MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with KRAS G12D or KRAS G12V alteration.
DOI:
10.1200/jco.2025.43.4_suppl.726
Publication Date:
2025-01-27T14:31:24Z
AUTHORS (19)
ABSTRACT
726
Background:
Up to 95% of pancreatic ductal adenocarcinomas (PDAC) are driven by oncogenic alterations in the
KRAS
gene, with
KRAS
G12D (40%) and
KRAS
G12V (30%) mutations being the most common. However, in most cases,
KRAS
alterations are accompanied by alterations in other tumor suppressors such as
TP53
,
CDKN2A/B
, and
SMAD4
. Therefore, targeting
KRAS
alone may not be sufficient for effective treatment of PDAC . As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the effectiveness of MEK inhibitor (MEK-inh)-based therapy, tailored to the unique molecular alterations of each patient’s tumor, in treating metastatic PDAC (mPDAC) with
KRAS
G12D or
KRAS
G12V alterations.
Methods:
From April 2022 to December 2023, 19 patients (
KRAS
G12D=10 (53%),
KRAS
G12V=9 (47%)) were treated with MEK-inh-based therapy. Comprehensive genomic profiling was performed using Tempus xT (648 genes) in 15 patients (79%), FoundationOne (324 genes) in 4 patients (21%), and STRATA (429 genes) in 1 patient. The genomic characteristics, matched therapies, and treatment outcomes are provided (Table).
Results:
Of the 19 patients, 11 (58%) were female. The median age at the initiation of MEK-inh-based therapy was 67 years. Six (32%) patients received MEK-inh-based therapy as first or second-line treatment, while 13 (68%) patients were treated in the third to fifth-line. Among the 19 patients, the median overall survival (mOS) and median progression-free survival (mPFS) from the initiation of MEK-inh-based therapy were 5 and 2 months, respectively. The mOS from the time of MEK-inh-based therapy was 5.1 months for
KRAS
G12D, and 4.7 months for
KRAS
G12V (P=0.87). The mPFS from the time of MEK-inh-based therapy was 2.3 months for
KRAS
G12D and 1.4 months for
KRAS
G12V (P=0.12). Among all 19 patients, 4 (21%) patients had mPFS above 4 months (
KRAS
G12V=1,
KRAS
G12D=3; 4.1, 4.3, 4.7, 9.9 months).
Conclusions:
The efficacy of MEK-inh-based therapy was limited in the late-line treatment of mPDAC for patients with
KRAS
G12D and
KRAS
G12V mutations. The potential role of MEK inhibitors in earlier lines of therapy, and their combination with
KRAS
inhibitors, requires further prospective evaluation.
Tumor alterations and matched therapies.
Altered gene
KRAS G12V(N=9)
KRAS G12D(N=10)
Patients matched(N=19)
Type of matched therapy
KRAS G12D/V
9 (100%)
10 (100%)
19 (100%)
MEK inhibitor
TP53
7 (78%)
8 (80%)
8 (42%)
VEGF/VEGR inhibitor*
CDKN2A/B
8 (89%)
5 (50%)
9 (47%)
CDK4/6 inhibitor**
SMAD4
3 (33%)
4 (40%)
4 (21%)
MEK inhibitor + (EGFR or pan-HER inhibitor) ***
*PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091.
N= number of patients.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (0)
CITATIONS (0)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....