Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center, discusses the evaluation of DCC-3116 in combination with ripretinib (Qinlock) in patients with advanced gastrointestinal stromal tumor (GIST) in a Phase 1/2 clinical trial (NCT05957367).

This trial is enrolling patients with advanced disease who have not previously received treatment with ripretinib, Kelly begins. It is investigating the effectiveness of combining ripretinib with a new therapeutic, DCC-3116, a ULK1/2 kinase inhibitor, she explains.

The rationale for investigating this combination in patients with GIST lies in preclinical data that have shown that activation of ULK1/2 leads to the initiation of autophagy, Kelly continues. Autophagy is a process that cells use to survive under stress, including the stress caused by targeted therapies such as receptor tyrosine kinase inhibitors of the RAS/MEK/MAPk pathway, Kelly says. Essentially, autophagy may serve as a protective mechanism for GIST cells when they are subjected to this therapeutic pressure, allowing them to adapt and potentially resist treatment, she adds.

DCC-3116 is designed to inhibit ULK1/2 kinase activity, thereby suppressing autophagy, Kelly says. By blocking this adaptive stress response, the drug is designed to make GIST cells more susceptible to treatment, Kelly explains. In preclinical GIST models, the combination of ripretinib and DCC-3116 proved highly effective, leading to complete tumor regression, she notes. These results have paved the way for the ongoing Phase 1/2 clinical trial, she explains.

Researchers and clinicians are eagerly awaiting the results of this study because their experimental combination represents a novel therapeutic approach for treating patients with advanced GIST, Kelly reports. If the study shows similar efficacy in humans as in preclinical models, it could represent a significant advance in the treatment of this difficult disease, Kelly concludes.