Phase Ib Study of Ulixertinib Plus Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Adenocarcinoma

Abstract

Background Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. Methods We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS). Results Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively. Conclusion Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

“…1d ). A recent phase 1b clinical trial combining ulixertinib, gemcitabine, and nab-paclitaxel conducted at Washington University in St. Louis was prematurely terminated due to poor patient tolerability, although ulixertinib was able to downregulate KRAS-dependent gene signatures in tumour samples 5 . This setback led us to explore other MAPK inhibitor-based therapeutic strategies that have strong preclinical efficacy.…”

“…Although the gemcitabine + ulixertinib + afatinib triplets showed more efficacy in PDX models, the DCR was merely 37.5%. In addition, afatinib and ulixertinib share overlapping side effects, including skin rash, fatigue, diarrhea, and anorexia 5 , and thus may not be well tolerated in patients. Because ulixertinib and trametinib upregulate HER2 expression, this provided us with an opportunity to test trastuzumab deruxtecan (DS-8201a), a humanized monoclonal anti-HER2 antibody (trastuzumab) conjugated with a topoisomerase 1 inhibitor (deruxtecan).…”

“…The MAPK pathway is considered one of the most critical therapeutic targets based on numerous preclinical studies 2 . However, MAPK inhibitors, in combination with targeted agents including PI3K inhibitors or chemotherapy, have lacked efficacy in clinical trials and have been shown to have significant side effects 3 – 5 . Our study aimed to develop MAPK inhibitor-based therapeutic combinations that are based on solid scientific rationale.…”

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2

“…Due to the prevalence of oncogenic mutations in Ras, RAF, and MEK, components of this pathway have been targeted for the development of successful anti-cancer therapies ( Halle and Johnson, 2021 ; Tangella et al, 2021 ; Canon et al, 2019 ; Ryan et al, 2020 ). Although inhibitors targeting ERK1/2 have not advanced to clinical use, clinical trials are ongoing for several, including ulixertinib/BVD523 (Biomed Valley Diagnostics), ravoxertinib/GDC0994 (Genentech), and tizakertib/ATG017/AZD0364 (Antengene), for the treatment of cancers with activating mutations in KRAS, BRAF, NRAS, MEK1/2, and ERK1/2 ( Grierson et al, 2023 ; Goodwin et al, 2023 ; Wu et al, 2021 ; Varga et al, 2020 ; Kong et al, 2023 ; Chen et al, 2021 ). Importantly, reversible ATP-competitive inhibitors targeting ERK1/2 have been shown to be effective in cancer cells and tumors with acquired resistance to BRAF and MEK inhibitors ( Ryan et al, 2015 ; Morris et al, 2013 ; Hatzivassiliou et al, 2012 ; Roskoski, 2019 ; Pan et al, 2022 ).…”

Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2

“…Due to the prevalence of oncogenic mutations in Ras, RAF and MEK, components of this pathway have been targeted for the development of successful anti-cancer therapies (Halle and Johnson, 2021; Tangella et al, 2021; Canon et al, 2019; Ryan et al, 2020). Although inhibitors targeting ERK1/2 have not advanced to clinical use, clinical trials are ongoing for several, including ulixertinib/BVD523 (Biomed Valley Diagnostics), ravoxertinib/GDC0994 (Genentech), and tizakertib/ATG017/AZD0364 (Antengene), for the treatment of cancers with activating mutations in KRAS, BRAF, NRAS, MEK1/2 and ERK1/2 (Grierson et al, 2023; Goodwin et al, 2023; Wu et al, 2021; Varga et al, 2019; Kong et al, 2023; Chen et al, 2021). Importantly, reversible ATP-competitive inhibitors targeting ERK1/2 have been shown to be effective in cancer cells and tumors with acquired resistance to BRAF and MEK inhibitors (Ryan et al, 2015; Morris et al, 2013; Hatzivassiliou et al, 2012; Roskoski et al, 2019; Pan et al, 2022).…”