Greater Grasp of Pediatric Rhabdoid Tumors Needed to Improve Outcomes

James I. Geller, MD

An improved understanding of pediatric non-brain rhabdoid tumors will not only improve outcomes for this patient population, but could aid in progress for other malignancies, explained James I. Geller, MD.

“There's so much to learn about cancer in general by looking at these rare cancers,” said Geller. “Treating them will benefit not just the [pediatric patients], but others. They really do provide an opportunity for our field to move forward in broad ways.”

Pediatric non-brain rhabdoid tumors account for approximately 30 cases in the United States annually. Work is ongoing to find targetable abnormalities and more effective treatment options for these patients, Geller added.

Patients with stage I/II disease currently have the brightest prognosis, as a curative and multimodal strategy is chemotherapy, surgery, and radiation. For stage III/IV disease, however, this approach is effective in approximately 20% of cases, Geller said.

However, data presented at the 2018 American Society of Pediatric Hematology/Oncology Conference showed that the EZH2 inhibitor tazemetostat has promising antitumor activity in pediatric patients with INI1-negative solid tumors, including rhabdoid cancers.

In the dose-escalation portion of a phase I study, 46 patients were treated with a range of 7 dose levels from 240 to 1200 mg/m² twice daily with tazemetostat. Four patients treated at doses between 520 and 900 mg/m² demonstrated a confirmed objective response.

In April 2018, the FDA placed a partial clinical hold on the entire tazemetostat program after it was released that a patient with poorly differentiated chordoma developed a secondary T-cell lymphoma while on study. In August 2018, Epizyme, the manufacturer of tazemetostat, reported that the company is taking the necessary steps and finishing its formal response to federal regulators to have the hold lifted.

OncLive: What is the prevalence of pediatric renal rhabdoid tumors?

What is the current standard of care for these patients?

Are there any new treatment options being investigated?

In an interview with OncLive^®, Geller, professor of Medicine at the Cincinnati Children’s Hospital, described the ongoing work in pediatric patients with rare rhabdoid tumors.Geller: Rhabdoid tumors, in general, are rare in pediatrics. When we talk about rhabdoid tumors, we talk about them in the kidney and in the brain. For clinical studies, we usually link the brain types on their own, and everything else is put together into a subgroup. When you consider all the ones outside the brain, including renal, there are about 30 cases total in the United States every year. Unfortunately, it is a very aggressive disease, and most children don't survive. We think [this is a population] worth trying to improve outcomes for.The current standard of care for stage I/II disease, based on our most recent clinical trials, is multimodality therapy. Our most recent trial showed that 5-drug chemotherapy with surgery and radiation can cure the majority of those children. For stage III/IV disease, which accounts for about 80% of these cases, the cure rate is about 20%. For those patients, we have not proven that any particular chemotherapy backbone is better than another. Right now, treatment is still surgery, chemotherapy, and radiation. It's just not very effective.At the 2018 ASPHO Conference, Susan N. Chi, MD, presented tazemetostat data, which is very interesting. It is an EZH2 inhibitor. These data show that infants and children with rhabdoid tumors will respond. We have a proposal in place to combine that with chemotherapy. For our most recent [clinical trial], our goal was to accrue 50 patients to improve survival by about 15% overall. We can achieve that in 3 or 4 years.

What is the biggest unmet need for rhabdoid tumors?

We can study this disease and we [will continue to do so]. We think that not only will it improve outcomes for the patients we're directly treating, but we're now finding that it teaches us the biology of cancer, which is relevant to millions of other patients. We are now finding that this INI1 gene, which is the hallmark of a rhabdoid tumor, is involved in a complex that is perturbed in about 20% of all adult cancers. Therefore, what we learn from this rare group may be translatable to a whole larger group. It's a missing piece in cancer care that requires attention and we're going to keep studying it.The biggest unmet need is new drugs; we have identified 1 or 2. For the non-brain ones, we hope to further study this EZH2 inhibitor. For the brain tumors, we can study CDK4/6 inhibitors. Having formulations of these drugs that are suitable to infants is also very important. Having drug companies willing to take the risk is critical. We continue to fight those fights and work with our partners in the industry and regulatory groups, and hopefully, we will be successful.

Chi S, Fouladi M, Shukla N, et al. Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma; and synovial sarcoma. In: Proceedings from the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, Pennsylvania. Abstract 2077.