BRAF wild-type

Our data show that baseline serum levels of hepcidin are an independent risk factor for OS in MSS mCRC patients undergoing standard first-line treatment. Further prospective and extensive studies are needed to confirm and validate our findings.

P=N/A, N=13, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2025 --> Sep 2025

P2, N=40, Recruiting, ImmunityBio, Inc. | Active, not recruiting --> Recruiting | N=147 --> 40

Triplet induction chemotherapy is a treatment of choice in selected patients with SMRC, allowing to adapt the therapeutic strategy to the response and invasiveness of the various sites.

The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.

P2, N=3, Terminated, Jonsson Comprehensive Cancer Center | N=28 --> 3 | Trial completion date: Jun 2026 --> Nov 2024 | Recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Nov 2024; poor enrollment

In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.

P3, N=131, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=674, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.

P1/2, N=29, Completed, Anaveon AG | Recruiting --> Completed | N=130 --> 29 | Trial completion date: Dec 2024 --> Aug 2024

The clinical significance of FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) plus anti-EGFR monoclonal antibody using cetuximab for metastatic colorectal cancer (mCRC) remains controversial...m-FOLFOXIRI plus cetuximab has clinical benefit for tumor shrinkage in RAS wt mCRC. The survival benefit for RAS/BRAF wt and left-sided mCRC needs further investigation.

Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

We found that, consistent with other Fgfr4 knockout animal models, the fgfr4 mutant fish developed normally; however, homozygous fgfr4 mutant zebrafish were significantly smaller than wildtype fish at three months post fertilization. These fgfr4 knockout zebrafish lines are a valuable tool to study the role of FGFR4 in vertebrate development and its viability as a potential therapeutic target in pediatric and adult cancers, as well as other diseases.

P2, N=59, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting | N=30 --> 59

Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3. Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

These preliminary findings suggest that evaluation of in vitro cytotoxicity together with CD107a expression in mCRC patients derived PBMC could be a useful tool to identify early responders after only 8 weeks of treatment with cetuximab plus avelumab. In addition, we aim to further investigate the potential role of CCL5 secreted by peripheral immune cells and its cut-off as a predictive biomarker of mCRC progression in a larger cohort of patients.

The LIBImAb Study is a phase III, randomized, openlabel, comparative, multi-center trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI in mCRC pts, RAS/BRAFwt on tumor tissue and RAS/BRAF mutant (RAS/BRAFmut) at liquid biopsy... These data indicate the feasibility of cfDNA-based prospective enrolment in an interventional trial using a test with a rapid TAT for screening of RAS/ BRAF status in plasma. Our preliminary findings also suggest that ctDNA testing might better recapitulate the tumor heterogeneity of mCRC pts thus complementing tissue genomic profiling.

TRIPLETE is a phase III trial where 435 pts with RAS/BRAF wt – per local assessment – mCRC were randomized to receive first-line FOLFOX/ panitumumab (pan) or mFOLFOXIRI/pan... In contrast to previous data, negative hyperselection both through tissue and plasma analysis failed to demonstrate a prognostic role among pMMR RAS/BRAF wt mCRC pts treated with first-line chemotherapy plus pan. The confounding effect of the associated chemotherapy is a potential explanation for this finding. Tissue and plasma analyses at baseline failed to provide fully concordant results.

Materials and The phase II CAPRI 2-GOIM trial investigates the efficacy and safety of biomarkerdriven, cetuximab-based, sequence of three treatment lines in mCRC... Baseline plasma-based comprehensive genomic profiling is feasible with high concordance with tissue-based analysis. Liquid biopsy allows identification of misdiagnosed RAS/BRAF alterations and the ultra-selection of pts, which could benefit from anti-EGFR therapies. Finally, potentially actionable gene alterations were found in half of the pts.

P3, N=520, Completed, Taizhou Mabtech Pharmaceutical Co.,Ltd | Active, not recruiting --> Completed

P2, N=34, Recruiting, National Cancer Institute, Naples | Trial completion date: Sep 2024 --> Sep 2025

In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

P2, N=122, Completed, Daiichi Sankyo | Active, not recruiting --> Completed | Trial completion date: Jul 2024 --> Oct 2024

P2, N=29, Recruiting, Australasian Gastrointestinal Trials Group | Not yet recruiting --> Recruiting

Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Profiling copy number alterations in AF and related lesions emerge as a valuable tool for enhancing their differential diagnosis and facilitating the anticipation of disease progression. Our findings underscore the efficacy of copy number alteration analysis in determining the nature of lesions within AF and related lesions.

In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.

Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.

Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively...Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Trial primary completion date: Aug 2024 --> Jul 2025

Using patient tumor tissue before and after BRAFi+MEKi, two novel syngeneic murine models of BRAF V600E HGG, and patient-derived cell lines, we examined the effects of clinically relevant BRAFi+MEKi with dabrafenib and trametinib on tumor growth, cell states, and tumor-infiltrating T cells. The quadruple treatment overcame BRAFi+MEKi resistance by invigorating T cell-mediated anti-tumor immunity in murine BRAF V600E HGG. PD-L1 expression was elevated in human BRAF-mutant versus BRAF-wildtype glioblastoma clinical specimen, complementing experimental findings and suggesting translational relevance for patient care.

In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases.

There is still no general consensus on molecular markers for deciding the appropriateness of adjuvant treatment of early-stage melanoma. We have shown for the first time that the combined determination of the ctDNA BRAFmut oncogene (liquid biopsy) and the high level of tumor marker S100B in pre- and postoperative plasma samples can identify patients with the worst prognosis and the highest risk of tumor recurrence. Therefore, modern adjuvant therapy would be appropriate for these patients with resectable melanoma, regardless of disease stage.

Actionable gene fusions are more prevalent in MSI-H, RAS/BRAF wildtype, or RNF43-mutated CRC, as well as in colon cancer. Mapping of these molecular markers can markedly increase the fusion detection rate, which can help clinicians select candidates for fusion testing and targeted therapy.

Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

Further analysis on A375 and Mel501 cell lines expressing BRAFV600E revealed that compound 9s has a potent growth inhibitory activity with IC50 of 0.7 and 1.5 µM, respectively, in reference to sorafenib (IC50 = 8.7 and 0.3 µM, respectively)...Noteworthy, the examined candidates demonstrated a higher selectively towards BRAFV600E over BRAFWT highlighting their promising optimization for treating BRAFV600E expressing cancers. Molecular docking and molecular dynamics simulations in the inactive DFG-out kinase domain of BRAFWT/V600E protein kinases confirmed the planned design strategy.

P2, N=56, Active, not recruiting, Istari Oncology, Inc. | Trial primary completion date: Jun 2024 --> Oct 2024

Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.

P1, N=232, Recruiting, Genentech, Inc. | Active, not recruiting --> Recruiting

Aim: First-line (1L) immunotherapy has yielded superior overall survival (OS) in metastatic melanoma (MM) but some patients are ineligible for immunotherapy or need rapid response with 1L targeted therapy (TT).Materials & Retrospective cohort study of real-world patients treated with 1L immunotherapy (144 BRAF wild type, 85 BRAF-mutated) or 1L TT (143 BRAF-mutated) for MM in Finland during 2014-2021. Baseline brain metastases, liver metastases and elevated LDH were less common, 2-year OS rates were higher (60.3-63.5% vs. 33.8%) and more patients were alive without the next-line treatment (38.0-43.8% vs. 23.3%) in patients with 1L immunotherapy. Real-world patients with 1L immunotherapy for MM had favorable baseline characteristics and better treatment outcomes than observed in patients with 1L TT.

P1/2, N=28, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=63 --> 28