Slide 1: Platform study of neoadjuvant durvalumab in resectable early-stage NSCLC: NeoCOAST
Platform study of neoadjuvant durvalumab (anti-PD-L1) alone or combined with oleclumab (anti-CD73), monalizumab (anti-NKG2A), or danvatirsen (anti-STAT3) in patients with resectable, early-stage non-small-cell lung cancer: pharmacodynamic correlates and ctDNA dynamics in the NeoCOAST study Jonathan
Slide 2: Declaration of interests
Declaration of interests Jonathan Spicer, MD • Speaker fees: AstraZeneca, Bristol Myers Squibb, Merck, and Novartis. • Advisory board: AstraZeneca, Bristol Myers Squibb, Chemocentryx, Merck, Novartis, Protalix Biotherapeutics, and Roche. • Research grants: AstraZeneca, CLS Therapeutics, Merck, Prota
Slide 3: NeoCOAST: Neoadjuvant durvalumab +/– novel agents in resectable, early-stage NSCLC
NeoCOAST: Neoadjuvant durvalumab +/– novel agents in resectable, early-stage (I [>2cm] to IIIA) NSCLC Durva Durva + Ole Durva + Mona Durva + Danva One 28-day treatment cycle (n=27) (n=21) (n=20) (n=16) • Stage I (>2cm) to IIIA NSCLC* Durva Q4W Overall MPR 3/27 (11%) 4/21 (19%) 6/20 (30%) 5/16 (31%)
Slide 4: NeoCOAST: Translational assessments
NeoCOAST: Translational assessments Durva Q4W Days 29–42 Day 105 Durva Q4W + Ole Q2W End of R Surgery study Durva Q4W + Mona Q2W Danva Durva Q4W + Danva QW* (Days 1, 3, and 5) Pre-therapy Danvatirsen only Baseline End of treatment Follow up Day –21 to Pre-dose Day 1 Day 28 Day 29 to Day 105 Day –1 D
Slide 5: Pathological regressions at surgery, and association with somatic tumour alterations and TMB
Pathological regressions at surgery, and association with somatic tumour alterations and TMB Durva only Durva + Ole • TMB and somatic tumour EGFR/ALK/RET EGFR/ALK/RET KRAS STK11/KEAP1 KRAS STK11/KEAP1 alterations were profiled from −1 0 0 0 0 −1 −1 0 tumour DNA and matched blood Pathological respons
Slide 6: Baseline ctDNA VAF was associated with disease stage and tumour size, on-treatment ctDNA reductions were observed
Baseline ctDNA VAF was associated with disease stage and tumour size, on-treatment ctDNA reductions were observed 0.04 Kruskal-Wallis, Durva Durva + Ole Durva + Mona p value = 0.02 • ctDNA was profiled using a tumour-informed, 0.03 personalized panel of genes tracked in ctDNA at baseline (mean VAF)
Slide 7: Gene expression between tumours pre-therapy and at surgery reveals intratumoural immune activation
Evaluation of gene expression between tumours pre-therapy and at surgery reveals signatures of intratumoural immune activation Durva Durva + Ole Durva + Mona 6 10.0 7.5 –Log10 adj. p value –Log10 adj. p value –Log10 adj. p value 4 6 CXCL13 5.0 CD8A 4 GZMK 2 2.5 CD8A KLRC1 TLS signature GZMK 2 IFNG T
Slide 8: Case study: patient treated with durva + ole with pharmacodynamic evidence of immune activation
Case study: patient treated with durva + ole with pharmacodynamic evidence of intratumoural immune activation ctDNA detectable • Patient characteristics: 63F, former smoker, Negative 5 Stage IIB, squamous cell carcinoma. Positive 0.002 ctDNA (mean VAF in plasma) • Stable disease by RECIST v1.1, 50%
Slide 9: Summary and conclusions
Summary and conclusions • A single cycle of neoadjuvant durva combined with ole, mona, or danva produced numerically improved MPR rates (19–31.3%) compared with durva alone (11.1%). • Pathological regressions were not associated with TMB. • Molecular responses by ctDNA were observed in 25–60% of pat
Slide 10: Acknowledgements
Acknowledgements • The authors would like to thank the patients, their families and caregivers, and all the investigators involved in this study. • Editing support for the development of this presentation was provided by Connor Keating of Ashfield MedComms (Manchester, UK) an Inizio company, and fun