Trametinib in combination with hydroxychloroquine or palbociclib in advanced metastatic pancreatic cancer

\(\bf Background\) 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. \(\bf Methods\) 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. \(\bf Results\) 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. \(\bf Conclusion\) THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.