P1, N=79, Suspended, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. | Phase classification: P1a/1b --> P1 | N=37 --> 79 | Trial completion date: Mar 2023 --> Apr 2024 | Recruiting --> Suspended | Trial primary completion date: Sep 2022 --> Apr 2023

Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

P3, N=162, Recruiting, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. | Not yet recruiting --> Recruiting

The overall architecture of our CRAF2/14-3-32 and CRAF2/14-3-32/MEK12 cryo-EM structures is highly similar to corresponding BRAF structures in complex with 14-3-3 or 14-3-3/MEK1 and represent the activated dimeric RAF conformation. Our CRAF cryo-EM structures provide additional insights into structural understanding of the activated CRAF2/14-3-32/MEK12 complex.

P2, N=60, Recruiting, Recursion Pharmaceuticals Inc. | Not yet recruiting --> Recruiting

Among the drugs identified to inhibit EV uptake without exerting significant cytotoxicity, we validated the dose-dependent effect of Trametinib (a MEK1/2 inhibitor) and Copanlisib (a PI3K inhibitor). Through a phenotypic screen, we found that MEK inhibitor Trametinib suppressed EV uptake and macropinocytosis in lung fibroblasts, and that EV uptake is mediated by MEK2 in these cells. Our results suggest that MEK2 inhibition could serve as a strategy to block cancer EV uptake by lung fibroblasts.

P2, N=60, Not yet recruiting, Recursion Pharmaceuticals Inc. | Initiation date: Oct 2023 --> Jan 2024

P1/2, N=73, Recruiting, Recursion Pharmaceuticals Inc. | Phase classification: P2 --> P1/2 | N=37 --> 73

P1/2, N=210, Recruiting, Immuneering Corporation | N=156 --> 210

BI-847325 showed a broader range of activity than the MEK inhibitor GDC-0623. In conclusion, dual MEK/Aurora kinase inhibition shows remarkable potential for treating multiple types of hematological and solid tumors. The combination with capecitabine was synergistic in colorectal, gastric, and mammary cancer.

P2, N=37, Recruiting, Recursion Pharmaceuticals Inc. | N=94 --> 37

In vitro, tunlametinib demonstrated high selectivity with approximately 19-fold greater potency against MEK kinase than MEK162, and nearly 10-100-fold greater potency against RAS/RAF mutant cell lines than AZD6244...Furthermore, tunlametinib combined with BRAF/KRAS/SHP2 inhibitors or docetaxel showed synergistically enhanced response and marked tumor inhibition. Tunlametinib exhibited a promising approach for treating RAS/RAF mutant cancers alone or as combination therapies, supporting the evaluation in clinical trials. Currently, the first-in-human phase 1 study and pivotal clinical trial of tunlametinib as monotherapy have been completed and pivotal trials as combination therapy are ongoing.

P2, N=160, Active, not recruiting, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. | Recruiting --> Active, not recruiting

P3, N=165, Not yet recruiting, Shanghai Kechow Pharma, Inc.

P3, N=165, Not yet recruiting, Shanghai Kechow Pharma, Inc.

P2, N=60, Not yet recruiting, Recursion Pharmaceuticals Inc.

Conclusions Tunlametinib in combination with vemurafenib showed promising antitumor activity and manageable safety profile in pts with BRAF V600-mutated solid tumors. Further studies are ongoing.

FCN-159 is well tolerated and easily manageable, without new safety signal observed. Long-term efficacy and safety follow-up are ongoing.

FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication.

P3, N=162, Not yet recruiting, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

P2, N=6, Completed, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School | Recruiting --> Completed | N=10 --> 6 | Trial completion date: Feb 2023 --> Jun 2023 | Trial primary completion date: Aug 2022 --> Jun 2023

P2, N=75, Not yet recruiting, Shanghai Kechow Pharma, Inc.

P1, N=45, Recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Aug 2022 --> Dec 2023 | Trial primary completion date: Aug 2022 --> Dec 2023

P2, N=186, Recruiting, Shanghai Kechow Pharma, Inc. | Not yet recruiting --> Recruiting

P2, N=100, Completed, Shanghai Kechow Pharma, Inc. | Recruiting --> Completed | Trial completion date: Nov 2022 --> Feb 2023 | Trial primary completion date: Apr 2022 --> Feb 2023

P1/2, N=42, Completed, Shanghai Kechow Pharma, Inc. | Recruiting --> Completed

P1, N=112, Recruiting, ABM Therapeutics Corporation

A biopsy was positive for anaplastic thyroid carcinoma, and she was started on paclitaxel and carboplatin...Genomic testing was positive for BRAF and targeted therapy with dabrafenib and trametinib was initiated...Repeat TSH was 0.086UIU/mL and free T4 was 0.730ng/dL and she was started on levothyroxine supplementation...However, the normal PTH level suggests that there may have been some degree of parathyroid dysfunction. Mechanisms that have been proposed for this are mass effect or tumor infiltration from thyroid cancer. Calcium levels should be checked upon diagnosis of anaplastic thyroid cancer and monitored closely throughout the clinical course.

This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions...Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1-mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM.

Our results suggest that Daurisoline is a dual inhibitor of MEK1 and MEK2 and suppresses ESCC growth both in vitro and in vivo by inactivating the ERK1/2 signaling pathway. This is first report on the use of MEK inhibitor for ESCC and highlights its potential applications for ESCC treatment and prevention.

Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.

We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

In addition, and quite interestingly, the dabrafenib and trametinib resistant A375 (A375DT) cells formed globe shaped 3D spheroids and showed different profiles in cellular metabolism while the mRNA expression of these molecules that were tested as above were different compared with A375 cells. These current findings suggest that 3D spheroid configuration has the potential for serving as an indicator of the pathophysiological activities associated with MM.

The basal migration advantage of high SMAD3 fibroblasts provides a straightforward mechanism underlying the larger accumulation of TAFs previously reported in ADC compared to SCC. Moreover, our results encourage using MEK inhibitors in ADC-TAFs but not SCC-TAFs.

The depth of response to IMM-1-104 was evaluated across a panel of diverse 3D-TGA tumor models and led to identification of a biomarker signature for therapeutically addressable MAPK pathway addiction. To translate these findings into a relevant clinical application, a response algorithm was developed and applied to the GENIE database, which has cataloged the molecular profiles of over 100,000 cancer patients. Mutational landscapes of patients within GENIE helped identify preclinical models that better represent patient profiles likely to be encountered in the clinic.

In-vitro data showed the similar on-target enzyme activity of ABM-168 to marketed MEK inhibitors, as well as high anti-proliferation activities (IC50 <30nM) in multiple cancer cell lines with BRAF or RAS or NF1 mutation like A375, Colo-829, HT-29, MiaPaca-2, LN-229 etc. In vivo pharmacology studies demonstrated that ABM-168 had good potencies of tumor growth inhibitions with oral dose alone or combo with other drugs or compounds in multiple xenograft cancer models: In an A375-luc intracardiac melanoma metastatic model, ABM-168 at 2 mg/kg PO BID demonstrated an antitumor activity comparable to ABM-1310 (A highly BBB-permeable BRAF inhibitor developed by ABM Therapeutics) at different dose levels and frequencies. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs were all completed. Based on these supportive preclinical study results, the IND of ABM-168 was submitted in 2022 Q3 to investigate its safety in human, which will be followed by further clinic development as a single agent, or in combination with other molecules to treat advanced cancers resulted from the abnormal MAPK signal pathway, particularly with brain tumors.

ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.

The results suggest that the sensitivity toward trametinib, refametinib (RDEA119), and selumetinib correlates to the expression of WDR76. ROC analysis showed that the area under the curve (AUC) of all genes in the regulatory axis was greater than 0.7. The identified hsa_circ_0000417/hsa_circ_0002688/hsa_circ_0001387--hsa-miR-199a-5p--WDR76 regulatory axis may provide new insights into the progression, clinical diagnosis, and treatment of HCC.

In vivo combination of trametinib with BCL-2 inhibitors led to tumor inhibition in NRAS-mutant and NF1-deleted xenografts. Together, these results show that combining MEK inhibition with BCL-2 family member inhibition could potentially improve therapeutic outcomes for RAS-MAPK-mutated neuroblastoma patients.

Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.

P1, N=39, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023