Updated results from two Phase 1 trials of entrectinib, an investigational, orally available, CNS-active tyrosine kinase inhibitor targeting tumours that harbour TRK, ROS1 or ALK fusions—have been published in the journal Cancer Discovery.

The studies showed entrectinib to be well tolerated, with responses observed in non-small cell lung cancer (NSCLC), colorectal cancer, mammary analogue secretory carcinoma (MASC), melanoma and renal cell carcinoma as early as four weeks after first treatment and lasting as long as 2.5 years and still ongoing.

Entrectinib is currently being studied in a separate registration-enabling global Phase 2 basket clinical trial known as STARTRK-2.

“These studies show promising potential for entrectinib in both TRK- and ROS1-driven tumours. The anti-tumour activity seen across cancer types and entrectinib’s ability to treat bulky CNS disease, particularly important given the propensity for many solid tumours to metastasize to the brain, is extremely encouraging,” said Alexander Drilon, M.D., Memorial Sloan Kettering Cancer Center, one of the lead co-authors on the paper. “In addition, these studies emphasise the utility of basket clinical trials that focus on molecular selection, independent of tumour histology, particularly in NTRK gene fusions, which are detected across multiple cancer types.”

Dr Drilon last spoke with ecancer at AACR 2016, in which the first results of entrectinib were announced.

Entrectinib demonstrated robust anti-tumor activity in both studies across the twenty-five patients who harbored recurrent gene fusions involving NTRK1/2/3, ROS1 or ALK, had not received prior TKI treatment targeting these fusions and were treated at doses that achieved exposures consistent with the recommended Phase 2 dose of 600 mg of entrectinib daily.

A median duration of response of 17.4 months and 7.4 months was seen for ROS1 and ALK-rearranged cancers, respectively.

Among 13 patients with ROS1-rearranged NSCLC, the median duration of response was 17.3 months

In three NTRK1/2/3-rearranged solid tumours (NSCLC, MASC and colorectal cancer) with RECIST-measurable disease, the objective response rate (ORR) was 100%, including complete resolution of brain metastases in the patient with NSCLC.

An additional patient with an NTRK1-rearranged glioneuronal tumour experienced 60% reduction in tumour burden by 3-dimensional volumetric assessment (stable disease by RECIST, which is not validated for primary brain tumours).

Entrectinib was well tolerated, with no responding patients discontinuing the study due to adverse events and no evidence of cumulative toxicity, renal or hepatic toxicity, or QTc prolongation.

The majority of treatment-related adverse events (AEs) were Grade 1 or 2 in severity; Grade 3 events were reversible with dose modifications.

Only one Grade 4 and no treatment-related Grade 5 AEs were reported across the two studies.

“Entrectinib remains the only TRK inhibitor to have published data demonstrating RECIST responses in NSCLC and in patients with cancer in the CNS. Additionally, the impressive response rate of 85% and median duration of response of 17.3 months observed in ROS1-fusion positive NSCLC are comparable to those seen with crizotinib, the only currently approved treatment for ROS1 positive NSCLC, but with the added benefit of robust CNS activity.”said Jonathan Lim, M.D., Chairman and CEO of Ignyta, the company producing entrectinib.

Source: Cancer Discovery & BusinessWire