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Multicenter Study
. 2024 Oct 1;150(10):438.
doi: 10.1007/s00432-024-05954-5.

Trametinib in combination with hydroxychloroquine or palbociclib in advanced metastatic pancreatic cancer: data from a retrospective, multicentric cohort (AIO AIO-TF/PAK-0123)

David Witte  1 , Ina Pretzell  2 , Timm M Reissig  3   4 , Alexander Stein  5 , Janna-Lisa Velthaus  5   6 , Annabel Alig  7 , Hanibal Bohnenberger  8 , Maren Knödler  9 , Annika Kurreck  7 , Sabrina Sulzer  10 , Georg Beyer  11   12 , Klara Dorman  13   14 , Tabea Fröhlich  15 , Stefanie Hegenberg  16 , Celine Lugnier  16 , Anna Saborowski  17 , Arndt Vogel  17 , Sebastian Lange  18 , Maximilian Reichert  14   18 , Franziska Flade  19 , Lioba Klaas  20 , Kirsten Utpatel  21 , Heiko Becker  22 , Annalen Bleckmann  23 , Klaus Wethmar  23 , Anke Reinacher-Schick #  16 , Christoph Benedikt Westphalen #  13   14
Affiliations
Multicenter Study

Trametinib in combination with hydroxychloroquine or palbociclib in advanced metastatic pancreatic cancer: data from a retrospective, multicentric cohort (AIO AIO-TF/PAK-0123)

David Witte et al. J Cancer Res Clin Oncol. .

Abstract

Background: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs.

Methods: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany.

Results: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP.

Conclusion: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.

Keywords: Autophagy; CDK inhibitor; MEK inhibitor; Molecular guided treatment; Pancreatic cancer; Targeted therapy.

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Conflict of interest statement

Ina Pretzell is an editorial board member of the Journal of Cancer Research and Clinical Oncology. Timm M Reissig has received research funding from Bristol Myers Squibb. Janna-Lisa Velthaus has received honoraria from Roche, Janssen and Sanofi. Annabel Alig has received travel reimbursement from Nordic, Servier, Merck, MSD, Pierre-Fabre, Roche, AMGEN and Daiichi Sankyo and honoria by MSD, Servier, Merck, Pierre-Fabre, Roche, AMGEN and BMS. Annika Kurreck served on advisory boards for Merck and MSD; has received honoraria from AMGEN, Servier, Taiho, Takeda and Merck; and has received travel grants by AMGEN, medac, Jazz, Merck and Servier. Klara Dorman has received honoraria from AstraZeneca; and has received travel reimbursement from Servier, GlaxoSmithKline, Bristol-Myers Squibb and AstraZeneca. Celine Lugnier has received honoraria from TAIHO. Anna Saborowski has received honoraria from BMS, Roche, Servier, Ipsen, Lilly, AstraZeneca, MSD and Eisai; has received travel reimbursement by Ipsen, Servier, Pierre-Fabre, MSD, Eisai; and served on advisory boards for Eisai, MSD, Roche and Incyte. AV reports consulting fees, honoraria, and participation in advisory or data safety monitoring boards for AstraZeneca, Amgen, BeiGene, Boehringer Mannheim, Bristol Myers Squibb, BTG, Daichi-Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Tahio, and Terumo; honoraria from GSK, Imaging Equipment (AAA), and Jiangsu Hengrui Medicines; and support for attending meetings or travel from Roche, MSD, and Astellas. Sebastian Lange served as speaker for AstraZeneca, Janssen-Cilag and MSD; served on advisory boards for AstraZeneca and Taiho; and has received research funding from Illumina. Maximilian Reichert has received honoraria from Celgene, Falk, Roche and Servier. Kirsten Utpatel has received honoraria from Roche, Amgen, MSD, Lilly, Stemline and BMS. Heiko Becker has received honoraria from BMS, GSK, MSD, Merck, Roche and Servier. Klaus Wethmar has received honoraria from Pfizer, AstraZeneca, MSD, Merck, Pierre Fabre and Amgen; and served on advisory boards for Amgen and Takeda. Anke Reinacher-Schick has received honoraria from Amgen, Roche, Merck Serono, Bristol Myers Squibb, MSD, MCI and AstraZeneca; served on advisory boards for Amgen, AstraZeneca, Aurikamed, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Merck Serono, MSD, Pierre Fabre, Roche and Servier; has received travel support from Amgen, MSD, Pierre Fabre, Roche; and has received research funding from Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, Astra Zeneca, Lilly, Servier, AIO Studien gGmbH, Rafael Pharmaceuticals, Erytech Pharma and BioNTech. Christoph Benedikt Westphalen has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, and Taiho; served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier, and Taiho, has received institutional research grants by Roche, is a member of the EU Commission expert group Mission Board for cancer, is a member of the forum #Zukunftsstrategie of the German government and is an editorial board member of the Journal of Cancer Research and Clinical Oncology. David Witte, Alexander Stein, Hanibal Bohnenberger, Maren Knödler, Sabrina Sulzer, Georg Beyer, Tabea Fröhlich, Stefanie Hegenberg, Franziska Flade, Lioba Klaas and Annalen Bleckmann have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Kaplan-Meier plots of the survival of patients treated with trametinib/HCQ (THCQ) or trametinib/palbociclib (TP). A: Progression-free survival (PFS) of patients treated with THCQ; B: Overall survival (OS) of patients treated with THCQ; C: PFS of patients treated with TP; D: OS of patients treated with TP. The dotted vertical line indicates the respective median PFS and OS
See this image and copyright information in PMC

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