Entrectinib produces rapid and durable responses in children with refractory CNS and solid tumours

Medical writer: Jasenka Piljac Žegarac, PhD

Entrectinib, an oral inhibitor of TRKA/B/C, ROS1, and ALK tyrosine kinases and a central nervous system (CNS)–penetrant, was well tolerated and produced rapid and durable responses in patients with refractory CNS and solid tumours harboring NTRK1/2/3, ROS1, and ALK fusions, as well as in a patient with ALK-mutated neuroblastoma (Abstract 10009).

“Entrectinib is extremely promising in its anti-tumour activity and progression-free survival, and, because there were no responses in nontarget patients, this study now remains open but only for patients with target gene fusions,” Giles W. Robinson, MD, of St. Jude Children’s Research Hospital, said during an Oral Abstract Session on June 2.

Entrectinib has shown efficacy in several prior phase I (STARTRK-1 and ALKA-372-001) and phase II (STARTRK-2) trials of patients with NTRK fusion–positive solid tumours. In May 2017, it was granted a Breakthrough Therapy Designation by the U.S. Food and Drug Administration for use in adult and pediatric patients with NTRK-positive solid tumours who have either progressed following prior therapies or who are left with no other treatment options.

Dr. Robinson presented the results of a phase I/Ib trial of the agent, which enrolled 29 pediatric patients, age 20 or younger, with recurrent/refractory solid or CNS tumours—16 in the dose-finding phase and 13 in phase Ib who received 550 mg/m²entrectinib daily. The median age of enrolled patients was 7 (range 0-20), and 51.7% (15) were male. Sixteen patients had neuroblastoma, six had sarcoma, five had high-grade glioma, and one had melanoma or CNS embryonal tumour, respectively.

“About half of the population had fusions and alterations, and about half of the population did not,” Dr. Robinson said, adding that “these are heavily pre-treated patients who have received chemotherapy, radiation therapy, and a variety of other therapies, even immunotherapy and some targeted therapy.”

Patient responses were evaluated according to the response assessment in neuro-oncology (RANO) criteria for CNS tumours, RECIST for solid tumours, and Curie score for neuroblastoma. October 31, 2018, was the data cut off.

Measurable and durable responses were attained in both extracranial solid and CNS tumours. The main takeaway of the trial, Dr. Robinson said, was that “if you have a fusion, then you are likely to respond,” and “once [the patients have] responded, they continued to maintain that response for long periods of time afterward.” He also noted that “75% of these patients still continue therapy and still continue to derive a benefit.”

Dr. Robinson specifically emphasized the responses achieved in five patients with high-grade glioma who were enrolled in the study because they had different NTRK1 and ROS1 fusions.

“What I hope you can see is that the burden of disease starts very high at baseline and then decreases over time, and then, in certain patients, it actually disappears over time,” he said. “These patients [had] high-grade gliomas, and high-grade gliomas at relapse are universally fatal.

“The median duration of response was 56 days for the patients who did not respond and 281 days and counting for the patients who did respond,” he continued, noting that entrectinib was very well tolerated overall. Dose-limiting toxicities included elevated blood creatinine, dysgeusia, and pulmonary edema, which were reversible upon dose interruption and/or reduction, he said, adding that “there were no deaths related to this drug.” According to Dr. Robinson, weight gain was an interesting treatment-related adverse event and the most common reason for dose reduction.

Daniel A. Morgenstern, MBBChir, PhD, of the University College London, United Kingdom, was the discussant for the abstract. Despite very promising results outlined by Dr. Robinson, he noted that many questions remain regarding the use of TRK inhibitors, such as entrectinib and larotrectinib.

“One of the key questions is how we are actually going to identify patients to treat with these inhibitors,” he said. The other unanswered questions Dr. Morgenstern raised related to the duration of treatment after achieving a complete response, the drug’s long-term effects, especially on neurodevelopment, and the potential incorporation of TRK inhibitors into the upfront treatment.

“Clearly there are more data that we need to collect about the potential long-term toxicity of these agents, even though the short-term toxicity, so far, looks very good,” he said.



Posted on 15 July 201923 April 2024