Ashton Leeds, 8, was treated with larotrectinib at Seattle Children’s for thyroid cancer that had spread to his lungs and lymph nodes.

Dr. Doug Hawkins, division chief of Hematology and Oncology at Seattle Children’s, remembers matching one of the first pediatric cancer patients to an experimental drug that targets a specific set of genetic alterations associated with soft tissue tumors. The drug, larotrectinib, is designed to selectively stop the resulting abnormal tropomyosin receptor kinase (TRK) fusion proteins from promoting cancer cell growth.

“I was so excited to share the test results with the family and present them with the option of enrolling in a clinical trial for this new medication,” Hawkins said. “At the time, I had a pretty good inkling the drug was going to work, but there was very limited evidence of its effectiveness in children. It’s incredibly special that families were willing to take a chance on this drug early on.”

Today, the promising evidence in support of larotrectinib is building. A paper published in The New England Journal of Medicine documents the drug’s effectiveness in treating TRK fusion-positive cancers regardless of patient age or tumor type. The paper includes data from 55 patients, ages 4 months to 76 years and representing 17 different TRK fusion-positive tumor types, treated with larotrectinib. Overall, 75% of patients responded to the treatment and at one year, 71% experienced no disease progression since starting treatment.

According to Hawkins, a co-author on the paper led by investigators from Memorial Sloan Kettering Cancer Center, these results provide compelling proof that larotrectinib is incredibly effective and is likely to produce long-lived responses in patients if they have the right target.

Hawkins helped design the pediatric arm of the multicenter phase 1/2 clinical trial in which Seattle Children’s is treating more children with larotrectinib than any other site involved in the trial. Six patients enrolled in this trial, and his team at the Cancer and Blood Disorders Center has treated seven patients.

First drug developed independent of tumor type

After learning he was a candidate, Ashton and his family started making the trip to Seattle Children’s from their home outside Calgary once a month to get larotrectinib.

If larotrectinib receives approval from the U.S. Food and Drug Administration, it will represent the first time a drug is initially approved because it targets a specific molecular change independent of tumor type. Larotrectinib’s maker, Loxo Oncology, is also one of the first to develop a cancer drug, almost in parallel, in adults and children.

Loxo Oncology realized the value the drug provided to pediatric patients at the outset, especially those with infantile fibrosarcoma, a cancer that usually occurs at or shortly after birth. Because virtually all infantile fibrosarcomas have the genetic change larotrectinib treats, the company took several steps to make the drug accessible to pediatric patients at the outset.

First, they developed a liquid formulation of the drug because many children dislike or cannot swallow pills. Second, they established a sophisticated way to measure the amount of the drug in a patient’s body to get the dosing levels right for children. Finally, they worked closely with pediatric cancer research groups across the country to ensure patients could get access to the drug.

Within a year of treating the first adult, the first child was treated with larotrectinib.

“Most drugs aren’t tested in children until they are much further along in the approval process, so including children this early in the process was very unusual,” Hawkins said. “In my mind, this stands as the model for how to work collaboratively with pediatric research groups to develop a drug.”

A dream drug for doctors and patients

Last year, On the Pulse shared how larotrectinib successfully shrank 6-year-old Connor Pearcy’s soft tissue sarcoma tumor below his right knee that had failed to respond to standard chemotherapy and surgery by an astonishing 78% after only two months of treatment. Today, his scans show no tumor at all and he continues to take larotrectinib with no side effects.

Similarly, Ashton Leeds, 8, started taking larotrectinib to treat the thyroid cancer that had metastasized to his lungs and lymph nodes in his neck and chest. Despite undergoing two rounds of aggressive radioactive iodine treatment, the cancer persisted. His lung function suffered, causing him to need continuous oxygen support. As soon as his parents learned that Ashton was a candidate for larotrectinib, they started making the 1,000-mile trip to Seattle Children’s from their home outside of Calgary once a month to get the drug.

Now eight months later, the tumors riddling Ashton’s lungs have nearly disappeared. He no longer needs oxygen support, and he brags to his mom, Kayley Leeds, that he’s now the fastest runner in his class at school.

“We’re so thankful,” Leeds said. “I can’t imagine where we would be without the treatment we got at Seattle Children’s. The drug seems like a dream for both doctors and patients.”

Hawkins acknowledged it is unusual to have a cancer drug that is so effective also be so well tolerated.

“Patients are doing so well on larotrectinib that we really don’t know how long we should treat them,” he said, pointing out that the first adult enrolled in the trial two years ago is still on the medication today.

Next steps for larotrectinib

The key to broader success with larotrectinib is finding the patients with TRK-fusion alterations.

“Only a small percentage of children with cancer will have this genetic change,” Hawkins said. “Now, for those patients this is an incredibly attractive drug, especially if other treatments have already failed.”

As precision medicine approaches like this continue to gather momentum, Dr. Erin Rudzinski, a pathologist at Seattle Children’s and a co-author on the paper with Hawkins, is helping identify which pediatric tumor types are the most likely to harbor TRK fusions, as well as  developing clinically validated diagnostic tests to improve recognition of these tumors. The goal is to rapidly identify TRK-fusions in cases where there is a high likelihood that the result will change the patient’s diagnosis and treatment.

Hawkins and Dr. Katie Albert, the current principal investigator of the larotrectinib trial at Seattle Children’s, are looking ahead to testing larotrectinib as an initial therapy for patients with TRK-fusion positive cancers.

“We’re already asking whether it’s possible to give children this drug before radiation or chemotherapy,” Hawkins said. “That’s really exciting to even consider at this phase.”

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