Entrectinib Active Against Cancers With Various Gene Rearrangements

New data indicates that entrectinib has clinical activity in patients with a variety of cancers with gene alterations in NTRK1/2/3, ROS1, or ALK who had never been treated with agents designed to target those alterations.

Updated results from a phase I study (abstract CT007) presented at the 2016 American Association for Cancer Research (AACR) Annual Meeting, held April 16–20 in New Orleans, showed that 79% of patients with extracranial solid tumors were able to achieve a confirmed response.

“Our data show that entrectinib, a potent oral inhibitor of TrkA/B/C, ROS1, and ALK proteins, can achieve rapid and durable responses in patients with a range of advanced or metastatic solid tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions,” said Alexander Drilon, MD, of the developmental therapeutics clinic and thoracic oncology service at Memorial Sloan Kettering Cancer Center in New York, in a press release.

In addition, entrectinib also helped achieve durable responses in primary brain tumors and patient with brain metastases, including one patient who had a complete response.

NTRK1/2/3, ROS1, or ALK are recurrent gene rearrangements that are oncogenic drivers across as many as 30 varieties of cancer. According to Drilon, they have a lower prevalence in some of the more common cancers, such as non–small-cell lung cancer (NSCLC) and colorectal cancer, but have a higher incidence in some rare adult and pediatric cancers. These fusions are currently detectable in clinic using a variety of platforms including FISH, RNA sequencing, and DNA-based next-generation sequencing.

During his presentation, Drilon first gave some background on the early phase evaluations of entrectinib. In September 2015, initial results from the two phase I clinical trials, STARTRK-1 and ALKA-372-001, were reported, establishing 600 mg of entrectinib administered orally once daily as the recommended phase II dose. Data from these two trials also showed an objective response rate of 72% among the 18 patients who met criteria for what was defined as a phase II–eligible population: the presence of NTRK1/2/3, ROS1, or ALK gene fusions in their tumors, no prior treatment with a TrkA/B/C-, ROS1-, or ALK-directed targeted therapeutic, and treatment at or above the recommended phase II dose.

Drilon and colleagues are now reporting updated data for additional patients in the two trials who met the phase II eligibility criteria, as well as updated safety data in additional patients.

In the trial, 80% of patients had tumor regression. Overall, 19 of 24 patients have achieved a confirmed response to entrectinib. According to Drilon, these responses occurred quickly, within 4 weeks, and were durable, with some lasting as long as 2 years.

Responses were seen in a variety of cancers, including NSCLC, colorectal cancer, and mammary analog secretory carcinoma of the salivary gland with NTRK1/2/3 gene fusions; NSCLC with ROS1 gene fusions; and NSCLC and colorectal cancer with ALK gene fusions.

In a subgroup of patients who had ROS1-rearranged cancer, responses occurred in 86% of tumors that had never been treated with a tyrosine kinase inhibitor, including two patients with complete responses. In NSCLC, the overall response rate was 85% with responses in 11 of 13 patients. The longest ongoing response is approaching more than 2 years and 3 months.

A phase II study called STARTRK-2 is currently examining whether these early results can be confirmed in a much large cohort of patients.

This study was funded by Ignyta.