RAF1 amplification

P2, N=16, Terminated, Anita Turk | N=35 --> 16 | Trial completion date: Jul 2024 --> Aug 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Aug 2023; Lack of efficacy.

P1/2, N=168, Recruiting, Day One Biopharmaceuticals, Inc. | Phase classification: P1b/2 --> P1/2

Patient 2 is a 30-year-old Asian female enrolled in FL-1 with metastatic undifferentiated spindle cell sarcoma harboring an APPL2-RAF1 fusion previously treated with radiation, multiple surgical resections, and 2 lines of systemic therapy (cisplatin + etoposide [best response of stable disease] followed by docetaxel + gemcitabine [best response of partial response {PR} but progressed after 6 cycles]). Tovorafenib has clinical activity and a manageable safety profile in these two AYA patients with RAF fusion sarcoma. These reports provide additional evidence of the antitumor activity of tovorafenib in RAF fusion-driven tumors beyond pLGG Early tumor shrinkage minimizing potential morbidities facilitated curative tumor resection in one patient where surgical intervention was not previously possible and a continued rapid, durable tumor response in another. Genomic analysis of all sarcomas is warranted to identify rare oncogenic gene fusions, especially when such alterations are targetable.

Previous therapy with pembrolizumab provided a best response of stable disease (SD) after 11 weeks of therapy...Patient 2 is a 35-year-old white male with a TRIM33-BRAF fusion malignant melanoma, and progressed after treatment with radiation, nivolumab, and nivolumab + ipilimumab... Early results from the first three patients of this ongoing trial showed tovorafenib is generally well tolerated and has encouraging antitumor activity in BRAF-fusion melanoma.

Approximately 25% patients with BC will present with muscle-invasive bladder cancer (MIBC) and for the past several decades the standard-of-care for MIBC and metastatic bladder cancer has been cisplatin-based chemotherapy...Additionally, we tested the impact of MAPK pathway modulation on tumor extrinsic properties including changes in the tumor microenvironment that could potentially affect responses to immunotherapeutic agents. Taken together, we have identified MAPK pathway alterations as a novel dependency in BC that can be targeted with emerging RAF inhibitors.

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P1/2, N=43, DOT Therapeutics-1 Inc. (Day One)

The BRAF signature may better help guide targeted therapy for melanoma, and such a framework can be applied to other cancers and mutations to provide more information than mutation status alone.

Furthermore, we found that bladder tumors with HRAS or NRAS activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a novel dependency in a subset comprising nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rationale therapeutic strategy.

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

P2, N=35, Recruiting, Anita Turk | Trial primary completion date: Sep 2021 --> Jun 2022

P1b/2, N=43, Recruiting, Day One Biopharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P2, N=35, Recruiting, Anita Turk | Not yet recruiting --> Recruiting

P2, N=35, Not yet recruiting, Anita Turk

After eighteenth anti-PD1 therapy, the treatment was changed to dacarbazine due to disease progression...The study of various genetic mutations identified in melanoma is an emerging issue. To analyze the factors affecting therapeutic outcome including genetic mutations and their associated target therapy, further studies of each genetic mutation and review of related mutations in melanoma are needed.