In short
TRI-611 is an investigational molecular glue degrader that targets anaplastic lymphoma kinase (ALK) fusion proteins, which drive certain lung cancers. It is being studied in a Phase 1/2 clinical trial in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). The trial, authorised in the EU, aims to characterise safety and determine a recommended Phase 2 dose.
Key points
- TRI-611 is an investigational molecular glue degrader of ALK fusion proteins.
- The only registered trial is a Phase 1/2 study in advanced ALK-positive NSCLC.
- The trial is currently authorised and plans to enrol 5 participants.
- Primary outcomes include safety and tolerability, dose-limiting toxicity rate, and objective response rate.
- Preclinical data show activity against drug-resistant ALK and brain metastases in animal models.
What is TRI-611?
TRI-611 is an investigational substance classified as a molecular glue degrader. It is a small molecule designed to bind to anaplastic lymphoma kinase (ALK) fusion proteins and mark them for destruction inside cancer cells. According to a peer-reviewed article in Nature, TRI-611 is described as the first clinical-stage molecular glue degrader targeting an oncogenic gene fusion.
The full name used in the registry is TRI-611. It has no marketing authorisation and is not an approved medicine; it is being investigated in clinical trials for the first time in humans.
How does TRI-611 work?
TRI-611 works differently from standard ALK inhibitors. Instead of simply blocking the activity of the ALK protein, it promotes the proximity of the ALK kinase domain and a cellular machinery component called CRL4 substrate adaptor CRBN. This interaction occurs through a unique degron interface distal from the kinase active site. As a result, the ALK fusion protein is tagged for degradation and broken down by the cell's own protein disposal system.
Because the binding site is distinct from where existing ALK tyrosine kinase inhibitors (TKIs) attach, TRI-611 retains activity against ALK fusion proteins that have become resistant to those drugs. Preclinical studies showed that TRI-611 induces degradation of all forms of ALK fusion proteins, including wild-type and ALK TKI-resistant versions. It also penetrates the brain, which is relevant because ALK-positive NSCLC can spread to the brain.
Which conditions is it studied for?
- Advanced ALK-positive non-small cell lung cancer (NSCLC) — a form of lung cancer driven by a genetic alteration called an ALK gene fusion, in which the cancer has spread or is not curable by surgery. The registered clinical trial of TRI-611 enrols patients with this condition.
How is TRI-611 given?
In the registered trial, TRI-611 is administered orally. The intervention is listed as "Drug: TRI-611 (ORAL)", meaning it is taken by mouth. The trial does not report a specific dose in the registry record; the study is designed to explore different dose levels in its dose-escalation part.
What do the clinical trials show?
One clinical trial of TRI-611 is registered: a Phase 1/2 dose escalation and expansion study in advanced ALK-positive NSCLC. The trial is authorised, meaning it has received regulatory approval to begin enrolling participants. It plans to enrol 5 participants in total.
The trial has two main goals. The first is to characterise the safety and tolerability of TRI-611 monotherapy, including the rate of dose-limiting toxicities (DLTs), and to support determination of a recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). The second is to evaluate antitumour activity using RECIST v1.1, a standard set of criteria for measuring tumour shrinkage. The primary outcome measures include the overall safety profile — assessed by the type, frequency, severity, timing, and relationship to the study drug of adverse events, changes in vital signs, electrocardiograms (ECGs), and safety laboratory tests — as well as objective response rate (ORR), which is the proportion of patients whose tumours shrink, and duration of response (DofR), which is how long that shrinkage lasts.
The trial is interventional, meaning participants receive the study drug rather than only being observed. The registry record does not specify detailed eligibility criteria beyond the condition studied.
What side effects are known?
No side effects of TRI-611 in humans have been reported in the available sources. The registered clinical trial is designed to assess the safety profile of TRI-611, including adverse events and dose-limiting toxicities, but results are not yet available. The preclinical article does not report human side effect data. Because TRI-611 is in early clinical development, its side effect profile in patients is not yet known.