NEW YORK (GenomeWeb) – An interim analysis of the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) study — a precision medicine clinical trial for pediatric cancer — has found that 24 percent of participants are eligible to receive treatment with a targeted therapy, a match rate significantly higher than the 10 percent the researchers expected at the outset of the trial.
The study is the pediatric counterpart to the ongoing NCI-MATCH trial, which began in June 2015 and only accepts cancer patients who are aged 18 years and older. The Pediatric MATCH researchers are aiming to identify the specific genetic alterations occurring in each patient's cancer, match patients to drugs targeted to those mutations, and then evaluate the effects of treatments ostensibly meant for adult patients on pediatric patients.
The interim results were released in the run-up to the American Society of Clinical Oncology's annual meeting in Chicago next month. At a press conference to announce the results on Wednesday, COG Study Chair and Baylor College of Medicine Pediatrics-Oncology Professor Will Parsons said that 422 children, adolescents, and young adults between the ages of one and 21 years old were enrolled in the study between July 24, 2017, and Dec. 31, 2018.
"This is the first nationwide precision oncology trial for children," Parsons said. "We initially projected a match rate of approximately 10 percent, and that was based on our understanding of the genetics of pediatric cancers — largely newly diagnosed cancers — but also the experience with adult-equivalent or similar adult studies."
The pediatric patients were diagnosed with more than 60 different cancers, including 101 patients with various brain tumors, 300 patients with other solid tumors, and 21 patients with lymphomas or rare histiocytic disorders of the immune system. Of the patients with brain tumors, 47 percent were diagnosed with astrocytomas, and osteosarcomas made up the largest group of solid tumor diagnoses with 29 percent of the patients presenting with such a diagnosis.
Of the 422 patients who were enrolled, tumor samples were submitted for 390 of them, and testing was successfully completed on 357 of those. The researchers performed both DNA and RNA sequencing on more than 160 genes in the tumors to identify oncogenic alterations and to see if they could match the patients to one or more of the 10 targeted therapies being studied: larotrectinib (Vitrakvi), targeting NTRK; erdafitinib (Balversa), targeting FGFR; tazemetostat, an experimental drug targeting EZH2 and other genes in the SWI/SNF gene complex; LY3023414, a drug being developed to target the PI3K/MTOR pathway; selumetinib and ulixertinib, investigational therapies targeting the MAPK pathway; ensartinib, targeting ALK or ROS1; vemurafenib (Zelboraf), targeting BRAF; olaparib (Lynparza), targeting defects in DNA damage repair genes; and palbociclib (Ibrance), targeting cell cycle genes.
Parsons noted that the median turnaround time from receipt of the tumor to assignment of treatment was about 15 days.
Of the 390 patients whose tumors were submitted to the researchers, 112 (29 percent) were found to have a targetable genetic alteration such as a mutation, a fusion, or gene copy number, and 95 of the patients (24 percent) were found eligible for assignment to one of the treatment arms. As of the end of 2018, 39 of the patients had actually enrolled in a Pediatric MATCH treatment trial.
Importantly, Parsons noted in his presentation, the researchers detected targetable mutations in 26 percent of the patients with non-central nervous system solid tumors and in more than 40 percent of the patients with brain tumors. In the case of astrocytoma, the study found targetable mutations in 74 percent of patients with that diagnosis and was able to match those patients to nine of the 10 treatment arms.
The data demonstrated that this type of tumor sequencing has utility for both rare and common pediatric cancers, he said. There was also no significant difference in the detection rate between younger and older patients.
The broader implications
The results have implications beyond the immediate treatment of pediatric oncology patients. They also point to a viable strategy for nationwide molecular screening of children with cancer and could lead to a change in how pharmaceutical companies develop and test targeted cancer therapies.
Vivek Subbiah, an associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, told GenomeWeb that he was surprised and encouraged by how much higher the study's actual match rate was compared to its anticipated match rate.
"We have reached a therapeutic plateau with conventional chemotherapy. Further refinements in chemotherapy have not rendered dramatic additional benefits in pediatric cancers and, unfortunately, a subset of pediatric patients with relapsed or refractory disease continue to have poor outcomes," he said. "Pediatric cancer has been, I would say, the stepchild in drug therapies because industry-funded studies of new molecules rarely include pediatric patients. And the pediatric oncology research community has been dogged by lack of funding, lower patient numbers for clinical trial participation, and limited awareness of the benefits of clinical trials."
But, despite these challenges, Subbiah added, he believes the Pediatric MATCH trial will "refresh" the field, providing renewed momentum and energy for COG and other pediatric research groups to work together on new studies and clinical trials, and accelerating close collaboration among academia, industry, regulators, and third party payors "to step up for that stepchild in drug development."
He also noted that the interim results further emphasize the need to sequence every child with cancer. "If you want to win the battle against cancer in children, I think we need to have all the intelligence about that. Even if we don't have drugs today, then we may be developing drugs tomorrow," Subbiah said. "I think [the Pediatric MATCH study] shows that we are able to find actionable aberrations … even in relapsed or refractory patients."
Indeed, the interim results seem to justify the growing popularity of combined DNA and RNA sequencing in pediatric cancer research. In February 2018 at the Molecular Medicine Tri-Conference in San Francisco, University of California, Santa Cruz Biomolecular Engineering Professor David Haussler gave an update on the California Kids Cancer Comparison (CKCC) project, saying researchers had been able to match 100 percent of their samples to possible treatments for the patients using molecular and gene expression data.
Researchers from the University of California, Santa Cruz — which is part of the Treehouse Childhood Cancer Initiative — have developed what they're calling gene expression outlier analysis to see if they can identify overexpressed genes in pediatric cancers that can then be targeted with available cancer treatments.
And at the annual meeting of the American Association for Cancer Research in Atlanta in April, Co-Executive Director of the Institute for Genomic Medicine at Nationwide Children's Hospital Elaine Mardis detailed her center's efforts to combine DNA and RNA sequencing in the clinical cancer care setting in order to help patients.
"For about 25 percent of the kids, we don't find anything informative. But that means we have a 75 percent batting average," Mardis said during her presentation. "The RNA really adds to the batting average, which really adds to my enthusiasm for it."
Subbiah also emphasized that revising the pediatric oncology drug development landscape wouldn't require a complete overhaul of how things are currently done or a slew of new drugs.
"If aberrations are present in children like BRAF or MSI-high, we have drugs for those. The easiest thing would be to rearrange all the drugs that are already ongoing in most cancers," he said. "So, if it's an IV drug, it's easy — we can develop quick dosing schema for the kids. If it's an oral drug, it's important for us to develop oral suspension or liquid formulations so that kids can swallow the medication. One of the major problems we have in oral therapy is that if it's a pill, a small child may not be able to swallow."
The important thing is to get pediatric patients involved in the drug development and clinical trial process much earlier than they are now, he added, so that drug companies can start to take such considerations into account when formulating new therapies.
Parsons said that there are clearly some areas where new therapeutics targeted specifically to the needs of children are needed. "In pediatrics, broadly speaking, we need more targeted therapies to go after some of the more pediatric-specific targets such as these epigenetic changes that we see in pediatric cancers," he noted.
Giles Robinson, a pediatric brain tumor oncologist at St. Jude Children's Research Hospital who had also given a presentation in advance of the ASCO meeting, further noted that deep sequencing studies of pediatric cancers and having a new understanding of the molecular landscape of these diseases have only advanced in the last decade.
"There are many tumors that are being sequenced that either do not have a targeted mutation or don't have really any mutations within the disease where we need to step up and figure things out," he added. "Certainly, we're coming up with some mutations that don't have a target and we would really need pharmaceutical companies to maybe invest some of their resources towards actually going for those targets and those are the epigenetic mutations that are relatively exclusive for some pediatric diseases."
The Pediatric MATCH trial is ongoing. The researchers intend to enroll at least 1,000 participants and are planning to add new targeted therapies to increase the number of matched patients. They're currently developing protocols for four additional drugs.
But Parsons is also starting to think more strategically. "There are several areas in which we've discussed or started to strategize evolution of matches. Obviously, we're looking to continue to add single targeted agents that we'd like to study in kids, as well as, conceivably, combinations of therapies," he said. "The other thing to consider is checkpoint inhibitors or other immune-based therapies. That's something we're actively considering and have been looking at, but there's not been a decision yet about doing that."