Targeted Tx Improves Outcomes in High-Risk Pediatric Cancers

Unlike adult cancers, in which targeted therapies have improved outcomes for some patients, the same has not been true for pediatric cancers.

Pediatric oncology is really lagging behind, said Cornelis van Tilburg, MD, PhD, from the Hopp Children's Cancer Center, Heidelberg, Germany.

But new data suggest that children can also benefit from this approach.

Results from the INFORM (Individualized Therapy for Relapsed Malignancies in Childhood) registry show that for children with relapsed/refractory disease who were treated with targeted therapies (directed at molecular targets identified by an algorithm), progression-free survival (PFS) was about 3 months longer than for similar children for whom a target was not available. However, there was no difference in the overall survival (OS) between the two groups. "This is the first time that clinical outcomes in a real-world setting of a large-scale, multinational, personalized pediatric oncology platform was assessed," van Tilburg commented. "Very high priority level targets identified by INFORM provided therapeutic opportunities, such as off-label adult drugs, for subgroups of children.

"Importantly, new diagnostic information could be offered to children and families," he added.

The findings are due to be presented at the plenary session of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, held virtually this year because of the coronavirus pandemic. Van Tilburg offered a glimpse of the results at a premeeting press cast.

"This is a start, and it is so encouraging for pediatric patients in that there are innovative treatments," commented Vivek Subbiah, MD, an associate professor in the Department of Investigational Cancer Therapeutics and clinical medical director of the Clinical Center for Targeted Therapy at the University of Texas MD Anderson Cancer Center, Houston. "It has opened up the landscape in pediatric oncology," he added.

He hopes that in the future, targeted therapy will be used in a less refractory setting. "Genetic testing should be done earlier in the disease process rather than later," he said.

Matched Therapies Improve Outcomes

The INFORM registry was initiated by a consortium of pediatric oncologists and genomics researchers to assess the efficacy of precision medicine–based approaches for pediatric oncology patients with high-risk relapsed or therapy-refractory disease.

At the core of the study was a seven-step algorithm that was developed to prioritize molecular alterations or affected pathways. In theory, these could be targeted by a commercially available drug or an investigational agent. The priority levels were based on several characteristics, including "druggability," genetic change/expression, and direct drug target/pathway activation.

Using this algorithm, van Tilburg and colleagues identified subgroups of patients with genomic or molecular characteristics that were classified on the basis of priority for pairing with a targeted drug. Treating oncologists were able to access the algorithm and could use it when making clinical decisions. INFORM also provided diagnostic information for detecting underlying cancer predisposition syndromes as well as diagnostic refinements in brain tumors.

A total of 1300 patients from 72 centers in eight countries were enrolled. Of this group, 526 completed the follow-up and were included in the analysis. The median age of the patients was 12 years.

Within this cohort, 8% of patients were found to have a very high priority target; 14.8%, a high priority target; 20.3%, moderate priority; 23.6%, intermediate; 4.4%, borderline; 2.5%, low; and 1%, very low; 15.4% had no actionable target.

Overall, 149 patients received targeted therapy that was based on the identified targets. Of this group, 20 patients had a very high priority target (mostly ALK, BRAF, and NRAS mutations and MET and NTRK fusions).

Median PFS for the entire group was 116 days. For the patients who received targeted therapy, median PFS was 204.5 days..

However, there were no clinically relevant differences in OS between the children who received with targeted therapies and the others; the median OS was 289 days.

Identifying Predisposition Syndromes

Possible predisposition syndromes were identified in 7.8% of patients (n = 40). Half of these syndromes were newly diagnosed. Methylation analysis provided a diagnostic refinement in 8% of brain tumors.

This study shows that "pediatric precision oncology in a real-world, multinational setting is feasible," said van Tilburg. "There is an urgent need for biomarker-driven pediatric interventional clinical trials, and further layers of molecular and functional data should be incorporated in future programs."

Opening the Landscape in Pediatric Oncology

Approached for comment, Subbiah noted that for the past 5 or 6 decades, the seminal story in pediatric oncology has been the implementation of cytotoxic chemotherapy. "It took a village — the oncology community came together to make these advances," he said. They have "resulted in the expectation that 4 of 5 children presenting with cancer will survive."

However, a therapeutic plateau has been reached with chemotherapy, he said. Additional refinements with these chemotherapies haven't yielded dramatic benefits.

The cure rates for many pediatric cancers are very high, but relapsed high-risk disease continues to be associated with a poor prognosis. For children with refractory, relapsed, and progressive high-risk malignancies, OS is less than 20% (median survival, 9.5 months).

"The main concern is the relapsed and refractory tumors and bone and soft tissue sarcomas — and to some extent, acute myeloid leukemia," he said.

Up to now, targeted therapy trials have rarely included pediatric patients. "The challenges that plague other diseases when it comes to clinical trials is accelerated in childhood cancers," Subbiah pointed out. "Lack of funding and, to an extent, limited advocacy, small populations, limited number of trained investigators, and rare cancers make a nonviable priority for drug companies."

Next-generation sequencing has opened up precision oncology. "In this context, we have this late-breaking abstract," said Subbiah. "They have real-world evidence data for matching patients to targeted therapies, and in these very high risk patients, they prioritized the targets."

The study was funded by German Cancer Aid, the German Childhood Oncology Foundation, Ein Herz fur Kinder Foundation, and the German Cancer Consortium. Van Tilburg has a consulting or advisory role with Bayer and Novartis; several coauthors have also disclosed relationships with industry, as noted in the abstract. Subbiah has a consulting or advisory role with Helsinn Therapeutics, Loxo, MedImmune, QED Pharma, and R-Pharma-US and has received research funding (institutional) from many pharmaceutical companies.

2020 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA10503

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