mosperafenib (RG6344) / Roche - LARVOL DELTA

Phase I Study of Mosperafenib, a Novel Paradox Breaker B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) Inhibitor, in Patients With BRAF V600-Mutant Solid Tumors. (PubMed, J Clin Oncol) - "Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-naïve and BRAFi-exposed patients."

Journal • P1 data • Colorectal Cancer • Dermatology • Melanoma • Oncology • Solid Tumor

Prior BRAF Inhibitor Exposure Is Not Enough to Define Resistance in the Phase I Mosperafenib Study. (PubMed, J Clin Oncol) - No abstract available

Journal • P1 data

Reply to: Prior BRAF Inhibitor Exposure Is Not Enough to Define Resistance in the Phase I Mosperafenib Study. (PubMed, J Clin Oncol) - No abstract available

Journal • P1 data

Further back in Roche’s pipeline, the company discontinued a clutch of phase 1-stage drugs (FierceBiotech) - "Aside from the TCE, these included mosperafenib, a BRAF inhibitor that was being evaluated for solid tumors....Mosperafenib was joined on the discard pile by another solid tumor candidate in the form of RG6468, which was being assessed in combination with Tecentriq. Roche didn’t confirm RG6468’s mode of action, but did tell Fierce that the company had decided to halt the program after reviewing the phase 1 data."

Discontinued • Solid Tumor

Results of first-in-human (FiH) study of mosperafenib in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) (ESMO-GI 2026) - "Patients with CRC had a median of 3 (range 1-6) prior treatment lines including BRAFi in 59% (37) patients, majority (32) of which received it in combination with cetuximab. Low baseline ctDNA (≤10% cTF in 26/48 biomarker evaluable pts) was associated with improved mPFS (HR=0.32, p<0.00051); non-responders had significantly higher baseline ctDNA. Conclusions Mosperafenib showed differentiated safety profile and promising preliminary single agent activity; patients previously treated with BRAFi containing regimens also obtained meaningful benefit."

Clinical • First-in-human • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Early ctDNA dynamics predict response to mosperafenib in BRAF V600-mutant metastatic colorectal cancer. (PubMed, Cancer Res Commun) - "This response is largely confined to BRAFi-naive patients, as pre-existing MAPK pathway alterations in BRAFi-experienced patients correlate with lack of response. These findings support using early ctDNA dynamics as an efficacy endpoint in future trials."

Circulating tumor DNA • Journal • Colorectal Cancer • Oncology • Solid Tumor • BRAF

A phase I study evaluating safety, pharmacokinetics, and clinical activity of the novel, paradox breaker BRAF inhibitor RG6344 in patients with BRAF V600-mutant solid tumors (AACR 2025) - "RG6344 (RO7276389) is a novel brain penetrant paradox breaker BRAFi designed to address the limitations of approved BRAFi. Dose escalation of RG6344, as a single agent and in combination with standard dose of cobimetinib, is being conducted in participants with solid tumors harboring a BRAF V600E mutation up to the protocol specified maximum daily dose. RG6344 is well tolerated allowing unprecedented exposure for pERK inhibition and shows promising preliminary activity."

Clinical • P1 data • PK/PD data • Colorectal Cancer • Melanoma • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • EGFR

The novel brain-penetrant paradox breaker BRAF inhibitor RG6344 manifests exceptional activity in BRAF mutant colorectal cancers (AACR 2025) - "In BRAFi naïve xenograft models (LS411N, HT29) RG6344 as monotherapy outperformed Encorafenib/Cetuximab at all doses tested indicating higher activity of this agent even at doses targeting only IC80 p-ERK inhibition, the same BRAF inhibition levels reached by Encorafenib in CRC approved clinical regimens. RG6344 activity was further strengthened in combination with cetuximab and demonstrated long-lasting responses in PDX models derived from patients that progressed to Encorafenib/Cetuximab therapy supporting the use of RG6344 even in BRAFi experienced patients.Additional combination studies of RG6344 with FOLFOX in BRAFi naive models resulted in tumor regression and dramatic superiority compared to the same combination with Encorafenib.These data collectively provide strong preclinical translational evidence for the potentially transformative activity of RG6344 in BRAF mutated CRC."

Colorectal Cancer • Oncology • Solid Tumor

A Study to Evaluate Safety, Pharmacokinetics, and Preliminary Clinical Activity of RO7276389 Alone and in Combination with Cobimetinib in Participants with BRAF-V600 Mutation-Positive Advanced Solid Tumor or BRAF-V600 Mutation-Positive Melanoma with Central Nervous System Metastases (clinicaltrialsregister.eu) - P1 | N=70 | Completed | Sponsor: F. Hoffmann-La Roche AG | Recruiting ➔ Completed

Trial completion • Melanoma • Oncology • Solid Tumor • BRAF

A Study to Evaluate Safety, Pharmacokinetics, and Preliminary Clinical Activity of RO7276389 Alone and in Combination with Cobimetinib in Participants with BRAF-V600 Mutation-Positive Advanced Solid Tumor or BRAF-V600 Mutation-Positive Melanoma with Central Nervous System Metastases (clinicaltrialsregister.eu) - P1 | N=70 | Recruiting | Sponsor: F. Hoffmann-La Roche AG | -> Recruiting | Phase classification: PN/A ➔ P1

Enrollment open • Phase classification • Melanoma • Oncology • Solid Tumor • BRAF

Discovery of F-18 labeled repurposed CNS drugs by computational strategy for effective tau imaging and alzheimer's diagnosis. (PubMed, PLoS One) - "Drug 416 (reported BRAF inhibitor, RG6344) shows a binding free energy of ΔG = -7.91 kcal/mol, while Drug 610 (Iloperidone/HP 873), a D2/5-HT2 receptor antagonist, exhibits a predicted binding free energy of ΔG = -6.88 kcal/mol with the target Tau protein respectively. The F-18 label enabled real-time PET imaging, allowing non-invasive tracking of the drug's binding to Tau in the brain. Our approach provides a comprehensive solution to the current limitations in Alzheimer's diagnosis by offering F-18 labeled drugs that effectively target Tau protein without compromising their biological activity, advancing both diagnostic and therapeutic strategies for AD."

Journal • Alzheimer's Disease • CNS Disorders

Mosperafenib, a novel paradox breaker BRAF inhibitor with potent preclinical activity in BRAF mutated colorectal cancer. (PubMed, Mol Cancer Ther) - "The therapeutic benefit of the combination of the first generation BRAFi encorafenib and the EGFR blocking antibody cetuximab in second line metastatic colorectal cancers (CRC) harboring BRAF V600E mutations remains limited and short lived...Additional combination studies of mosperafenib with FOLFOX resulted in tumor regression and superior activity compared to the same combination with encorafenib. Collectively these data provide a strong preclinical rationale for the potentially transformative activity of mosperafenib as monotherapy and as a preferred backbone BRAFi for combinatorial regimen for BRAF mutated CRC."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Evaluating ctDNA as a predictive biomarker in a phase I clinical trial of mosperafenib in BRAFV600E-mutant colorectal cancer (ESMO 2025) - "Conclusions This study demonstrates that RG6344 exhibits promising clinical efficacy in mCRC patients, including those with prior BRAFi treatment (mPFS = 3.7 months). The findings suggest ctDNA is a robust biomarker for monitoring of on-treatment tumor dynamics and treatment response."

Biomarker • Circulating tumor DNA • Clinical • P1 data • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Sarah Cannon Research Institute to Showcase Cancer Insights at 2025 ASCO Annual Meeting (Businesswire) - "Today, Sarah Cannon Research Institute (SCRI), one of the world’s leading oncology research organizations conducting community-based clinical trials, announced that it will showcase its latest research highlights through more than 155 accepted abstracts and presentations at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago from May 30-June 3, 2025. Over 75 investigators from more than 20 research sites in SCRI’s network are first authors and co-authors on the clinical trial updates featured at the Annual Meeting, including findings from 55 early-phase clinical trials."

Clinical data • Platinum resistant • Biliary Tract Cancer • Colorectal Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Solid Tumor

Preliminary safety, pharmacokinetics, and clinical activity of RG6344 in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). (ASCO 2025) - "RG6344 is well tolerated allowing unprecedented exposure for pERK inhibition and shows promising preliminary single-agent activity."

Clinical • Metastases • PK/PD data • Colorectal Cancer • Dermatology • Fatigue • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • BRAF