRs had longer OS vs non-MRs with D (HR 0.51, 95% CI 0.31–0.86) and D + T (0.58, 0.36–0.94) but not CT (1.2, 0.83–1.7).

Conclusions

Results indicate that baseline ctDNA level is prognostic in 1L mNSCLC; further, MR is predictive of clinical benefit with IO but not CT. On-treatment ctDNA dynamics may have important predictive value for long-term outcomes with IO, complementing radiologic assessment and enabling early decision-making.

Clinical trial identification

NCT02453282; Release date: 25 May 2015.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by James Holland, PhD, of Ashfield MedComms (Macclesfield, UK), an Ashfield Health company, and funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca Plc.

Funding

AstraZeneca.

Disclosure

S. Peters: Consultation / Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp & Dohme, Merck Serono, Merrimack, Mirati, Novartis, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp & Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda. Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp & Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. N.A. Rizvi: Financial Interests, Personal, Other, Personal fees: AbbVie, Apricity, AstraZeneca, Boehringer Ingelheim, Calithera, Dracen, Editas, EMD Serono, G1 Therapeutics, Genentech, Gilead, GlaxoSmithKline, Illumina, Lilly, Merck, Neogenomics, Novartis, Takeda; Financial Interests, Personal, Other, Personal fees and stock options: Brooklyn Immuno Therapeutics, Bellicum, Arcus, Gritstone; Financial Interests, Personal, Stocks/Shares, Stock options: Gritstone; Financial Interests, Personal and Institutional, Royalties, Patent filed for “Identifying determinants of cancer response to immunotherapy” (PCT/US2015/062208), licensed to Personal Genome Diagnostics: Memorial Sloan Kettering Cancer Center. M. Kuziora: 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, Stocks/Shares: AstraZeneca. Y. Shrestha: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Dey: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J.C. Barrett: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. U. Scheuring: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. L. Poole: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Abbosh: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant, Contracted/support research grant: AstraZeneca; Financial Interests, Personal, Royalties, Author on two pending patents: “Method of detecting tumor recurrence” and “Methods for lung cancer detection that utilise ctDNA as a lung cancer detection tool”: AstraZeneca; Financial Interests, Personal and Institutional, Other, Current AstraZeneca Physician Fellow (grant to University College London) (myself/spouse): AstraZeneca. R. Raja: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal and Institutional, Other, Patent pending for Tumor Mutation Burden: AstraZeneca. M.D. Hellmann: Non-Financial Interests, Personal, Other, Non-financial support: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Other, Personal fees: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, Personal fees: Merck, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint Medicines, Achilles; Financial Interests, Personal, Other, Personal fees (including options): Immunai, Arcus, Shattuck Labs; Non-Financial Interests, Personal, Other, Non-financial support: Eli Lilly; Financial Interests, Personal and Institutional, Other, Patent pending related to \"Use of Tumor Mutation Burden to Predict Response to Immunotherapy\" and licensed to PGDx (PCT/US2015/062208): PGDx.