Dr Kelly on Ongoing Trials in Patients With GIST

Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center, discusses ongoing trials to further enhance the treatment of patients with gastrointestinal stromal tumor (GIST).

Several ongoing clinical trials are particularly promising for patients with GIST, offering new treatment avenues, Kelly begins. One exciting development came from the 

, where data on 2 pan-KIT inhibitors, NB003 and IDRX-42, were presented, she states. These inhibitors have shown promising clinical activity and have been well tolerated across a broad range of GIST genotypes within the 

-mutant population, according to Kelly. With ongoing expansions in both studies, there is considerable anticipation for further results that could significantly impact treatment strategies for GIST, Kelly explains.

Another critical study is the ongoing phase 3 Peak trial (NCT05208047), which explores sunitinib (Sutent) with or without bezuclastinib (CGT9486) in patients with advanced GIST who have either progressed on or are intolerant to imatinib (Gleevec) in the second-line setting, she continues. Early data from this study have demonstrated promising activity with sunitinib plus bezuclastinib, indicating that this combination could offer a valuable new option for patients with limited treatment choices, Kelly emphasizes. The forthcoming results from the randomized phase 3 portion of the trial are highly anticipated, as they will provide deeper insights into the efficacy of this combination therapy, she states.

Additionally, the phase 2 SARC044 trial (NCT06208748) is examining the same combination of sunitinib and bezuclastinib in patients who have previously progressed on sunitinib, Kelly expands. This combination represents another potential treatment option for those who have exhausted both imatinib and sunitinib, which are standard therapies in GIST management, she notes.

Overall, these trials represent significant advancements in GIST treatment, particularly for patients with limited options after progression on existing therapies, Kelly emphasizes, concluding by stating that results from these studies will be critical in shaping the future of GIST treatment.

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Ciara Kelly, MBBCh, BAO, discusses ongoing trials to further enhance the treatment of patients with gastrointestinal stromal tumor.

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.

Ciara Kelly, MBBCh, BAO, discusses the evaluation of DCC-3116 in combination with ripretinib in advanced gastrointestinal stromal tumor.

Dr Kelly on the Importance of Testing For Genetic Abnormalities in GIST

Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center (MSKCC), discusses the treatment of patients with gastrointestinal stromal tumors (GIST), highlighting the importance of testing for genetic abnormalities and noting how she performs testing in her own clinical practice.

When treating patients with GIST, determining the optimal timing and approach for genetic testing is crucial, Kelly begins. Ideally, tumor sequencing should be performed at baseline, during recurrence, and serially in cases of metastatic disease where TKI therapies are involved, Kelly says. She states that in her practice, she prioritizes sequencing GIST tumors at baseline to identify the specific molecular subtype of the tumor, which informs the initial treatment strategy. Additionally, she noted that she performs sequencing again if there is a recurrence to reassess the tumor’s genetic profile. At certain points during the course of treatment, additional sequencing may also be considered, Kelly reports, especially if the findings may impact decisions regarding treatment adjustments.

The standard approach to molecularly characterizing GIST involves sequencing tumor tissue, a technique that has significantly evolved over the years due to advancements in sequencing technology, she continues. At MSKCC, oncologists utilize a next-generation sequencing platform to achieve precise genetic characterization of GIST tumors, she says. Another emerging sequencing method is circulating tumor DNA (ctDNA) analysis, which detects gene mutations by examining extracellular DNA released by tumor cells, Kelly explains. This technology has gained traction as an FDA-approved companion diagnostic in various cancers and is increasingly being applied to GIST cases as well, she states.

Moreover, ctDNA is becoming more prevalent in clinical trials focused on GIST, providing valuable insights into its effectiveness and utility in this disease, Kelly says. The integration of ctDNA testing into these trials has broadened the understanding of its role in managing GIST, potentially leading to more refined and personalized treatment strategies for patients in the future, she concludes.

Ciara Kelly, MBBCh, BAO, discusses the importance of genetic abnormality testing for patients with gastrointestinal stromal tumors.

Dr Kelly on the Treatment and Heterogeneity of GIST

Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center (MSKCC), 

discusses how the heterogeneity of gastrointestinal stromal tumors (GIST) affects treatment decisions

 and highlights the importance of testing for genetic abnormalities in this patient population.

GIST is defined at the molecular level, with individual subtypes identified based on primary oncogenic alterations in each patient, Kelly begins. Most patients exhibit 

 alterations, which generally respond well to imatinib (Gleevec), she explains. Other patients have 

 alterations, and rarer subtypes of GIST include SDH-deficient GIST, 

-associated GIST, and fusion-driven GIST, Kelly notes.

The primary oncogenic alteration in a patient’s tumor can predict the potential effectiveness of treatments such as imatinib, she continues. Patients with 

-mutated metastatic GIST often develop secondary resistance alterations after exposure to TKIs, Kelly states. Research indicates that there is heterogeneity both between different metastatic sites and within a single metastatic site of GIST, she elucidates.

Regarding patients with GIST harboring genetic abnormalities, Kelly says that ideally, tumors would be sequenced at baseline, upon recurrence, and serially during the progression of metastatic disease treated with TKIs. She goes on to add that in her own practice, she sequences GIST tumors at baseline to determine their molecular subtypes, then again at recurrence. At selected points, Kelly notes that she considers sequencing if its results may influence treatment decisions.

The standard method for molecularly characterizing GIST is tumor tissue sequencing, which has advanced significantly over the years, Kelly reports. At MSKCC, she says that treatment providers use a next-generation sequencing platform, Kelly explains. Circulating tumor DNA (ctDNA) is also becoming popular for identifying gene mutations by analyzing extracellular DNA from tumor cells, which reveals specific mutations, she says. ctDNA sequencing technology is FDA-approved as a companion diagnostic in other cancers and is increasingly used in GIST, according to Kelly. Many GIST trials now incorporate ctDNA technology, providing valuable insights into its utility in this disease, Kelly concludes.

Ciara Kelly, MBBCh, BAO, discusses how the heterogeneity of GIST affects treatment decisions and the importance of testing for genetic abnormalities.

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In today’s episode, sponsored by Aadi Biosciences, we had the pleasure of speaking with Nam Bui, MD, and Ciara Kelly, MBBCh, BAO, about long-term findings from the phase 2 AMPECT trial (NCT02494570) investigating nab-sirolimus (Fyarro) in patients with advanced malignant perivascular epithelioid cell tumors (PEComa). Dr Bui is a sarcoma specialist and a clinical assistant professor of medicine at the Stanford Cancer Institute in California. Dr Kelly is the interim clinical director of the Sarcoma Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.

In our exclusive interview, Drs Bui and Kelly discussed key long-term efficacy and safety findings from AMPECT, how nab-sirolimus performed in patients requiring dose reductions on the trial, and the clinical utility of this agent in all patients with PEComa, regardless of biomarker status.

That’s all we have for today! Thank you for listening to this episode of 

, sponsored by Aadi Biosciences. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Drs Bui and Kelly discuss key long-term findings from the AMPECT trial investigating nab-sirolimus in patients with advanced malignant PEComa.

Bui and Kelly Discuss the Utility of Nab-Sirolimus in Advanced Malignant PEComa

Dr Kelly on the Role of Ripretinib in the GIST Treatment Paradigm

Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center, discusses the current and potential roles for ripretinib (Qinlock) in the gastrointestinal stromal tumor (GIST) treatment paradigm.

 for patients with advanced GIST who progressed on at least 3 prior kinase inhibitors, including imatinib (Gleevec). This regulatory decision was supported by data from the randomized, placebo-controlled, phase 3 INVICTUS trial (NCT03353753), in which ripretinib significantly increased median progression-free survival (PFS) from 1.0 months (95% CI, 0.9-1.7) in the placebo arm to 6.3 months (95% CI, 4.6-6.9; HR, 0.15 [95% CI, 0.09-0.25; 

Additionally, the National Comprehensive Cancer Network Guidelines also currently 

recommend ripretinib for the second-line treatment

 of patients with advanced GIST who are intolerant to sunitinib (Sutent), Kelly adds. This recommendation is supported by findings from the phase 3 INTRIGUE trial (NCT03673501), which evaluated ripretinib vs sunitinib in the second-line setting. For patients in the 

-mutant population, the study’s primary end point was PFS, she notes.

Results showed that the median PFS for patients with GIST harboring only mutations in 

 exon 11 and exons 13/14 was 15.0 months with sunitinib (n = 20) vs 4.0 months with ripretinib (n = 21; HR, 3.94; 95% CI, 1.71-9.11; nominal 

= .0005). Furthermore, PFS outcomes with ripretinib were more favorable than those with sunitinib in patients with mutations in 

 exon 11 and exons 17/18 at 14.2 months vs 1.5 months in the ripretinib (n = 27) and sunitinib (n = 25) arms, respectively (HR, 0.22; 95% CI, 0.11-0.44; nominal 

Importantly, ripretinib was associated with a more favorable safety profile compared with sunitinib, with fewer grade 3 and 4 adverse effects, Kelly continues. Additionally, ripretinib generated better patient-reported outcomes with respect to tolerability, she notes. These findings highlight ripretinib’s value as a treatment option for patients with GIST, particularly those who cannot tolerate other second-line therapies.

Ciara Kelly, MBBCh, BAO, discusses the current and potential roles for ripretinib in the gastrointestinal stromal tumor treatment paradigm.