ulixertinib (BVD-523)

Treatment with the neural precursor cell expressed developmentally downregulated protein 8-activating enzyme inhibitor pevonedistat resulted in increased hPRLrL and the death of breast cancer cells. Treatment of breast cancer cells with ERK1/2 inhibitor ulixertinib resulted in decreased colony-forming ability and less proliferation. These studies suggest that the hPRLrI I-tail contributed to breast oncogenesis and may be a promising target for the development of new breast cancer therapies.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.

ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

P1, N=27, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P1, N=18, Completed, University of Utah | Active, not recruiting --> Completed

P2, N=101, Terminated, BioMed Valley Discoveries, Inc | Active, not recruiting --> Terminated; Enrollment challenges

P2, N=215, Recruiting, BioMed Valley Discoveries, Inc | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=27, Suspended, M.D. Anderson Cancer Center | Phase classification: P1b --> P1 | Not yet recruiting --> Suspended

Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Mar 2026

P1b, N=27, Not yet recruiting, M.D. Anderson Cancer Center

Our study highlights the exacerbation of lung-to-brain metastasis via miR-21-rich EV secretion. This underlines the therapeutic promise of targeting the miR-21/ERK/STAT3 pathway with ulixertinib for managing brain metastasis from lung cancer.

Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2023 --> Apr 2024

P1, N=20, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Sep 2023 --> Apr 2023

P1, N=20, Not yet recruiting, M.D. Anderson Cancer Center

KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups.In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated.

BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC...The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit...The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition.

In live imaging experiments, we found that blocking ERK activity with the ERK inhibitor Ulixertinib blocks the induction of cell death after IFNg treatment in 17 of 23 (~74%) IFNg-sensitive PDM lines covering all the MAPK mutant and triple wildtype molecular subtypes of melanoma...This pathway is active in all melanoma subtypes, making it an attractive target to enhance IFNg GI in tumor cells. Our results provide a new understanding of the IFNg GI pathway that will also be crucial to define mechanisms of GI resistance in tumor cells.

P1, N=18, Active, not recruiting, University of Utah | Recruiting --> Active, not recruiting | N=12 --> 18

SARS-CoV-2-correlated ASGR1 is a novel marker that can be used for treating and identifying multiple human cancers.

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=101, Active, not recruiting, BioMed Valley Discoveries, Inc | Recruiting --> Active, not recruiting | N=528 --> 101

Additionally, ulixertinib treatment significantly sensitized NB cells to the conventional chemotherapeutic agent doxorubicin. Furthermore, ulixertinib potently inhibited NB tumor growth and prolonged the overall survival of the treated mice in two different NB mice models. Our preclinical study demonstrates that ulixertinib, either as a single agent or in combination with current therapies, is a novel and practical therapeutic approach for NB.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Active, not recruiting --> Recruiting

P1, N=45, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2023 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Jul 2024

Based on these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). Additionally, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to PDAC patients.

The clinically available MAPK inhibitor Ulixertinib showed enhanced toxicity in FLCN cells...Also, we identified that FLCN inactivation resulted in dephosphorylation of TFEB Ser109, Ser114, and Ser122, which may be linked to increased oxidative stress levels in FLCN cells. Together, our study highlights differential phosphorylation of specific kinases and substrates in FLCN renal cells. This provides insight into BHD-associated renal tumorigenesis and may point to several novel candidates for targeted therapies.

Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors.

These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment.

P2, N=215, Recruiting, BioMed Valley Discoveries, Inc | Not yet recruiting --> Recruiting

The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission.

We examined the efficacy of inhibitors of MEK (trametinib), ERK (ulixertinib) or mTOR (rapamycin) alone or in combination on growth in vitro and in vivo. In patient-derived models of NF1-mutated sarcoma, we observed activation of the MAPK and MTOR pathways. Combined inhibition of MEK or ERK and MTOR were effective at inhibiting tumor growth. These results confirm the possibility of targeting different elements of the MAPK and MTOR pathways to increase the response for NF1-mutated sarcomas.

Furthermore, ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with orthotopic BT40 xenografts.Ulixertinib showed indications for anti-proliferative synergy in vitro, according to the Loewe and Bliss independence models, in combination with MEK inhibitors (trametinib, binimetinib) or senolytics (navitoclax, A1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive...The combination of ulixertinib with navitoclax was further investigated in the BT40 PDX mouse model, where tumor growth and survival were comparable to ulixertinib monotherapy.In conclusion, our data indicate a strong potential for ulixertinib as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and senolytics was noted and warrants further investigation.