The widespread belief that early clinical trials in children are risky “is a misconception that must be changed,” Dr Moreno told Cancer Therapy Advisor.
“Currently, for most adult anticancer drugs, the time span from completion of adult phase 1 studies to initiation of pediatric trials is far too long and this deprives children and adolescents from access to innovative therapies,” Dr Moreno said. “This study shows that, in cases with a robust biological rationale and a high unmet need, drugs can be rapidly translated into pediatric trials and provide benefit to patient populations that have been traditionally excluded from early clinical trials such as infants.”
TRK receptors are involved in brain development and neuronal function — a potential concern for young cancer survivors with years of neurodevelopment ahead of them.
While the study yielded no evidence of neurotoxicities, Dr Moreno noted this that was not particularly surprising, as early-phase trials have a short follow-up period. Long-term follow-up of patients treated with any novel targeted drug is needed when patients have a chance of long-term survival — as is the case with the children in this study.
Animal studies suggest that TRK receptors are primarily involved in brain development in utero, Dr Laetsch noted. “After birth, these functions seem to be more limited, and that follow-up of these patients is ongoing to evaluate for longer term side effects,” he said. A larger proportion of human brain development occurs after birth in humans, however, than in other mammals, and TRK proteins involved in neuronal differentiation might be active in postnatal development of the prefrontal cortex.5
“We are witnessing several examples of very successful drugs targeting oncogenic genomic drivers in early clinical trials, such as ALK, BRAF or TRK,” Dr Moreno said. “Now that these drugs will be given to patients at earlier times in treatment and will give children significant chances of long-term cure, it is crucial to incorporate long-term follow up plans for these patients, including all potential toxicities that could arise.”
Additional trials are already underway.
“There are now ongoing clinical trials to get additional data on the efficacy of larotrectinib in pediatric patients with TRK fusion–positive solid tumors, including both the phase 2 component of the trial we reported, and one arm of the NCI/COG Pediatric MATCH study,” Dr Laetsch said.
“Personally, I also think that larotrectinib should be studied in newly-diagnosed patients with TRK-fusion-positive solid tumors to attempt to spare them the side effects of traditional chemotherapy and the large surgeries that are often required to resect these tumors, especially infantile fibrosarcomas.”
“One of the remarkable things about this study is that only 1 of the 17 children has developed resistance so far,” he said. “In that patient, there was another mutation that developed in the TRK fusion itself that blocked the ability of larotrectinib to bind to the fusion protein and inhibit it. That patient was treated with LOXO-195, a next-generation TRK inhibitor, which can inhibit these resistance mutations, and again had a response to therapy.
“This mechanism of resistance is similar to what has been seen in adult patients. Mutations that block the ability of the TRK inhibitor to bind the fusion protein are found in the vast majority of patients who develop resistance.”
A safety and preliminary efficacy trial of LOXO-195 is underway for patients who develop resistance to larotrectinib or other TRK inhibitors, Dr Laetsch added. Researchers are also evaluating how to quickly detect TRK fusions in tumors in which they are less common.
- Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018 March 29. doi: 10.1016/S1470-2045(18)30119-0 [Epub ahead of print]
- Moreno L. An active drug for TRK-positive paediatric solid tumors. Lancet Oncol. 2018 March 29. doi: 10.1016/S1470-2045(18)30191-8 [Epub ahead of print]
- Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS. Targeting TRK family proteins in cancer. Pharmacol Ther. 2017 Feb 4. doi: 10.1016/j.pharmathera.2017.02.006 [Epub ahead of print]
- Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-9. doi: 10.1056/NEJMoa1714448
- Luberg K, Wong J, Weickert CS, Timmusk T. Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. J Neurochem. 2010;113(4):952-64.