Clinical Testing of Pan-TRK Inhibitor Progresses Across Multiple Tumor Types

Ariela Katz
Published: Monday, Feb 12, 2018
Dr Alexander Drilon
Alexander Drilon, MD
The pan-TRK inhibitor entrectinib (RXDX101) is being tested simultaneously in multiple locally advanced or metastatic solid tumor types as a treatment for patients harboring fusions involving the NTRK1/2/3, ROS1, or ALK genes.

The phase II, multicenter, STARTRK-2 basket trial (NCT02568267) stratifies patients based on their tumor type and genetic fusion. In 2 prior phase I trials, investigators tested entrectinib for safety and efficacy and demonstrated robust activity in multiple tumor types. The trials showed that the drug was well tolerated, with generally reversible and manageable low-grade adverse events (AEs).1

In all, STARTRK-2 consists of 9 arms in which patients will receive single-agent entrectinib therapy. There are 3 arms for non–small cell lung cancer (NSCLC): 1 each based on whether the patient has an NTRK1/2/3 or ROS1 rearrangement, or either ALK– or ROS1–rearranged disease with central nervous system (CNS)-only progression. There are 3 arms for metastatic colorectal cancer (CRC) and 3 for other solid tumors, with patients assigned to arms within each tumor type based on whether they have NTRK1/2/3, ROS1, or ALK rearrangements (FIGURE).


Figure. Entrectinib in Solid Tumors With NTRK1/2/3, ROS1, or ALK Gene Fusions

Additionally, investigators are allowing patients with CNS involvement, including leptomeningeal carcinomatosis, that is either asymptomatic or previously treated and controlled. This is because entrectinib has demonstrated active coverage of the CNS, according to Alexander Drilon, MD, a medical oncologist and principal investigator for STARTRK-2 at Memorial Sloan Kettering Cancer Center in New York, New York. One patient with SQSTM1-NTRK1-rearranged lung cancer achieved a complete CNS response, and entrectinib was identified as a CNS-penetrant drug.1

Another TRK inhibitor, larotrectinib (LOXO-101), has also shown penetration of the CNS. In a phase I trial of adult patients, 1 patient with TRK fusion–positive NSCLC had regression of a nontarget lesion in the brain.2 Additionally, in a pediatric phase I study, 1 patient with TRK fusion–positive glioblastoma multiforme who had failed multiple treatments demonstrated a radiographic and clinical response with larotrectinib.3

Entrectinib is an ATP-competitive tyrosine kinase inhibitor (TKI) that has demonstrated low to subnanomolar efficacy against 5 kinases: TRK A, B, and C; ROS1; and ALK. Rearrangements of NTRK1/2/3, the genes that encode the TRK proteins, as well as ROS1, and ALK rearrangements occur in multiple types of cancer, especially some less common malignancies, such as glioblastoma, Spitz melanoma, cholangiocarcinomas, and papilloma thyroid cancer. The drug also is active at low nanomolar concentrations, allowing for once-daily administration to patients with the relevant gene fusions.1

Notably, STARTRK-2 will include patients with pancreatic and neuroendocrine tumors, which are notoriously difficult disease types to diagnose and treat effectively, especially in the metastatic setting. In an earlier study, entrectinib demonstrated prolonged stable disease in a patient with ROS1-rearranged pancreatic cancer.4

In October, promising results for entrectinib were presented for patients with ROS1-positive NSCLC at the World Conference on Lung Cancer.5 In this trial, the objective response rate (ORR) with entrectinib was 68.8% by blinded independent central review (BICR), which included 2 complete responses (6.3%). Entrectinib also demonstrated an intracranial ORR by BICR of 83.3% for those with measurable CNS lesions at baseline (95% CI, 35.9%-99.6%).

In combined results from 2 phase I trials, entrectinib demonstrated similar efficacy.1 Of the 119 patients in the trial, the most common tumor types were NSCLC (60%) and gastrointestinal cancers (15%). Patients in this analysis were not all specifically selected based on mutation status, with 60 having a gene rearrangement in NTRK1/2/3, ROS1, or ALK, with 30 meeting the criteria for the phase II study and 25 evaluable for efficacy.1

Of those with NTRK alterations (n = 3), the ORR was 100% (95% CI, 44%-100%). In patients with ROS1 rearrangements, the ORR was 86% (95% CI, 60%-96%), which included 2 complete responses. In the ALK-rearranged cohort, the ORR was 57% (95% CI, 25%-84%).

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