NEW YORK – Day One Biopharmaceuticals is planning its first regulatory submission for tovorafenib in pediatric brain cancer as positive data rolls in from a pivotal Phase II trial.
This week, Day One reported initial results from its Phase II FIREFLY-1 trial studying tovorafenib in pediatric patients with relapsed low-grade glioma harboring a BRAF fusion or BRAF V600 mutation. The results included data from the first 22 evaluable patients in the study and showed tovorafenib had anti-tumor activity in this setting.
Among the 22 patients, more than half (64 percent) responded to tovorafenib monotherapy, with 13 patients having a confirmed partial response and one patient with an unconfirmed partial response. Six patients also had stable disease on the treatment, leading to a clinical benefit rate of 91 percent.
Day One CEO Jeremy Bender said on a call with investors that the company will report further data from the registrational cohort of the FIREFLY-1 trial later this year, which may support a new drug application submission to the US Food and Drug Administration.
"Based on these initial data, we're optimistic that data from the full population will support submission of an NDA, which we have planned for the first half of 2023," Bender said. "These data give us even greater conviction that monotherapy tovorafenib should be evaluated as a frontline therapy for pediatric low-grade glioma patients."
Later this year, Day One will begin a pivotal Phase III trial, dubbed FIREFLY-2, exploring the drug as a frontline therapy versus standard chemotherapy for newly diagnosed pediatric low-grade glioma with RAF alterations. Day One Chief Medical Officer Sam Blackman said there is no approved drug specifically for pediatric low-grade glioma, either in the relapsed or frontline setting, and oncologists typically use chemo regimens to treat the disease.
"Like most treatments in pediatric oncology, we're using drugs that are 20 to 40 years old and regimens that academic institutions and cooperative groups have come up with over time," Blackman said. "The modern scientific advances, that most adults have been lucky enough to take advantage of in this past 10-year revolutionary period of cancer therapeutic development, have not trickled down to children."
Tovorafenib, a pan-RAF inhibitor, was being explored in low-grade glioma because most cases are driven by BRAF fusions or mutations. About 85 percent of pediatric low-grade glioma patients harbor a KIAA1549-BRAF fusion and 15 percent harbor a BRAF V600 mutation.
The FIREFLY-1 trial accrued a similar proportion of patients with these two BRAF biomarkers. When stratified by the two types of BRAF alterations, there were two patients with a BRAF V600E mutation, both of whom responded to tovorafenib, and a 60 percent response rate among 20 patients with a BRAF fusion. The median time to response was 2.8 months and 17 patients, including all those who responded to tovorafenib, were on treatment as of the April 14 data cutoff.
Patients included in the study were also heavily pretreated, with a median of three prior lines of therapy, and 72 percent of patients had received a prior MAPK pathway targeted therapy.
"We're very encouraged by the frequency and depth of these responses. Of the six patients who achieved best response of stable disease, all six had reduction in the size of their tumor," Blackman said. "We're particularly focused on the duration of response and whether we observe any additional tumor reduction in any of these partial response or stable disease patients."
The initial safety data also showed that tovorafenib was well tolerated with most treatment-related adverse events being grade 1 or 2, and nine patients (36 percent) experiencing grade 3 or higher adverse events. No patients discontinued treatment due to adverse events.
Day One is continuing to enroll patients in the trial. The initial data presented this week was from cohort one, which will enroll 60 patients. Tovorafenib is also being evaluated in other cohorts in this study, including in pediatric patients with low-grade glioma and extracranial solid tumors characterized by activating RAF alterations.
The company expects to announce more data from cohort one at a medical conference in the second half of 2022, and Bender said the firm expects to report data from the full cohort of 60 patients in the first quarter of 2023.
Alongside this study in relapsed low-grade glioma and its potential regulatory filing, Day One is also planning a global Phase III trial of tovorafenib versus chemo in newly diagnosed pediatric low-grade glioma. This trial, which Day One is conducting with LOGGIC consortium, a group of international experts in pediatric low-grade glioma research, will enroll 400 patients across 100 sites in the US, Canada, Europe, Australia, and Asia.
Patients must be between the ages of six months and 25 years and have low-grade glioma harboring a RAF alteration. They will be stratified by the location of their tumor, genomic alterations, CDKN2A status, and whether they had an infant chiasmatic hypothalamic glioma diagnosis.
"Though the study is a Day One sponsored trial, the team at Day One and the LOGGIC team worked concurrently on the study design and discussions with US and EU regulatory authorities," Blackman said.
Since its founding, Day One has focused on developing drugs for pediatric cancers. In fact, part of its development strategy has been to acquire early-stage drugs from other companies that have shown potential for pediatric cancers. In 2020, the firm acquired tovorafenib from Takeda after the drug showed early activity in both adult and pediatric patients with RAS/MAP kinase pathway alterations.
"When Day One was started about four years ago, we went looking for assets that have been deprioritized by big pharma companies, or any company, where we knew there's either existing clinical data or a strong hypothesis to underlie taking those assets and retargeting them for pediatric development," said Blackman, a cofounder of the South San Francisco, California-based firm.
He noted that the firm chose tovorafenib because it was a brain penetrant pan-RAF inhibitor, meaning it could both cross the blood-brain barrier and target BRAF mutations, which are the oncogenic drivers of pediatric gliomas. "We immediately jumped … all over it," he said.
The company similarly acquired its MEK inhibitor, pimasertib, from Merck KGaA in 2021. The goal with this candidate is to combine it with tovorafenib to target multiple nodes in the RAS/MAPK pathway. In a trial called FIRELIGHT-1, Day One is exploring pimasertib alone or pimasertib plus tovorafenib in adult and adolescent patients with recurrent or progressive solid tumors with activating RAF alterations.
"The data showing that combining a pan-RAF inhibitor and a MEK inhibitor is potentially synergistic led us to go out and look for a MEK inhibitor that we could wholly own as opposed to either combining with an existing commercially approved MEK inhibitor, or somebody else's developmental MEK inhibitor," Blackman said.
At Merck KGaA, pimasertib had been studied in NRAS-mutant melanoma, and while it had shown superiority against chemotherapy in terms of response rate, it did not improve overall survival in that setting. "They had decided to wind down the program, and we were able to partner with them and actually take on that asset," Blackman said.
The company's goal of repurposing these "deprioritized" drugs for pediatric cancers comes as US lawmakers consider new measures to encourage pharma companies to study more drugs in pediatric populations. A bill called the Give Kids a Chance Act has been introduced in Congress that would expand the FDA's authority to require that drug sponsors conduct pediatric studies of combination therapies. Currently, the RACE for Children Act, passed in 2017, requires pharma to submit pediatric study plans to the FDA for single-agent cancer therapies.
Blackman noted that challenges in pediatric cancer drug development often occur when drugs fail in adult populations, like with pimasertib, and a company ends the program rather than continuing to develop it for a smaller group of patients.
"Having an obligation to study a drug in pediatric patients is not a mandate to actually develop it in pediatrics. Nobody can force you to develop a drug, but that then creates a gap [in development]," Blackman said. "Part of the challenge is that drugs fail in adults and companies can't see beyond that first failure to secondary adult indications or they can't see the intrinsic value of developing it for pediatrics from an economic point of view."
Further, the pharmaceutical industry tends to be reluctant to pursue pediatric drug development because they believe the trials may not accrue due to the rarity of these cancers or that a serious adverse event in children could end the whole program. "That's simply a myth," Blackman said.
He highlighted that Day One was able to fully enroll its pediatric FIREFLY-1 trial in less than a year, and credited Day One's partnerships with pediatric oncology centers and other institutions for the quick and efficient accrual.
"The barriers to doing this are just historical fallacies," Blackman said. "The pediatric oncology community has caught up and has made it possible for companies like ours, a small company with not even 100 people, to be able to design and execute studies at the speed of the industry, at the speed of biotech, and to bring new drugs forward for children."