MEK inhibitor-based genomically matched combinatorial targeted therapies in metastatic pancreatic adenocarcinoma with KRAS alterations.

abstract cc by

AbstractIntroductionPancreatic ductal adenocarcinoma (PDAC) is often caused by mutations in multiple genes, including KRAS (activating the Ras-Raf-MEK-ERK pathway). This study evaluated the role of MEK inhibitor (MEKi)–based combinatorial targeted therapies in patients with PDAC.MethodsThis is a retrospective/prospective observational, single-institution study, including 29 patients with metastatic PDAC with KRAS alterations, treated with MEKi therapies between 2022 and 2024.ResultsTen patients had KRAS G12R (34.5%), ten G12D (34.5%), and nine G12V (31%). The majority of patients received MEKi therapy as third-line and beyond (KRAS G12R/G12D/G12V: 60%/50%/78%, respectively). Median overall survival from MEKi initiation for KRAS G12R/G12D/G12V was 8.2/5.1/4.7 months (P = .5), respectively, and median progression-free survival was 4.4/2.3/1.4 months (P = .11). Six (21%) patients discontinued at least one drug in the treatment combination due to toxicity.ConclusionsMEKi–based combinatorial therapies had modest disease control in patients with KRAS G12R, and minimal disease control in patients with KRAS G12D/V in the late-line setting.

introduction cc by

Up to 95% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by oncogenic alterations in the KRAS gene, most commonly KRAS G12D (40%), KRAS G12V (30%), and KRAS G12R (20%) [1]. These mutations lead to activation of the Ras-Raf-MAPK kinase (MEK)–extracellular signal-related kinase (ERK) pathway, resulting in cancer initiation and propagation [2]. MEK inhibitors alone, or with chemotherapy, have provided suboptimal results in unselected populations with PDAC [3]. This is partly because KRAS alterations, nearly in all cases, are also accompanied by additional alterations in tumor suppressors, such as TP53, CDKN2A/B, and SMAD4, which create a complex network of drivers, resulting in early resistance if unopposed [3]. Potential for matching targeted therapies to these genomic alterations is present for these genes: TP53 matched to vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitor [4]; CDKN2A/B matched to cyclin dependent kinase (CDK) 4/6 inhibitor [5]; SMAD4 matched to MEK inhibitor (MEKi) +/− epidermal growth factor receptor (EGFR) or pan-human epidermal growth factor receptor (HER) inhibitors [6, 7]. The overarching question in this study was the utility of matching targeted therapies to multiple genomic alterations at once in each individual (individualized matched therapies). This study investigated the efficacy of MEKi–based genomically matched individualized combinatorial targeted therapies in patients with metastatic PDAC with KRAS alterations.

materials and methods cc by

This study was a retrospective review of records of patients retrospectively/prospectively enrolled in the institutional review board-approved protocols (PRO00045718[NCT05630989]; PRO00044894[NCT05802069]) at a single, tertiary care academic center with precision oncology expertise. Adults with metastatic PDAC treated with MEKi combinatorial therapies (excluding MEKi plus hydroxychloroquine) between March 2022 and September 2024 were included. The choice of treatment was made by the treating physician, based on suggestions of the Medical College of Wisconsin molecular tumor board. Next-generation sequencing was performed by Clinical Laboratory Improvement Amendments certified commercial vendors on tissue in all patients. Targeted therapies were started at 50% of the standard drug dose in 2-drug combination therapies, and 33%-50% of the standard dose when three or more drugs were combined, to decrease toxicities. If a specific drug led to a certain toxicity in a combination therapy, that drug alone was interrupted/discontinued, and other drugs were continued. Only toxicities which were at least possibly related to any of the combinatorial targeted therapies and led to treatment interruptions or discontinuations are reported. Overall survival (OS) and progression-free survival (PFS) from the time of MEKi initiation were estimated using the Kaplan-Meier method. The Log-rank test was used for comparison of OS and PFS between patients with different KRAS alterations (G12R, G12D, G12V). Analyses were performed using R 4.3.1 (R Foundation for Computing, Vienna, Austria).

results cc by

Twenty nine patients were included in the study: ten (34.5%) KRAS G12D, ten (34.5%) G12R, and nine (31%) G12V mutations (Table 1; Supplementary Table 1). Median age (years) of patients at MEKi therapy initiation was 67, and 59% were female. Demographic characteristics were not significantly different between patients based on KRAS alterations (G12R/G12D/G12V). For metastatic PDAC disease, 60% of patients with G12R alteration, 50% with G12D, and 78% with G12V received MEKi therapy as third-line or beyond. Most matched alterations: treatments were: KRAS: MEKi (KRAS alterations in N = 29/29: matched to trametinib N = 25/29 [86%], cobimetinib N = 5/29 [14%]); TP53: VEGF/VEGFR inhibitor (TP53 alterations in N = 24/29 [83%]: matched to bevacizumab N = 12/24 [50%]); CDKN2A/B: CDK4/6 inhibitor (CDKN2A alterations in N = 18/29 [62%]: matched to palbociclib N = 12/18 [67%] and abemaciclib N = 2/18 [10%]); SMAD4: MEKi+/-EGFR or pan-HER inhibitor (alterations in N = 9/29 [31%]: matched to MEKi in N = 9/9 plus afatinib [pan-HER inhibitor] in N = 3/9 [33%] and erlotinib [EGFR inhibitor] in N = 3/9 [33%]). Median OS from MEKi therapy initiation for patients with KRAS G12R alterations was 8.2 months, G12D 5.1 months, and G12V 4.7 months (Figure 1A). Median PFS from MEKi therapy initiation for patients with KRAS G12R alteration was 4.4 months, G12D 2.3 months, and G12V 1.4 months (Figure 1B). The difference between OS and PFS for groups of patients with different KRAS alterations (G12R/G12D/G12V) was not statistically significant. Fifteen patients (52%) experienced interruption of at least one drug in their treatment combination due to any level of drug–related toxicity (none grade 4 or 5). In 6 of 29 (21%) at least one drug in their treatment combination was discontinued due to any level of drug–related toxicity (none grade 4 or 5). Three patients (10%) discontinued both drugs in 2-drug combination regimens due to disease progression/clinical decline and suspected drug–related toxicities: trametinib/palbociclib due to mucositis/cytopenia (N = 1) and gastrointestinal discomfort (N = 1); trametinib/bevacizumab due to diarrhea/hypertension (N = 1).

discussion cc by

Of the 29 patients with metastatic PDAC who were treated with MEKi combinatorial targeted therapies at our institution, 5 of 10 (50%) of patients with KRAS G12R were free of progression by 4 months (PFS in months among the 5 patients [line of therapy]: 6.9 [3rd], 5.6 [4th], 5.5 [1st], 4.9 [1st] and 4.4 [1st]), compared to 3/10 (30%) in KRAS G12D (PFS in months among the 3 patients [line of therapy]: 9.9 [3rd], 4.8 [3rd], 4.3 [3rd]), and 1/9 (11%) in KRAS G12V (PFS 5.03 months [2nd line]). The benchmark PFS for chemotherapy in the second line of treatment for PDAC is 3.1 months [8]. MEKi-genomically matched individualized combinatorial targeted therapies in patients with metastatic PDAC with KRAS alterations in our study, therefore, had modest benefit, which was most prominent in patients with KRAS G12R alterations. A prior study showed the clinical benefit rate (stable disease >6 months/complete response/partial response) was 80% in first line versus 8% beyond first line for similar targeted therapy in a pilot investigation in PDAC [3]. While KRAS G12C inhibitors are FDA approved for other cancers, the rarity of this alteration in PDAC (<1%) has limited their impact [9]. Daraxtonrasib (RMC-6236), the most clinically advanced pan-RAS(ON) inhibitor so far, showed promising PFS of 7.6 months in the second line in a phase 1 trial [10]. Whether this promising result stands in a larger population is being tested in the RASolute-302 phase 3 clinical study.

conclusions cc by

While awaiting trial completion for KRAS inhibitors, there may be a role for MEKi combinatorial targeted therapies in patients with metastatic PDAC, specifically in those with KRAS G12R alteration and as earlier lines of therapy.