CCO_ESMO_Congress_Paris_1737MO

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CheckMate 274 Exploratory Analysis: Background
Phase III CheckMate 274 trial evaluated adjuvant nivolumab vs placebo in patients
with high-risk muscle-invasive urothelial carcinoma following radical resection1
Trial met both primary endpoints of improving DFS in ITT (HR: 0.70; P <.001) and
PD-L1 ≥1% (HR: 0.55; P <.001) patient populations
Adjuvant treatment with nivolumab is now approved for patients with high-risk
muscle-invasive urothelial carcinoma following radical resection2
Clinical trial data from immunotherapy studies in urothelial carcinoma suggest
predictive association with PD-L1, TMB, immune infiltration (CD8 and CD4), and
activation signatures (eg, IFN-γ)3-7
This exploratory biomarker analysis assessed clinical association of pretreatment tumor and immune features with DFS in patients with muscle-invasive urothelial carcinoma receiving adjuvant nivolumab in CheckMate 274 trial8
1. Bajorin. NEJM. 2021;384:2102. 2. Nivolumab PI. 3. Wang. Nature Commun. 2018;9:3503.
4. van Dijk. Nat Med. 2020;26:1839. 5. Zheng. Front Genet. 2021;12:764184.
6. Sharma. Lancet Oncol. 2017;18:312. 7. Galsky. Clin Can Res. 2020;26:5120. 8. Necchi. ESMO 2022. Abstr 1737MO.

CheckMate 274 Exploratory Analysis: Study Design1
Patient Population
CheckMate 274 (n = 699)
Minimum follow-up: 11.0 mo
Median follow-up: 23.3 mo
Patient baseline characteristics
similar between all-treated and biomarker-evaluable populations
All patient groups (all treated, biomarker evaluable, and biomarker not evaluable) had similar DFS
Exploratory Analyses
RNA-seq*: gene signature (IFN-γ2;
n = 323; 46%) and gene expression (CD4; n = 323; 46%)
WES: TMB† (n = 458; 66%)
IHC: CD8‡ (n = 445; 64%)
Continuous-Scale Analyses
Cox proportional hazard models including biomarker, treatment arm, biomarker by arm interaction, and nodal status
1. Necchi. ESMO 2022. Abstr 1737MO. 2. Sharma. Lancet Oncol. 2017;18:312.
*RNA-seq analysis of CD4 gene expression and IFN-γ gene signature performed using hybridization protocol to enrich for coding RNAs from total RNA sequencing libraries.
†TMB measure by whole exome sequencing and calculated as number of somatic missense mutations in target region of each sample. ‡Performed using anti-CD8 antibody C8/144B.

CheckMate 274 Exploratory Analysis: IFN-γ Signature, CD4 Gene Expression Predict Nivolumab Efficacy
In IFN-γ gene signature score tertiles comparisons (n = 323)
IFN-γ gene signature score and DFS were positively associated (P <.001)
IFN-γ gene signature score varied with treatment effect
(P = .013)
Higher IFN-γ gene signature score was associated with improved DFS with nivolumab but not placebo
In CD4 gene expression tertiles comparisons (n = 323)
CD4 gene expression and DFS were positively associated (P = .001)
CD4 gene expression varied with treatment effect (P <.001)
Higher CD4 gene expression was associated with improved DFS with nivolumab but not placebo
Necchi. ESMO 2022. Abstr 1737MO.

CheckMate 274 Exploratory Analysis:
CD8 and TMB Prognostic of Improved DFS
Necchi. ESMO 2022. Abstr 1737MO.
In CD8 IHC score tertiles comparisons (n = 445)
CD8 digital IHC score and DFS were positively associated (P <.001)
Treatment effect did not appear to vary with CD8 IHC score (P = .153)
Higher CD8 infiltration associated with improved DFS for both nivolumab and placebo
Strong positive correlation was identified between IFN-γ gene signature and CD8 digital IHC score (r = 0.80)
In TMB score tertiles* comparisons (n = 458)
TMB score and DFS were positively associated (P <.001)
Higher TMB score was associated with improved DFS with nivolumab, but evidence that it differed with placebo is limited (P = .081)
Trend for higher IFN-γ signature,
CD4 gene expression, and CD8 digital IHC, but not TMB biomarker distribution, with PD-L1 ≥1% status
*TMB tertiles: low (<74 mutations), medium (≥74 and <172), and high (≥ 172).

CheckMate 274 Exploratory Analysis:
Investigators’ Conclusions
Positive association found for DFS and biomarkers of preexisting antitumor immunity1
Gene signature for IFN-γ and gene expression for CD4 found predictive of clinical benefit with adjuvant nivolumab2
CD8 infiltration was observed to be prognostic of DFS2
Efficacy with nivolumab was positively associated with TMB and DFS2
Investigators concluded that these results reinforce mechanism for benefit with immunotherapy2
Validation of prior findings in metastatic urothelial carcinoma to adjuvant setting
Additional research needed to confirm utility of these findings for clinical trial design and informing treatment decisions in real world
1. Chen. Nature. 2017;541:321. 2. Necchi. ESMO 2022. Abstr 1737MO.