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Entrectinib induces ‘rapid and durable’ responses in pediatric tumors with gene fusions
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Children with central nervous system or other solid tumors with specific gene fusions responded to treatment with the investigational tyrosine kinase inhibitor entrectinib, according to results of a phase 1/1b trial scheduled for presentation at ASCO Annual Meeting.
All 12 patients who responded to treatment with entrectinib (F. Hoffmann-La Roche) had NTRK1/2/3, ROS1 or ALK gene fusions or an ALK mutation. The responses were “rapid and durable,” according to Giles W. Robinson, MD, a pediatric neuro-oncologist at St. Jude Children’s Research Hospital in Memphis and one of the trial’s investigators.
“Although the target fusions are rare and the chances of finding the fusion may be low, clinicians should be looking for these gene aberrations because the impact of therapy is very promising — especially when alternative treatment options are limited,” Robinson told HemOnc Today.
The STARTRK-NG trial enrolled 29 children (median age, 7 years; range, 4.9 months to 20 years; 51.7% male) with neuroblastoma, CNS tumors or other solid tumors at 21 centers in North America between May 2016 and October 2018.
In the first phase of the trial, Robinson and colleagues sought to determine the optimal dose of entrectinib. They expanded the trial to evaluate patients with tumors that had NTRK1/2/3, ROS1 and ALK gene alterations; 12 of the 29 patients had tumors with NTRK1/2/3, ROS1 or ALK gene fusions or mutations.
The entrectinib dose ranged from 250 mg/m2 to 750 mg/m2 daily in the dose-finding phase 1 portion of the trial. Treatment responses occurred at doses 400 mg/m2. The recommended dose for the phase 1b basket trial portion was 550 mg/m2 daily (n = 7) or 400 mg/m2 daily (n = 6) in patients who could not swallow a capsule.
The median duration of entrectinib therapy was 85 days (range, 6-592), with a median duration of 281 days (range, 56-592) for patients who responded to therapy. The median time to response was 57 days (range 30–58).
Results showed entrectinib was well-tolerated at the recommended dose. Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue and pulmonary edema; weight gain was also noted as an on-target effect of entrectinib.
Twelve of the 28 evaluable patients responded to treatment. All responders had fusions in NTRK1/2/3, ROS1 or ALK genes (n = 11) or an ALK mutation (n = 1).
Among six patients with high-grade CMS tumors and gene fusions, one with an ETV6-NTRK3 fusion had a complete response; three with a confirmed TPR-NTRK1, EEF1G-ROS1 or EML1-NTRK2 fusion achieved partial responses; one with an unconfirmed GOPC-ROS1 fusion had a partial response and one with a KANK1-NTRK2 fusion had not yet been evaluated.
Eight patients with extracranial solid tumors received the study drug; one with a DCTN1-ALK gene fusion achieved complete response and five with other fusions — TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK and ETV6-NTRK3 — achieved partial responses.
Fifteen patients with neuroblastoma were treated with entrectinib, and one with an ALK F1174L gene fusion achieved complete response.
“If you had a fusion, then your tumor was likely to shrink,” Robinson said during a press conference announcing the results.
“I think the biggest surprise for me was the rapidity of response in brain tumors that were very advanced,” he told HemOnc Today. “The impact of the therapy on patients was not subtle and very gratifying.” – by Drew Amorosi
Reference:
Robinson GW, et al. Abstract 10009. Scheduled for presentation at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Robinson reports a consultant/advisory role with Eli Lilly and institutional research funding from Genentech/Roche and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
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Darrell Yamashiro, MD, PhD
There was a remarkable response to entrectinib in this study of children with recurrent or refractory solid or CNS tumors whose tumors had NTRK1/2/3, ROS1 or ALK fusions. All 11 patients with NTRK1/2/3, ROS1 or ALK fusions responded to treatment. This study demonstrates that sequencing of pediatric tumors can lead to highly effective targeted therapy.
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