Introduction: We previously conducted a phase I/Ib study (NCT03712943) with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the role of Xerna™ TME Panel in predicting the treatment response. Methods: Twenty-two archival pretreatment tumor samples were subjected to the Xerna™ TME Panel, a machine learning-based RNA-sequencing biomarker assay. The Xerna tumor microenvironment (TME) subtypes were evaluated for correlation with overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and other biomarkers including KRAS, PD-L1, CD8 expression, and Treg cells in TME. Results: Based on Xerna™ TME Panel, 4 patients with immune-active (IA) subtype and 6 patients with immune-suppressed subtype were classified as biomarker-positive, and five with angiogenic (A) subtype and seven with immune desert subtype were biomarker-negative. While not reaching statistical significance, Xerna TME biomarker-positive patients seemed to have longer median PFS (7.9 vs. 4.1 months, p = 0.254), median OS (15.75 vs. 11.9 months, p = 0.378), and higher DCR (70% vs. 58%, p = 0.675). The IA subtype in our cohort had higher levels of CD4+ FOXP3+ Treg cells, whereas the A subtype showed lower levels of Treg cells. Conclusion: Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab might be of value for predictive clinical benefit. Further studies are needed to evaluate the predictive role of Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC.

1.
Akin Telli
T
,
Bregni
G
,
Vanhooren
M
,
Saude Conde
R
,
Hendlisz
A
,
Sclafani
F
.
Regorafenib in combination with immune checkpoint inhibitors for mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer
.
Cancer Treat Rev
.
2022
;
110
:
102460
.
2.
Arai
H
,
Battaglin
F
,
Wang
J
,
Lo
JH
,
Soni
S
,
Zhang
W
.
Molecular insight of regorafenib treatment for colorectal cancer
.
Cancer Treat Rev
.
2019
;
81
:
101912
.
3.
Doleschel
D
,
Hoff
S
,
Koletnik
S
,
Rix
A
,
Zopf
D
,
Kiessling
F
.
Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth
.
J Exp Clin Cancer Res
.
2021
;
40
(
1
):
288
.
4.
Fukuoka
S
,
Hara
H
,
Takahashi
N
,
Kojima
T
,
Kawazoe
A
,
Asayama
M
.
Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase ib trial (REGONIVO, EPOC1603)
.
J Clin Oncol
.
2020
;
38
(
18
):
2053
61
.
5.
Wang
C
,
Chevalier
D
,
Saluja
J
,
Sandhu
J
,
Lau
C
,
Fakih
M
.
Regorafenib and nivolumab or pembrolizumab combination and circulating tumor DNA response assessment in refractory microsatellite stable colorectal cancer
.
Oncologist
.
2020
;
25
(
8
):
e1188
94
.
6.
Cousin
S
,
Cantarel
C
,
Guegan
JP
,
Gomez-Roca
C
,
Metges
JP
,
Adenis
A
.
Regorafenib-avelumab combination in patients with microsatellite stable colorectal cancer (REGOMUNE): a single-arm, open-label, phase II trial
.
Clin Cancer Res
.
2021
;
27
(
8
):
2139
47
.
7.
Wang
F
,
He
MM
,
Yao
YC
,
Zhao
X
,
Wang
ZQ
,
Jin
Y
.
Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/II clinical trial and gut microbiome analysis
.
Cell Rep Med
.
2021
;
2
(
9
):
100383
.
8.
Barzi
A
,
Azad
NS
,
Yang
Y
,
Tsao-Wei
D
,
Rehman
R
,
Fakih
M
.
Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC)
.
J Clin Oncol
.
2022
40
4 Suppl
15
–.
9.
Chen
B
,
Zhao
H
,
Huang
J
,
Lv
H
,
Xu
W
,
Nie
C
.
Efficacy of regorafenib combined with PD-1 inhibitors in elderly patients with advanced metastatic colorectal cancer
.
BMC Geriatr
.
2022
;
22
(
1
):
987
.
10.
He
WZ
,
Wang
L
,
Yin
CX
,
Yi
JH
,
Jin
YN
,
Jiang
C
.
Regorafenib with or without a programmed cell death protein 1 antibody as third-line treatment for microsatellite stable metastatic colorectal cancer
.
Cancer Med
.
2023
;
12
(
6
):
6488
98
.
11.
Kim
RD
,
Kovari
BP
,
Martinez
M
,
Xie
H
,
Sahin
IH
,
Mehta
R
.
A phase I/Ib study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer
.
Eur J Cancer
.
2022
;
169
:
93
102
.
12.
Wang
H
,
Liu
W
,
Zhao
Y
,
Hu
H
,
Zhang
B
,
Yang
S
.
Real-world effectiveness of regorafenib in the treatment of patients with metastatic colorectal cancer: a retrospective, observational study
.
Asia Pac J Clin Oncol
.
2023
;
19
(
5
):
e291
9
.
13.
Xu
YJ
,
Zhang
P
,
Hu
JL
,
Liang
H
,
Zhu
YY
,
Cui
Y
.
Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness
.
World J Gastrointest Oncol
.
2022
;
14
(
4
):
920
34
.
14.
Yang
K
,
Han
L
,
Wu
S
,
Qu
X
,
Li
Q
,
Zhao
C
.
Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: a multicenter study
.
Cancer Immunol Immunother
.
2022
;
71
(
6
):
1443
51
.
15.
Fakih
M
,
Raghav
KPS
,
Chang
DZ
,
Larson
T
,
Cohn
AL
,
Huyck
TK
.
Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study
.
EClinicalMedicine
.
2023
;
58
:
101917
.
16.
Uhlik
M
,
Pointing
D
,
Iyer
S
,
Ausec
L
,
Štajdohar
M
,
Cvitkovič
R
.
Xerna™ TME panel is a machine learning-based transcriptomic biomarker designed to predict therapeutic response in multiple cancers
.
Front Oncol
.
2023
;
13
:
1158345
.
17.
Fu
S
,
Corr
BR
,
Culm-Merdek
K
,
Mockbee
C
,
Youssoufian
H
,
Stagg
R
.
Phase ib study of navicixizumab plus paclitaxel in patients with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer
.
J Clin Oncol
.
2022
;
40
(
23
):
2568
77
.
18.
Iyer
S
,
Ausec
L
,
Pointing
D
,
Zganec
M
,
Cvitkovic
R
,
Stajdohar
M
.
Abstract 1232: Xerna TME Panel: a pan-cancer RNA-based investigational assay designed to predict patient responses to angiogenic and immune targeted therapies
.
Cancer Res
.
2022
82
12 Suppl
1232
2
.
19.
Uhlik
M
,
Fong
C
.
Predicting patient response to immune-targeted therapies via interrogation of the tumor microenvironment
.
Immuno Oncol Insights
.
2022
;
3
(
9
):
513
25
.
20.
Grothey
A
,
Blay
JY
,
Pavlakis
N
,
Yoshino
T
,
Bruix
J
.
Evolving role of regorafenib for the treatment of advanced cancers
.
Cancer Treat Rev
.
2020
;
86
:
101993
.
You do not currently have access to this content.