Entrectinib Effective across NTRK Fusion–Positive Cancers

Entrectinib (Ignyta) may be an effective therapy for patients with multiple types of NTRK fusion–positive solid tumors with and without brain metastases, according to findings presented at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany, in October. In a combined analysis from phase I and phase II trials, more than half of patients responded to the drug.

Entrectinib targets tropomyosin receptor kinases (TRKA/B/C) overexpressed by cancer cells with NTRK1, NTRK2, and NTRK3 fusions, and also targets ROS1 and ALK gene fusions. Results from the phase I ALKA-372-001 and STARTRK-1 trials demonstrated that the drug was well tolerated and active in patients with tumors harboring any of the five gene fusions. However, only four patients with NTRK fusion–positive tumors were evaluated in those trials. “We had a very small subset of patients from each, just to demonstrate this was possible—it was the proof of concept that this drug was active,” said Robert Doebele, MD, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, who coauthored the paper.

To further investigate entrectinib in patients with NTRK fusions, Doebele and his colleagues combined findings from the ALKA-372-001 and STARTRK-1 trials with data from the phase II STARTRK-2 trial. The pooled analysis, which was presented at the ESMO Congress, included 54 patients with 10 types of advanced or metastatic NTRK fusion–positive solid tumors who had not previously received a TRK inhibitor. Eleven of the patients had brain metastases.

Patients had an objective response rate (ORR) of 57.4%, with responses across all 10 cancer types. After a median follow-up of about 13 months, the median duration of response (DoR) was 10.4 months, the median progression-free survival (PFS) was 11.2 months, and the median overall survival was 20.9 months. Patients with brain metastases had an ORR of 54.5%.

“This drug is very active in NTRK1/2/3 fusions across broad tumor types and penetrates adequately into the brain and shrinks tumors at about the same rate as it does systemically,” said Doebele. “The next step is really completing the enrollment of the trial and seeking FDA approval.”

Doebele noted that entrectinib is also being developed for ROS1 fusion–positive cancers. At the 2018 World Conference on Lung Cancer in Toronto, Canada, he presented data showing that patients with ROS1 fusion–positive non–small cell lung cancer treated with the drug had an ORR of 77.4%, a median DoR of 24.6 months, and a median PFS of 19 months. Additionally, patients with brain metastases had an ORR of 55%.

Trever Bivona, MD, PhD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, who has not been involved in entrectinib research, said that the clinical data for entrectinib in NTRK fusion–positive cancers are strong. However, he questioned whether entrectinib can compete with the pan-TRK inhibitor larotrectinib (LOXO-101; Loxo Oncology), which is further along in development and seems more potent and selective, with milder side effects.

“If you're the oncologist, you're going to pick the one that you know the most—which is the one that's first out of the gate—and that you know is effective and safe, and so I think at this point you're going to reach for larotrectinib first,” Bivona said. –Catherine Caruso