Ojemda Shrank Tumors in 43% of Patients With Rare BRAF, CRAF Changes

Ojemda (tovorafenib) shrank tumors in 10 of 23 adults (43%) with melanoma or other solid tumors that had come back or stopped responding to treatment and carried rare changes in the BRAF or CRAF genes, according to results from a phase 2 substudy of the FIRELIGHT-1 trial published in JCO Precision Oncology.

Ojemda is an oral targeted therapy that blocks BRAF and CRAF, two proteins in a signaling pathway that controls how cells grow and survive. The gene changes studied were BRAF fusions (when part of the BRAF gene joins with another gene) and CRAF fusions or amplifications (extra copies of the CRAF gene). These changes are rare drivers of cancer growth across many tumor types, and patients whose tumors carry them have few targeted options.

Ojemda received accelerated approval from the U.S. Food and Drug Administration (FDA) in April 2024 for children and young adults with BRAF-altered pediatric low-grade glioma that has relapsed or stopped responding to treatment. Outside of that approval, no therapies are approved specifically for tumors with BRAF fusions, and none are approved for tumors with CRAF fusions or amplifications, according to the researchers.

How well did Ojemda work in the FIRELIGHT-1 substudy?

The study's primary end point was overall response rate, or the share of patients whose tumors shrank by a set amount, which reached 43%. One patient had a complete response, meaning no measurable tumor remained, and nine patients had a partial response. Four more patients had stable disease, in which tumors neither grew nor shrank enough to count as a response, bringing the clinical benefit rate to 61%.

Responses occurred in four of eight patients with melanoma (50%) and six of 15 patients with other solid tumors (40%). Among the patients with other tumors, four of eight with central nervous system (CNS) tumors responded (50%), as did two of seven with other tumor types (29%).

The complete response occurred in a patient with diffuse leptomeningeal glioneuronal tumor, a rare brain tumor. Two of three patients with high-grade gliomas responded, one with an anaplastic astrocytoma and one with glioblastoma, along with a patient who had a neuroepithelial neoplasm. Partial responses were also seen in one patient with pancreatic cancer and one with spindle cell sarcoma.

Ojemda worked across every type of gene change in the study. Responses occurred in six of 14 patients with BRAF fusions, two of six with CRAF fusions, one of two with CRAF amplification and the one patient whose tumor had both CRAF fusions and amplification.

Responses came quickly, with a median time to response of 1.8 months. The median duration of response was 9.2 months. Four patients had responses lasting more than nine months when the study closed, and five patients were still responding at that point.

All eight patients with melanoma had previously received PD-1 inhibitor immunotherapy, and three of the eight had also received a CTLA-4 inhibitor. The researchers noted that approved options are very limited for patients with advanced melanoma that has progressed after these treatments and whose tumors do not have a BRAF V600 mutation.

"Achieving responses in 50% of such patients in the current study is therefore encouraging," the researchers wrote.

Who was included in the phase 2 FIRELIGHT-1 substudy?

The open-label study enrolled 23 patients from six countries (Australia, Canada, Spain, France, the Republic of Korea and the United States) between November 2021 and July 2024. Eight patients joined a melanoma group. The other 15 joined a tumor-agnostic group, meaning they qualified based on the gene change in their tumor rather than where the cancer started; this group included eight patients with CNS tumors, four with pancreatic cancer, two with sarcoma and one with colorectal cancer.

The median age was 53 years, and 57% of patients had received two or more prior lines of treatment. Patients could not have previously received drugs that target the same growth pathway as Ojemda. Adults took Ojemda by mouth at 600 mg once a week in 28-day cycles, and the median time on treatment was 5.3 months.

The study sponsor closed the substudy in November 2023 because the gene changes are rare and enrolling patients in a timely way was difficult. The seven patients still receiving Ojemda at that time could continue treatment through programs such as compassionate use, but study follow-up for those patients ended. Because of the early closure, the researchers noted that the duration of response was likely underestimated.

What side effects did patients have with Ojemda in the FIRELIGHT-1 substudy?

Treatment-related side effects occurred in 91% of patients. The most common were anemia (39%), itching (30%), increased levels of creatine phosphokinase, a muscle enzyme measured in blood tests (26%), and rash (26%).

Grade 3 treatment-related side effects occurred in 22% of patients, most often anemia (9%), and there were no grade 4 or 5 treatment-related side effects. One patient had a serious treatment-related side effect, a grade 3 retinal hemorrhage (bleeding in the back of the eye).

Seven patients (30%) had treatment paused and six (26%) had their dose lowered because of side effects. One patient stopped Ojemda because of grade 2 muscle pain.

The researchers tracked eye problems as a side effect of special interest. Seven patients (30%) had eye side effects, which were grade 1 or 2 in five patients and grade 3 in two. No patients permanently stopped treatment because of eye side effects. The researchers noted that eye side effects appeared in a higher share of adults in this study than in children and young adults in the FIREFLY-1 trial, but otherwise the safety profile was consistent with previous studies and no new safety signals emerged.

What do the FIRELIGHT-1 results mean for patients with rare BRAF or CRAF changes?

The researchers concluded that Ojemda showed activity as a monotherapy across several types of solid tumors with BRAF fusions or CRAF fusions or amplification, with manageable side effects. Ojemda is not approved for these tumors, and the study was small and closed before reaching its planned enrollment.

"[Ojemda] may offer a new targeted treatment option for adult patients with tumors [that have] these rare genomic driver alterations," the researchers wrote.

The researchers added that the responses seen in patients with rare cancers highlight the value of genomic testing to find tumors that may respond to Ojemda or other targeted therapies. They noted that this testing would ideally use both DNA- and RNA-based next-generation sequencing (NGS), tests that read the genetic makeup of a tumor.

The findings were previously presented at the ESMO Congress 2024 in Barcelona, Spain. The study was supported by Day One Biopharmaceuticals.

Reference

1. Vieito M, et al. "Type II RAF Inhibitor Tovorafenib in Recurrent/Refractory Melanoma or Other Solid Tumors With BRAF Fusions or CRAF/RAF1 Fusions or Amplification: Phase II FIRELIGHT-1 Substudy." JCO Precision Oncology. Published October 2, 2026. doi.org/10.1200/PO-25-01187

For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.