Genomic alterations in circulating tumor DNA (ctDNA) and response to telisotuzumab adizutecan (ABBV-400) treatment in patients (pts) with colorectal cancer (CRC).
Authors: Cecchini Michael , Sharma Manish R , Kuboki Yasutoshi , Perets Ruth , Cohen Jonathan , Raimbourg Judith , Nakajima Takako Eguchi , Cruz-Correa Marcia , Ghiringhelli François , Raghav Kanwal Pratap Singh , Vasilopoulos Athanasios , Luo Xizhi (Adam) , Neagu Aristide Martha Raluca , Morrison Thiele Gladys , Hunter Zoe , Burns Michael Charles , Roberts-Rapp Lisa , Strickler John H 
Published: January 2025

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Background:
Telisotuzumab adizutecan is an antibody-drug conjugate comprising the c-Met–targeting antibody telisotuzumab conjugated to a topoisomerase 1 inhibitor payload, adizutecan. A phase 1 trial (NCT05029882) in advanced solid tumors reported higher response rates in pts with CRC and high c-Met expression. We present an analysis of responses based on genomic alterations in ctDNA.
Methods:
Pts with CRC that is refractory to standard treatment were enrolled. Telisotuzumab adizutecan was given IV Q3W. ctDNA was isolated from baseline (BL) and cycle 3, day 1 plasma samples and analyzed with the GuardantINFINITY assay. Circulating tumor fraction (cTF) was estimated on the basis of variant allele frequency of somatic mutations in a 74-gene panel and methylation signals across targeted regions of the GuardantINFINITY methylation panel. Molecular response (MR) was defined as 50% decrease in cTF from BL. Radiographic response (RR) was assessed by RECIST v1.1.
Results:
Overall, 113 pts had both BL ctDNA and RR data. Confirmed ORR was 18% (20/113). The most prevalent gene alterations included
TP53
(75%),
APC
(68%), and
KRAS
(66%) mut;
PTPRT
(56%),
ASXL1
(53%), and
FLT1
(52%) amp;
SMAD4
(44%) and
TP53
(43%) deletions; and
MET
(4%),
BRAF
,
FGFR3,
and
NRG1
(all 3%) fusions. The Table shows RRs in pts with specific CRC biomarkers, and MR using the 2 panels with corresponding clinical outcomes. RRs were seen in pts with positive plasma samples at BL for TMB,
RAS, BRAF,
and
HER2.
MRs were detected in 64% and 65% of pts using the 74-gene and methylation panel, respectively. ORR was higher in pts with MR (35%) than without MR (8%) using the 74-gene, and 35% vs 0% using the methylation panel, respectively. Median PFS (mPFS) was longer in pts with MR.
Conclusions:
Telisotuzumab adizutecan has promising efficacy. RRs were seen in CRC pts with heterogeneous genomic profiles, including pts positive for actionable biomarkers in the metastatic setting. More pts with MR experienced RRs and benefited from treatment.
Clinical trial information: NCT05029882
.

Pts with ctDNA and radiographic response data(N=113)

Radiographic cPR, n/N (%)
20/113 (18)

Genomic alteration

TMB
a
high

(
≥
20 mut/Mb)

KRAS

mut

KRAS

G12C mut

BRAF

mut
b

HER2

amp

cPR, n/N (%) Pos
11/48 (23)
11/73 (15)
1/5 (20)
4/14 (29)
2/9 (22)

Neg
9/51 (18)
9/40 (23)
19/108 (18)
16/99 (16)
18/104 (17)

MR, n/N (%)

74-gene panel
42/66 (64)

Methylation panel
48/74 (65)

ORR, n/N (%)

MR pos
15/42 (36)

MR neg
2/24 (8)

MR pos
17/48 (35)

MR neg
0/26 (0)

mPFS, mo (95% CI) Events (n/N)
6.1 (5.3, 6.9)28/42
3.5 (2.6, 4.3)21/24
5.9 (5.3, 6.8)31/48
3.5 (2.7, 4.1)23/26

MR in pts with SD, n/N (%)

74-gene panel
27/45 (60)

Methylation panel
31/53 (58)

mPFS, mo (95% CI)Events (n/N)

MR pos
5.3 (4.5, 5.9)21/27

MR neg
3.9 (2.8, 4.3)16/18

MR pos
5.3 (4.5, 5.9)23/31

MR neg
4 (2.8, 4.4)19/22

a
14 pts not evaluable for TMB. Threshold determined by Guardant.

b
1 pt had V600E mutation.

mo, months; neg, negative; pos, positive.