Entrectinib May Have a Future Beyond Pediatric Relapsed/Refractory Solid Tumors

Ami Vijay Desai, MD

Three patients with targeted gene fusions responded to the multikinase inhibitor entrectinib (RXDX-101), according to results from an ongoing phase I/Ib study of children and young adults with advanced, previously treated CNS tumors.

Lead author Ami Vijay Desai, MD, delivered data from the STARTRK-NG (NCT02650401) trial during the 2018 ASCO Annual Meeting. She believes that, in time, entrectinib could be used in adults and as frontline therapy for pediatric cancers.

“We are hopeful that this drug will bring benefit to the primary brain tumor as well,” said Desai, an assistant professor of Pediatrics at the University of Chicago Comer Children's Hospital. “We do know that this drug penetrates the central nervous system, so we are hopeful that this will improve outcomes for that patient population as well.”

One patient with DCTN1-ALK inflammatory myofibroblastic tumors (IMT) who received entrectinib had a complete response that was ongoing at 10 months. A patient with TFG-ROS1 IMT had a partial response (PR) that was ongoing at 8 months and a patient with EML4-NTRK3 infantile fibrosarcoma experienced a PR ongoing at 2.5 months. Four patients remain on treatment, including 1 with neuroblastoma.

Based on these results, Desai and her colleagues set the recommended phase II dose for children, adolescents, and young adults with solid tumors at 550 mg/m² of daily entrectinib.

Toxicity associated with the drug was similar to what was observed in prior trials involving adults with CNS tumors.

Entrectinib is a selective inhibitor of the tyrosine kinases TRK A/B/C, ROS1, and ALK. The drug crosses the blood-brain barrier, and studies demonstrated clinical activity in adults with primary brain tumors and secondary CNS metastases. Previous studies in preclinical models showed TRKB overexpression was associated with activity against neuroblastoma.

Patients aged 2 to 21 years with recurrent or refractory extracranial solid tumors and primary CNS tumors, with or without NTRK 1/2/3, ROS1, or ALK gene fusions were eligible. These data include findings from 15 patients evaluable for dose-limiting toxicity (DLT) who were treated at entrectinib doses of 250 mg to 750 mg.

Treatment-related adverse events data from adults in previous phase I/II studies were primarily grade 1/2 and reversible with dose modification. Investigators observed 2 DLTs at 800 mg daily in 1 trial: 1 case each of grade 3 cognitive disturbance and fatigue. Both cases resolved following drug interruption.

OncLive: Can you provide some insight into the rationale and design of this trial?

In an interview with OncLive, Desai discussed the ideal patient population for entrectinib and what the future could hold for the agent.Desai: We know there are some myosarcomas and various other types of tumors that do have our gene fusions of interest, and a lot of this initial study was developed due to some preclinical data in the neuroblastoma population also looking at TRKB overexpression and work conducted in the laboratory of Dr Garrett M. Brodeur at the Children's Hospital of Philadelphia.

What are the next steps?

What is the ideal patient population for entrectinib?

Our phase I study followed a 3+3 dose escalation. We investigated 4 dose levels. We were able to escalate to the fourth dose level. At the third level, we did have 1 dose-limiting toxicity of increased creatinine for greater than 7 days. That dose level was expanded. We then went to the fourth dose level where, unfortunately, we had 3 DLTs in 2 out of the 3 patients, and 1 patient had fatigue and dysgeusia for greater than 7 days. The other patient had pulmonary edema. All these DLTs were reversible upon discontinuation of drug, so the third dose level, 550 mg/m², was our recommended phase II dose in the pediatric population.Now that we have the recommended phase II dose, our dose-expansion cohorts are open and the cohorts that we're looking at include patients who have either primary CNS tumors or other extracranial solid tumors that have our gene fusions of interest. Those are the populations we will be focusing on moving forward.NTRK1-3, ROS1, and ALK gene rearrangements are found in similar populations, including some rare sarcomas such as infantile fibrosarcoma [and] inflammatory myofibroblastic tumors. We also know there are some glioblastoma tumors and primary brain tumors that actually have TRK fusions that have been identified as well. Those are potential populations that may benefit from this drug.

Traditionally, some of these patients—such as the rare sarcoma population—may have part of their treatment include surgery, but they may not be able to get to surgery because of their disease burdens, so this drug may help them get to that point. Some of our other patients with brain tumors may [have treatment with] chemotherapy that they may or may not be responsive to as well as surgery.

What other questions are you exploring in this drug?

Entrectinib, by targeting this gene fusion, may help all of these patient populations.What we learned in the phase I study, by looking at the toxicity profile and the safety of the drug, is that entrectinib is very well tolerated. Most toxicities were either grade 1 or 2. The most common toxicity was an increase in creatinine, which we think may be more related to entrectinib inhibiting 1 of the transporters that helps in creatinine excretion and may not truly reflect renal clearance. We don't know that for sure, but that's 1 of the hypotheses.

What are the current treatment options?

Do you have any plans to use entrectinib in the first-line setting?

There was a little bit of nausea—not many neurologic symptoms. That's one concern that comes up when inhibiting TRK A, B, and C. This is a drug that will hit the target but not cause a lot of additional toxicities.Sometimes surgery, if possible, is the best treatment option. There are other inhibitors of some other gene fusions that we find in some of these types of malignancies, so patients can go onto a study for those. There are some options out there but, unfortunately, some patients can't get to the point where they can go on to surgery. Hopefully by reducing disease burden or improving their disease state, they may be able to move on to forms of treatment that may help them with their cancer.We would hope to move this into the upfront setting rather than the relapsed/refractory setting, though we are some time away from that. At this point, it will be perhaps patients who have progressed and are eligible for phase II studies.

Desai AV, Brodeur GM, Foster J, et al. Phase I study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor, in children, adolescents, and young adults with recurrent or refractory solid tumors. J Clin Oncol. 2018;36 (suppl;abstr 10536).