Dr Kelly on the Evaluation of the Combination of Ripretinib and DCC-3116 in GIST

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 novel therapeutic agent, DCC-3116, which is an ULK1/2 kinase inhibitor, she explains.

The rationale for investigating this combination in patients with GIST stems from preclinical data, which have shown that the 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 induced by targeted therapies, such as receptor tyrosine kinase inhibitors of the RAS/MEK/MAPk pathway, according to Kelly. Essentially, autophagy can serve as a protective mechanism for GIST cells when they are subjected to these therapeutic pressures, 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 aims to make GIST cells more susceptible to treatment, Kelly explains. In preclinical models of GIST, the combination of ripretinib and DCC-3116 was shown to be highly effective, leading to complete tumor regression, she notes. These results have paved the way for the ongoing phase 1/2 clinical trial, she states.

Researchers and clinicians are eagerly anticipating the outcomes of this study, as its investigative combination represents a novel therapeutic approach for treating patients with advanced GIST, Kelly reports. Should the trial demonstrate similar efficacy in humans as seen in preclinical models, it could offer a significant advancement in the management of this challenging disease, Kelly concludes.