P2, N=101, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | N=20 --> 40

P2, N=15, Recruiting, Verastem, Inc.

P1, N=14, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting

P4, N=70, Not yet recruiting, The First Affiliated Hospital with Nanjing Medical University

P1/2, N=85, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Dec 2024

P=N/A, N=25, Not yet recruiting, Zhongshan Hospital; Zhongshan Hospital

P=N/A, N=40, Recruiting, HenanCancerHospital; HenanCancerHospital

P2, N=13, Recruiting, The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital with Nanjing Medical University

P2, N=94, Recruiting, Vall d'Hebron Institute of Oncology | Not yet recruiting --> Recruiting

P2, N=24, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=40 --> 24

MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited...In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells.

No abstract available

Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

P3, N=921, Completed, Pfizer | Active, not recruiting --> Completed

Intriguingly, reducing intratumoral DAG by fenofibrate or Pf-06471553 restores the antitumor efficacy of encorafenib/cetuximab on resistant BRAFV600E-mutant mCRC, interrupted PKCα-CRAF-MEK-ERK signaling. These findings reveal the critical metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate may prove beneficial for resistant BRAFV600E-mutant mCRC patients.

The STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D.

P2, N=98, Active, not recruiting, Pfizer | Trial completion date: Dec 2024 --> Oct 2025

P2, N=119, Recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial primary completion date: Sep 2024 --> Dec 2024

P2, N=25, Recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

The BRAF V600E mutation has been identified in a subset of malignant GT, highlighting a promising therapeutic target. Here, we report the impressive clinical and morpho-metabolic response of a metastatic BRAF V600E-mutated glomangiosarcoma after treatment with encorafenib and binimetinib.

Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.

These findings highlight the impact of oxidative stress on signaling pathways, such as those triggered by UV irradiation. A deeper understanding of these molecular changes may aid in developing therapies targeting diseases linked to oxidative stress, including cancer.

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Aug 2024 --> Nov 2024

P2, N=84, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Feb 2026 | Trial primary completion date: Aug 2024 --> Feb 2026

P1/2, N=182, Recruiting, Institute of Cancer Research, United Kingdom

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781.

P2, N=86, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Aug 2024 --> Oct 2025

P1/2, N=38, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=56, Completed, Pfizer | Active, not recruiting --> Completed

The present study demonstrates a notably high V600E frequency (12.2%) in comparison to global reported data, which ranges from 0.4 to 18%. This finding reflects the importance of upfront BRAF testing of the genetically distinct population of Pakistan. Previously unreported mutations identified in the sample may be of clinical significance and warrant further investigation. The concomitant high expression and significant association between CD133 and BRAFV600E represent vital actionable genes that may be targeted together to improve CRC patient management.

P=N/A, N=108, Recruiting, Sun Yat-sen University

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224.

The combination therapy of binimetinib, encorafenib, and cetuximab ("triplet regimen") was approved in Japan in November 2020 for the second-line treatment of BRAF V600E mutation-positive colorectal cancer. Hepatic failure occurred in 45.9% (222/484) of the patients within three months, but no specific timing of onset was reported. Since it is important to disseminate novel adverse events to the public, we report the results of this study based on a literature review.

P2, N=38, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=150 --> 38

The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6-9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings.

This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

Ramalingam and Carlisle discuss the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. The podcast provides an overview of the data from the recent Pfizer-sponsored phase 2 PHAROS (NCT03915951) study, which were the basis for the recent US Food and Drug Administration approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer.

P=N/A, N=204, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

P2, N=16, Recruiting, Gruppo Oncologico del Nord-Ovest