929MO - Platform study of neoadjuvant durvalumab (D) alone or combined with novel agents in patients (pts) with resectable, early-stage non-small cell lung cancer (NSCLC): Pharmacodynamic correlates and circulating tumor DNA (ctDNA) dynamics in the NeoCOAST study

Background

Neoadjuvant therapy with PD-(L)1 inhibitors, both as monotherapy and in combination, leads to pathological responses in resectable, early-stage NSCLC. NeoCOAST (NCT03794544) is a phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) D alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy.

Methods

Pts with untreated, stage I [>2 cm]–IIIA NSCLC were randomized to receive 1 cycle of D alone or in combination. The primary endpoint was investigator-assessed major pathological response (MPR) rate. In a subset of pts, treatment-induced transcriptomic changes were assessed by RNA sequencing from tumor tissue collected pre-treatment and at surgery. Using a tumor-informed method, ctDNA was analyzed pre-treatment, after treatment, and post-surgery. Molecular response (MR) is defined as ≥50% reduction in variant allelic fraction from pre-treatment.

Results

As previously reported, MPR was numerically higher in all combination arms [D+O (n=4/21, 19%), D+M (n=6/20, 30%), and D+Da (n=5/16, 31%)], compared with D monotherapy [n=3/27, 11%]. Among pts with an MPR, 2 had EGFR driver mutations (both D+O arm); KRAS, STK11, RET and ALK alterations were observed in pts without an MPR. Expression of genes associated with NK cells (KLRC1, GNLY) and CD8 T cells (CD8A, GZMK) increased after treatment in all arms; with a greater increase with D+O and D+M (1–5 log₂FC, adj p < 0.1) than D alone (0–1 log₂FC, n.s.). Tertiary lymphoid structure, interferon, and inflammatory signatures were significantly upregulated after treatment in the D+O and D+M arms. Analysis of ctDNA identified pts who had MR (25–60% per arm after treatment, and 75–100% post-surgery), including pts without an MPR. Association of tumor mutational burden and additional biomarkers with clinical outcomes will be reported.

Conclusions

Single cycle of D+O and D+M resulted in greater intra-tumoral immunomodulation than D alone.

Clinical trial identification

NCT03794544.

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J. Spicer: Financial Interests, Personal, Invited Speaker: Merck, BMS, Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board: Merck, BMS, Novartis, AstraZeneca, Roche, Chemocentryx, Protalix Biotherapeutics; Financial Interests, Personal, Research Grant: Merck, AstraZeneca, Roche, Protalix Biotherapeutics, CLS Therapeutics. T. Cascone: Financial Interests, Personal, Invited Speaker: SITC, Bristol-Myers Squibb, Roche, Medscape, Peerview; Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Merck, Genentech, Arrowhead Pharmaceuticals; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono. G. Kar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Blando: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Cheng: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. R. Mager: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. O. Hamid: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Y. Soo-Hoo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Other, Personal, Proprietary Information: AstraZeneca. W. Weder: Financial Interests, Personal, Advisory Board: AstraZeneca. M.R. Garcia Campelo: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen. I. Grenga: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Kumar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Project Lead: AstraZeneca. L. McGrath: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Jounce Therapeutics. All other authors have declared no conflicts of interest.