Addressing Unmet Need: Could Children With Low-Grade Gliomas Have a New Treatment in Tovorafenib?

Breathtaking advances in cancer care over the past 20 years have nonetheless left gaps, and a notable one is the need for more options for children with brain tumors. These young patients face hurdles at every turn. Even for adults, brain cancer is notoriously hard to treat; the blood-brain barrier that spares the brain and spinal cord injury from harmful agents also blocks most types of therapy. Depending on where the tumor sits, surgery can be a challenge, and radiation can damage surrounding tissue.¹

Given safety concerns, trials for new treatments in pediatric cancers generally lag behind studies in adults. Advocacy groups for pediatric cancer highlight the dearth of research dollars that flow to this area, despite unmet need—and they note the funding chasm relative to research dollars for cancers common in adults.² Thus, therapeutic options for children with brain tumors are very limited—typically the choice is chemotherapy, despite adverse events (AEs) and concerns about long-term cardiotoxicity.

Bender

It’s a void that the company Day One Biopharmaceuticals is trying to fill as it meets with FDA about a regulatory path for its lead therapy, tovorafenib. So far, the oral therapy has been studied in more than 325 patients—including those with pediatric low-grade glioma (pLGG), the most common type of childhood brain cancer.³ Tovorafenib, which penetrates the brain, is a highly selective type II pan-RAF kinase inhibitor that targets a key enzyme in the MAPK signaling pathway, which is implicated in multiple cancer types. The therapy is being studied in both brain tumors and in brain metastases of solid tumors.^3,4

In January, Day One announced topline results from one section of the FIREFLY-1 trial (NCT04775485); this is a phase 2 study of children and young adults (aged 6 months to 25 years) with recurrent or progressive pLGG. Day One reported that tovorafenib achieved a 64% objective response rate (ORR) when given alone to the 77 patients in the study.⁵ Additional results showed:

• A clinical benefit rate of 91% in 69 heavily pretreated patients eligible for Response Assessment in Neuro-oncology (RANO)
• Median duration of response of 8.4 months on therapy, with 77% of patients on treatment at the data cutoff of September 28, 2022.⁵

Tovorafenib has already received FDA’s Breakthrough Therapy and Rare Pediatric Disease designations, and Day One officials met with the agency in April regarding next steps.³ According to Day One CEO Jeremy Bender, PhD, MBA, who spoke with The American Journal of Managed Care® (AJMC) earlier this spring, discussions with FDA will involve whether to seek approval under an accelerated pathway.

“We’re seeing very encouraging signs of activity for tovorafenib in these patients,” Bender said during the interview. “We’ve observed a very substantial fraction of the patients have responses, according to the primary end point of the study—which is response rate as assessed by MRI—and that most of those patients have so far had durable responses.”

What's more, the safety effects with tovorafenib have been far less severe than seen with chemotherapy, although Bender noted that patients will have to be followed to evaluate long-term effects. This is an important issue for patients with pLGG; a 2019 study of 51 patients diagnosed at St. Jude Children's Hospital found that when children are diagnosed with a tumor in the first year of life, "chronic health deficits are highly prevalent and multi-systemic in survivors, warranting pre-emptive counseling and dedicated multidisciplinary management."⁶

Day One has also started enrolling patients in the phase 3, registrational FIREFLY2/LOGGIC trial (NCT05566795), which will examine tovorafenib given as monotherapy once weekly in patients newly diagnosed with pLGG when they have a known activating RAF alteration.⁷

As the calendar turned to Brain Cancer Awareness Month in May, Day One Bio is now scheduled to present data at 3 upcoming scientific meetings: the American Society of Pediatric Oncology/Hematology Conference, which runs May 10-13; the American Society of Clinical Oncology Annual meeting, taking place June 2-6; and the Society for Neuro-Oncology Biennial Pediatric Neuro-Oncology Research Conference, set for June 23-24.³

What follows is a lightly edited interview held following the release of topline data for FIREFLY-1.

AJMC: Can you discuss the unmet need in pediatric cancers generally and in pediatric brain cancer specifically?

Bender: The degree of unmet need in pediatric cancers is extraordinary, particularly relative to adult cancers. In recent decades, we’ve seen numerous drug approvals—in the adult setting, dozens and dozens [have been] approved, but very few new drugs are approved for pediatric indications.⁸ For agents that do eventually get approved to treat pediatric tumors, the average period is 6.5 years from approval in the adult indication to approval for children—at least for those agents available in both settings.

Day One was founded to address that unmet need and to develop new medicines for patients living with life-threatening diseases of all ages—not just adults, not just pediatrics—but we do have a specific focus on pediatric populations. Now, in the brain tumor setting, there are profound unmet needs and again, very few approved therapies.

Most patients that are treated for pediatric brain tumors are in clinical trials because there aren't existing therapeutic options that are effective. And we think there are real opportunities to improve patient outcomes in brain tumors in children who have identifiable driver mutations that can be targeted through novel programs like ours. That includes the most frequent brain tumor in children—which is low-grade glioma—and that's the lead indication for our most advanced program, which is tovorafenib. That product is a type II pan-RAF inhibitor; 70% of low-grade glioma patients who are children have tumors that are driven by changes in the RAF molecule, which we hope our [therapy] can address.

AJMC: Can you discuss the challenges of conducting clinical trials with children?

Bender: The challenges are quite significant to doing a clinical trial in children, and they come in several different ways. One is just the patient population; you’re talking about relatively rare tumors, fortunately, but that means that identifying patients so that you can get a sufficient number to have a reliable clinical trial, and results from that clinical trial can be a challenge.

The second challenge is that historically, there have been concerns about potential safety effects for new drugs, or new agents in development. And that's led regulators, both here in the United States and outside the United States, to typically require that new [therapies] go first into adults where they can be evaluated for safety in early clinical trials, before they can be tested in children. That can create a delay as well. And then the final reason that it's challenging is just that there are fewer examples of companies that have conducted company sponsored clinical trials and have developed relationships and with sites that can help run those clinical trials. So, the experience that is evident in the adult oncology world with running those trials is just not as apparent—and the resources available to investigators, to sites, and to companies that are running those trials are fewer.

AJMC: Can you discuss the FIREFLY-1 trial?

Bender: FIREFLY-1 is a phase 2, single-arm, open-label study, where we're looking at the use of monotherapy tovorafenib in relapsed and refractory or progressive pediatric, low-grade glioma patients. These are patients that have gone through a prior systemic therapy and their tumors have continued to grow. They need an additional therapy. The trial is focused on those patients within that group that have tumors that are driven by RAF alterations, and that’s because we have a RAF inhibitor that we're testing in these patients.

The study started enrolling patients in the second quarter of 2021, and we are now fully enrolled in the study, which has a total of 77 patients. We’ve released some interim results from the first cohort of patients—the first 25 patients last June; more recently, in January, on the full 77 patients that had been followed for at least 6 months after enrolling in the trial.⁹

AJMC: What are the next steps before filing a New Drug Application (NDA)?

Bender: An important element of treating these patients and seeing them improve over time is not just to see an initial response or stabilization in their tumor, but for that stabilization to persist over time—to be durable. So, we're continuing to follow these patients…. [If talks with FDA proceed positively], we’re assuming that we will file the NDA in the first half of the year. The FDA will be evaluating not just the efficacy that we've seen in terms of responses, but also the durability of those responses, as well as the safety profile of the agent and whether the agent has been tolerable for patients—meaning, whether being able to stay on therapy has been viable based on the overall side effect profile.

AJMC: So, you examining whether the FDA would be amenable to the accelerated pathway versus the traditional pathway?

Bender: Yes, that’s right. The default assumption for us is that it'll be an accelerated approval on the basis of FIREFLY-1. There are other scenarios where we could envision a different pathway for approval, potentially full approval, but the default is accelerated approval because we have a single-arm study. What we're seeing so far in the clinical results is a data package that looks to be consistent with clinical benefit for a patient population like this—relapsed, progressive pediatric low-grade glioma that has very few treatment options and for which there's significant unmet need. There's certainly the potential for an approval on the basis of a non-randomized or single-arm study.

AJMC: In talking to parents of children with low-grade glioma, a key concern they have about chemotherapy is long-term adverse effects, particularly cardiotoxicity. What are some of the potential safety advantages of tovorafenib compared with traditional treatments?

Bender: The only clear standard of care today for children who have a low-grade glioma, and this is just in the frontline setting, is chemotherapy. The duration of chemotherapy that can be administered for children is limited, because of the toxicities. So those toxicities include bone marrow suppression, they include cardiotoxicity, and a whole host of other of other AEs, or safety considerations, [that are more serious] that we’ve seen with tovorafenib. We’re hopeful that we'll have an agent that can be used for much longer periods of time to keep the tumor in check than you can with chemotherapy. And we're hopeful that there won't be the same kinds of long-term side effects that you see with those chemotherapeutic regimens.

Those long-term side effects can include changes in growth and metabolism, secondary malignancies at times, certainly long-term cardiovascular toxicity—in particular, heart attacks. In tovorafenib, there are safety effects, but they’re less frequent and they're less severe than what you see with chemotherapy. The most significant side effect, and the one that we try to manage actively in our clinical trials, is some skin rash. And that's been fairly manageable for most patients, and there are other safety effects that occur in smaller numbers. But that's the major one that we look to address. We don't yet know whether there could be long-term side effects associated with the treatment with tovorafenib. We're hopeful that there would not be, but of course, we would need to continue monitoring patients.

References

1. Brain tumor: types of treatment. Cancer.net. Updated September 2021. Accessed May 5, 2023. https://www.cancer.net/cancer-types/brain-tumor/types-treatment
2. Childhood cancer facts—United States. Alex’s Lemonade Stand. Accessed May 5, 2023. https://bit.ly/3LXURH0
3. Day One announces abstracts accepted for presentation at the 2023 American Society of Clinical Oncology (ASCO) annual meeting. Globe Newswire. Published April 26, 2023. Accessed May 5, 2023. https://bit.ly/3nA8aUF
4. Tkacik E, Li K, Gonazles-Del Pino, G, et al. Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib. J Biol Chem. 2023;299(5):104634. doi: 10.1016/j.jbc.2023.104634.
5. Day One announces topline data from pivotal phase 2 FIREFLY-1 trial demonstrating meaningful responses with tovorafenib (DAY101) in recurrent or progressive pediatric low-grade glioma. News release. Day One Biopharmaceuticals. January 8, 2023. Accessed May 5, 2023. https://bit.ly/3GR401w6.
6. Liu APY, Hastings C, Wu S, et al. Treatment burden and long-term health deficits of patients with low-grade glioma or glioneuronal tumors diagnosed during the first year of life. Cancer. 2019;125(7):1163–1175. doi: 10.1002/cncr.31918
7. The FIREFLY-2 Trial. Day One Biopharmaceuticals. Accessed May 5, 2023. https://www.dayoneclinicaltrials.com/the-firefly-2-trial/
8. Novel drug approvals for 2022. FDA newsroom. Updated January 10, 2023. Accessed May 5, 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022
9. Kilburn L, Landi D, Leary S, et al. CTNI-68. FIREFLY-1 (PNOC026): phase 2 study of pan-RAF inhibitor tovorafenib in pediatric and young adult patients with RAF-altered recurrent or progressive low-grade glioma or advanced solid tumors. Neuro-oncology. 2022;24(7):vii89. https://doi.org/10.1093/neuonc/noac209.333