Tempus Ai, Inc. · NASDAQ:TEM
Tempus Ai — ESMO GI 2022
22 slides from Tempus Ai's conference presentation, Jul 1, 2022
Slide 1: Good Science, Better Medicine, Best Practice
GOOD SCIENCE BETTER MEDICINE BEST PRACTICE
Slide 2: Impact of BRAF V600E mutation on immunologic characteristics of the TME
LBA SO-34 Impact of BRAFV600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch- repair–deficient (dMMR) colorectal cancer (CRC) Mohamed E. Salem Levine Cancer Institute,
Slide 3: Impact of BRAF V600E mutation on TME: authors and affiliations
Impact of BRAFV600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch- repair–deficient (dMMR) colorectal cancer (CRC) Mohamed E. Salem1,Thierry Andre2, Sherif El-Refai3,
Slide 4: Background
Background • Immune checkpoint inhibitors radically changed clinical management of patients with MSI/dMMR CRC. 1,2 • The BRAFV600E mutation is associated with the hypermethylator phenotype CIMP (CpG island methylator phenotype), which can also lead to the microsatellite instability-high (MSI- H) phe
Slide 5: Objectives
Objectives • Primary Aim: • To examine the impact of BRAFV600E mutation on immunologic characteristics of the tumor microenvironment (TME) in patients with MSI-H/dMMR CRC. • Secondary Aims : • To describe associated genomic alterations with BRAFV600E, and • Examine the relationship between BRAFV600E
Slide 6: Methods
Methods • A retrospective review of patients with MSI-H/dMMR CRC that underwent Tempus xT next-generation sequencing was performed. The Tempus platform was employed for the following: • MSI-H was determined by assessment of 239 loci and dMMR by IHC • Tumor mutational burden (TMB), neoantigen tumor b
Slide 7: Results
Results
Slide 8: MSI-H/dMMR CRC tumors with known BRAF status
MSI-H/dMMR CRC tumors with known BRAF status (N=459) KRAS/RAS WILD TYPE BRAF-Wild type vs. BRAF V600Emut (n=336) (n=123) Compared in the current study
Slide 9: Clinical Characteristics
Clinical Characteristics Overall, BRAFWT, BRAF V600Emut, Characteristic N=459 n=336 n=123 *Gender, n (%) Female 269 (59%) 185 (55%) 84 (69%) Unknown 1 0 1 *Age, Median (IQR) 69 (57, 78) 62 (51, 73) 76 (70, 85) Unknown 126 108 18 Race, n (%) White 227 (83%) 170 (82%) 57 (86%) Black/African American 2
Slide 10: Oncogenic co-mutations in BRAF V600Emut vs. BRAFwt CRC
Oncogenic co-mutations in BRAF V600Emut vs. BRAFwt CRC • Significant differences in co-occurring genomic mutations with BRAF V600Emut compared to BRAFwt in MSI-H/dMMR CRC were observed in the following genes: • MSH6 (42% vs. 20%, q < 0.05), • B2M (33% vs. 16%, q < 0.05), • ATM (23% vs. 12%, q < 0.05
Slide 11: BRAFwt and mut MSI-H CRC tumors have the same Neoantigen Mutation Burden
BRAFwt and mut MSI-H CRC tumors have the same Neoantigen Mutation Burden BRAF Overall, BRAFWT, Characteristic V600Emut, p-value N=459 n=336 n=123 MSI-H, n (%) 444 (98%) 321 (97%) 123 (100%) 0.041* Unknown 4 4 0 TMB-H, n (%) 428 (96%) 305 (95%) 123 (100%) 0.008* Unknown 15 15 0 NTB, Median 15 (10, 20
Slide 12: Tumor Immune Microenvironment
Tumor Immune Microenvironment
Slide 13: BRAF V600Emut Impacts Colorectal Tumor Immune Microenvironment
BRAF V600Emut Impacts Colorectal Tumor Immune Microenvironment* • The proportion of natural killer (NK) cells was significantly higher in BRAF V600Emut compared with BRAFwt (median 21% vs. 15%, p <0.001); however, no significant differences were found amongst CD4+ and CD8+ T cells. • IMMUNE_TH1_GALO
Slide 14: Cancer Stem Cell Pathways Are Downregulated in BRAF V600Emut Tumor
Cancer Stem Cell Pathways Are Downregulated in BRAF V600Emut Tumor Cancer Stem Cell pathways showed significant downregulation including Notch and WNT/Catenin signaling pathways. *P values are unadjusted for false discovery
Slide 15: BRAF V600Emut CRCs Show Accelerated Growth and Metabolic Reprograming
BRAF V600Emut CRCs Show Accelerated Growth and Metabolic Reprograming Significant upregulation of 5 pathways among BRAF V600Emut tumors, 4 of which were cyclin-dependent cell signaling, glycerophospholipid metabolism, galactose metabolism and nucleotide metabolism.
Slide 16: Immune-related Pathways Differentially Expressed by BRAF V600Emut Status
Immune-related Pathways Differentially Expressed by BRAF V600Emut Status Pathway enrichment scores computed through GSVA were compared between BRAF V600Emut and BRAFwt via differential expression analysis. Differentially expressed pathways (at 5% alpha level) are shown and pathways differentially ex
Slide 17: RASmut CRC tumors have lower Neoantigen Mutation Burden than RASwt
RASmut CRC tumors have lower Neoantigen Mutation Burden than RASwt Overall, RASWT, RASmut, Characteristic p-Value N=463 n=353 n=110 MSI-H, n (%) 446 (97%) 340 (97%) 106 (97%) 0.8 Unknown 5 4 1 TMB-H, n (%) 432 (96%) 328 (97%) 104 (95%) 0.2 Unknown 15 15 0 *NTB, Median (IQR) 15 (10, 20) 16 (12, 20) 1
Slide 18: RASmut MSI-H CRC tumors are less inflamed than RASwt
RASmut MSI-H CRC tumors are less inflamed than RASwt p=0.025 0.6 0.4 p=0.003 Tumor inflammation is mainly IMMUNE_CD8MACRO_GALON 0.5 RASWT downregulated in RASmut tumors, IMMUNE_TH1_GALON 0.4 RASmut 0.3 enrichment score enrichment score 0.3 0.2 0.2 including key pathways: cytokine 0.1 0.0 0.1 signali
Slide 19: Limitations
Limitations • The retrospective nature of the analysis • Treatment and outcome data were not available for the entirety of this dataset • We used a TMB cut-off of 10 mut/Mb to define TMB-high vs. -low across all tumor types but the optimal threshold, if any, to identify a cancer as TMB-high for ICI
Slide 20: Summary of Findings
Summary of Findings Keynote-177 Salem et al. Stage | Newly diagnosed + BRAF BRAF wild type BRAFY OO KRAS or NRAS All wild type KRAS or NRAS mutant ae [2 Lower CTL Site of primary tumor Right San Left HH ol 1.0 10 0 = ~
Slide 21: Conclusions
Conclusions • BRAF V600Emut and BRAFwt MSI-H/dMMR CRCs exhibited similar NTB and T cell infiltration. They exhibited hyperproliferative characteristics associated with broad metabolic reprogramming. • BRAF V600Emut and BRAFwt MSI-H/dMMR CRCs appeared to have similar immunologic characteristics withi
Slide 22: Thank You
THANK YOU