‘Striking’ Responses in Pediatric Solid Tumors With Entrectinib

In Clinical Trials by Barbara Jacoby

By: Nick Mulcahy

From: medscape.com

The investigational oral therapy entrectinib (Genentech/Roche) produced “striking, rapid, and durable” objective responses in children with recurrent/refractory central nervous system (CNS) and solid tumors harboring a range of target gene fusions, said Giles Robinson, MD, pediatric neuro-oncologist, St Jude Children’s Research Hospital, Memphis, Tennessee.

The median age of these patients was 7 years old.

Robinson discussed “very promising” phase 1/2 study results with entrectinib with reporters during a press-cast that precedes presentation of the trial at the American Society of Clinical Oncology (ASCO) 2019 meeting in Chicago, Illinois.

During the press-cast, he showed scans from four study patients with high-grade gliomas, which are “universally fatal.”

“It gives me great pleasure as a pediatric brain tumor doctor to show you intracranial responses to this medicine,” he said.

“You can watch these tumors basically disappear or at least reduce significantly in size,” he observed while displaying a series of progressive scans.

Entrectinib is an oral inhibitor of tropomyosin receptor kinase (TRK), ROS1, and ALK tyrosine kinases, which penetrate the central nervous system (CNS).

It’s been established in the last few years, said Robinson, that these fusions act as “drivers” in some cancers, generating proteins that are “locked in the on position” and continuously drive tumor cell proliferation.

In the trial, responses to entrectinib were seen in 12 of the 28 evaluable patients. The 12 responses were among patients who had fusions in NTRK1/2/3, ROS1, or ALK genes (11 patients) or an ALK mutation (one patient). No responses were seen in tumors lacking aberrations in target fusions, a key insight that has led investigators to proceed in only enroling new patients with those fusions.

Median duration of therapy for confirmed fusion-positive responders was 10.5 months (3.8 to 17.7 months), and median time to response was 1.9 months (1 to 1.9 months).

The variety of solid tumors that responded, which included high-grade gliomas, three types of sarcoma, as well as a CNS embryonal tumor and a melanoma, is a source of satisfaction, suggested an expert.

The results are “yet another example of tumor-agnostic precision medicine therapy,” said Monica Bertagnolli, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and ASCO president. She hopes that eventual final results will reflect what has been seen in this early study.

The variety of targetable tumors was thrilling for investigator Robinson.

“What got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations,” he said.

But there is more good news: the list of potentially treatable tumors is growing as investigators do next generation sequencing outside the trial in a widening number of cancers.

“These fusions are coming out in tumors that we didn’t expect to see before,” he said.

Entrectinib belongs to the same class of drugs as larotrectinib (Vitrakvi, Bayer/Loxo Oncology), which has activity that is limited to NTRK1/2/3 but has nevertheless been hailed as a “game changer” for patients with tumors with those fusions.

Which drug would be better for patients with NTRK1/2/3 fusions?

Vivek Subbiah, MD, pediatric oncologist, MD Anderson Cancer Center, Houston, Texas, said that’s not currently known.

“It is difficult and not appropriate to make cross-trial comparisons given that this is an early phase trial, with different dosing levels and different eligibility in heterogeneous populations,” said Subbiah, who is not involved with these studies, when asked for comment.

Study Details

The new data on entrectinib come from the STARTRK-NG trial, an open-label dose-escalation and expansion study evaluating the safety and efficacy of the agent in children and adolescents with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1, or ALK fusions.

Entrectinib was well tolerated, said investigators. Dose-limiting toxicities were elevated creatinine, dysgeusia, fatigue, and one incidence of pulmonary edema.

In terms of complete and partial responses (CR and PR), in CNS tumors (n = 6), all were high-grade with gene fusions: one patient achieved a CR (ETV6-NTRK3); three achieved a PR (TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); one achieved an unconfirmed PR (GOPC-ROS1); and one has yet to be evaluated (KANK1-NTRK2).

In extracranial solid tumors (n = 8), six patients had a fusion, of whom one achieved a CR (DCTN1-ALK) and five achieved a PR (TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3).

In neuroblastoma (n = 15), one patient achieved a CR (ALKF1174L ). Median duration of therapy was 85 days for all patients, 56 days for nonresponders, and 281 days for responders.

The “take-away point” about the responses is that those with tumor shrinkage stayed on study much longer than those who did not have shrinkage, said Robinson.

The FDA recently granted priority review for entrectinib for pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have progressed following prior therapies or as initial therapy when there are no acceptable standard therapies, and for metastatic ROS1-positive nonsmall cell lung cancer.

The study was sponsored by and received funding from Roche. The study design and conduct were also supported by Alex’s Lemonade Stand Foundation Center of Excellence. Robinson has reported serving as a consultant/advisor for Eli Lilly and receiving research funding from Novartis, Genentech/Roche, and Novartis. Study authors include employees of Roche.