Gene Rearrangements: Attractive Targets in a Variety of Cancers


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Entrectinib, a potent investigational tyrosine kinase inhibitor, exhibited promising clinical activity in a pooled analysis of two phase I trials of patients with solid metastatic tumors that harbored any of five specific genetic rearrangements involving NTRK1, NTRK2, NTRK3, ROS1, or ALK.


Responses [to targeted therapy] can be dramatic and durable.
— Alexander Drilon, MD

“Alterations called gene fusions involving the NTRK1/2/3, ROS1, and ALK genes are detected in a variety of cancer types. These fusions are ‘tasty’ targets and serve as oncogenic drivers across a variety of cancer types,” said Alexander Drilon, MD, Assistant Attending Physician in the Developmental Therapeutics Clinic and the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, New York.

“These gene fusions are clinically actionable and detectable in the clinic by several techniques, including fluorescence in situ hybridization, RNA sequencing, and DNA-based next-generation sequencing,” he said. “Responses [to targeted therapy] can be dramatic and durable,” he added.

Molecularly Enriched Phase I Trials

Dr. Drilon reported pooled results of two phase I clinical trials—ALKA-372-001 and STARTRK-1—at the 2016 American Association for Cancer Research (AACR) Annual Meeting.1 In a way, these trials are similar to basket trial initiatives, grouping tumors according to molecular characteristics with actionable targets rather than by cancer type.

When first results of the phase I trials were reported in September 2015, the 600-mg/d oral dose of entrectinib was chosen as the recommended phase II dose. At that time, the objective response rate was 72% among the first 18 patients whose tumors harbored NTRK1/2/3, ROS1, and ALK gene fusions, were treated at an appropriate dose, and were naive to treatment with a relevant tyrosine kinase inhibitor.

Dr. Drilon reported updated results in a total of 119 patients on those two trials at the AACR meeting. ALKA-372-001 was a first-in-human trial in 54 patients treated with intermittent and continuous dosing of entrectinib. STARTRK-1 enrolled 65 patients who received continuous dosing only. At baseline, the majority of patients were heavily pretreated with at least four or more prior therapies.

The most common treatment-related side effects were fatigue, dysgeusia, paresthesia, and nausea. “These neurologic side effects are likely on-target toxicities,” Dr. Drilon explained. No renal toxicity, hepatic toxicity, or QT prolongation was observed.

Among the 119 patients, 25 had one of the five gene fusions, were not previously treated with a relevant tyrosine kinase inhibitor, and were treated at the recommended phase II dose. This population represented a “phase II–eligible population.” The remaining 94 patients did not have a gene rearrangement, were previously treated with a targeted inhibitor, or were treated at subtherapeutic exposures.

Key Data

Of the 25 “phase II–eligible patients,” 24 had RECIST-evaluable disease. The overall response rate was 79% (19 of 24) in all patients, with an overall response rate of 100% in those with NTRK1, NTRK2, or NTRK3 gene fusions, 86% in those with ROS1 fusions, and 57% in those with ALK fusions. An additional patient had an NTRK1-rearranged astrocytoma with a 45% reduction in his tumor volume based on volumetric assessment.

Responses occurred early, and clinical benefit was durable. “Response exceeded 6 months in more than 50% of patients, and we have one patient still in response at 2 years and 3 months,” he told listeners.

Entrectinib Under Study

  • Entrectinib is highly active in selected patients whose tumors harbor any of five gene rearrangements (or fusions): NTRK1, NTRK2, NTRK3, ROS1, or ALK.
  • Entrectinib is highly central nervous system–penetrant, shrinking both extracranial and intracranial tumors.
  • This drug will enter a phase II global basket trial.

One patient with metastatic non–small cell lung cancer harboring an NTRK1 gene fusion had several brain metastases. Entrectinib, which was designed to cross the blood-brain barrier, achieved both extracranial and intracranial tumor shrinkage in that patient. His extracranial extent of disease was reduced by 79%, and a durable complete response was achieved in the brain and maintained for more than 10 months.

Dr. Drilon also described a pediatric patient aged 20 months who was treated with entrectinib outside of the clinical trial. This child was diagnosed with an NTRK3-rearranged infantile fibrosarcoma at birth, necessitating amputation below the knee, and later developed metastases to the brain. After 5 weeks of therapy with entrectinib, he had dramatic tumor shrinkage in his brain lesions; concurrently, his alertness increased, and he was able to resume eating and crawling.

Based on these encouraging results, STARTRK-2, a global phase II basket trial, opened in the third quarter of 2015. ■

Disclosure: Dr. Drilon has been a member of the speakers bureau for Ignyta.

Reference

1. Drilon A, DeBraud FG, Siena S, et al: Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naive patients with advanced solid tumors harboring gene rearrangements: Updated phase I results. 2016 AACR Annual Meeting. Abstract CT007. Presented April 17, 2016.


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