Innovative Research Continues to Propel Individualized GIST Treatments

Recent developments in the gastrointestinal stromal tumor (GIST) treatment paradigm have substantially broadened treatment options for patients at all stages of this disease; however, further research is necessary to continue to make progress in this area, according to Ciara Kelly, MBBCh, BAO.

“With the advancement in technology with respect to molecularly characterizing tumors, including GIST, what I’m hopeful that we will see is greater optimization of treatment decision-making,” Kelly said in an interview with OncLive^® ahead of GIST Awareness Day, which takes place every year on July 13.

In the interview, Kelly, the interim clinical director of the Sarcoma Oncology Service at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York, discussed standard-of-care (SOC) GIST treatment options for patients across all lines of therapy, ongoing trials to keep to watch in the GIST space, and the importance of providing comprehensive supportive care to patients with GIST.

Kelly highlighted data from the phase 3 INTRIGUE trial (NCT03673501), in which patients with GIST harboring only mutations in KIT exon 11 and exons 13/14 achieved a median progression-free survival (PFS) of 15.0 months with sunitinib (Sutent; n = 20) vs 4.0 months with ripretinib (Qinlock; n = 21; HR, 3.94; 95% CI, 1.71-9.11; nominal P = .0005;).¹ PFS outcomes with ripretinib were more favorable than those with sunitinib in patients with mutations in KIT 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 P < .0001).

She also reviewed key updates from the ongoing phase 3 Peak trial (NCT05208047). In part 1 of Peak, sunitinib plus bezuclastinib (CGT9486) generated a median PFS of 10.2 months in patients with GIST, regardless of the number of prior lines of treatment, and a median PFS of 19.4 months in those who received the combination in the second-line setting.²

OncLive: How does the heterogeneity of GIST affect treatment decisions for patients in this population?

Kelly: GIST is a molecularly defined tumor. GIST can be broken down into individual molecular subtypes based on the primary oncogenic alteration evident [in an individual patient]. For example, [most patients] have KIT alterations that are generally sensitive to imatinib. Next, we see PDGFRA alterations. Beyond that, we see more rare subtypes, such as SDH-deficient GIST, BRAF-mutant GIST, and NF1-associated and fusion-driven GIST.

The underlying primary oncogenic alteration may predict the potential efficacy of, for example, imatinib therapy. In the setting of metastatic disease, where patients have been exposed to TKIs, we see the emergence of secondary resistance alterations in the KIT-mutant population. We know from research that heterogeneity is seen both between individual metastatic sites and within a metastatic site.

For patients with GIST, when do you recommend testing for genetic abnormalities, and how do you perform this testing in your practice?

In an ideal world, we would sequence patients’ tumors at baseline, in the setting of recurrence, and serially in the context of metastatic disease where they’re undergoing TKI therapeutics. I personally use sequencing of GIST tumors at baseline to understand the molecular subtype a patient has and then [sequence again] in the setting of recurrence. At selected points in a serial fashion, I will also consider [sequencing] where I feel it may influence treatment decision-making.

The standard methodology used to molecularly characterize GIST remains tumor tissue sequencing. This has evolved over several decades with advancements in sequencing technology. At [MSK], we use a next-generation sequencing platform. Circulating tumor DNA [ctDNA] is growing in popularity as a method of identifying gene mutations by analyzing extracellular DNA released by tumor cells that contain information on specific mutations. This is a technology that is FDA approved as a companion diagnostic in other cancers, and with its more widespread use in the oncology community, it’s being increasingly used in the GIST setting. Many of our GIST trials have also been incorporating this technology, which has helped inform us regarding the utility of [ctDNA] in this disease setting.

Given the data with ripretinib in GIST, how do you see this agent continuing to fit into this treatment paradigm?

Presently, ripretinib was FDA approved in the fourth-line setting for patients with advanced GIST following 3 or more prior lines of therapy, including imatinib. This [approval was] based on [findings from the phase 3] INVICTUS randomized, placebo-controlled trial [NCT03353753] where ripretinib demonstrated an improvement in median PFS at 6.3 months vs 1.0 month for the placebo arm.

Beyond this, the National Comprehensive Cancer Network Guidelines have also incorporated ripretinib as an option to consider for patients who are intolerant to sunitinib in the second-line setting. This [recommendation] is based on the INTRIGUE data. INTRIGUE was a randomized trial evaluating ripretinib vs sunitinib in the second-line setting. In this study, the primary end point was PFS. In the KIT-mutant population, for example, the median PFS was 8.3 months in the ripretinib arm vs 7.0 months in the sunitinib arm. However, it demonstrated was that ripretinib had a more favorable safety profile with a lower incidence of grade 3 and 4 adverse effects compared with sunitinib, and [ripretinib was] also [associated with] better patient-reported outcome measures with respect to tolerability.

In the INTRIGUE trial, how did ripretinib perform in patients with KIT exon 11 plus exon 17/18 mutations?

During the INTRIGUE trial, [investigators] collected ctDNA at baseline from patients enrolled in the study. Investigators then conducted an exploratory analysis to explore the genomic profiles of patients’ tumors at baseline using sequenced ctDNA, and then explore the patient outcomes with treatment. Notably, [among] these baseline sequenced ctDNA-detected KIT alterations, 59% [of patients had] baseline ctDNA [data] available for analysis.

Investigators conducted a mutational subgroup assessment, which identified 2 mutually exclusive populations with differential treatment effects. Patients who were found to have a KIT exon 11 alteration in addition to a secondary resistance alteration in KIT exons 17 or 18 had better PFS outcomes with ripretinib compared with sunitinib. The opposite was observed for patients with KIT exon 11 alterations in addition to KIT exons 13 and 14 alterations, who seemed to have better PFS outcomes with sunitinib compared with ripretinib. These results suggested that ctDNA sequencing may improve prediction of efficacy to single therapeutic drugs in this setting and has led to an ongoing phase 3 study called the INSIGHT trial [NCT05734105] exploring ripretinib vs sunitinib in the second-line setting again, whereby patients are eligible to enroll if they have been deemed to have a KIT exon 11 alteration in addition to KIT exons 17 and 18 alterations on baseline ctDNA analysis.

Although imatinib is the SOC for patients with unresectable or metastatic GIST, given that a proportion of patients will be initially resistant to imatinib, how do you approach treatment for this particular subgroup?

This is probably one of the most challenging areas the sarcoma community faces with respect to the treatment of patients with GIST. Often, imatinib resistance may be due to the underlying molecular subtype that a patient has, where they are known to be resistant to imatinib—for example, the SDH-deficient GIST population. In this setting, we are considering clinical trials for patients. We’ve been fortunate to have some studies in, for example, the SDH-deficient population that we can consider for our patients.

As more information is learned about the genetic differences within the GIST patient population, how do you anticipate treatment continuing to evolve to address these heterogeneous disease types?

With respect to GIST, I hope we will see [improvements in decision-making in] both in the adjuvant and metastatic settings. Colleagues of mine at MSK, Josephine Kam Tai Dermawan, MD, PhD, and Cristina Antonescu, MD, evaluated a cohort of patients with localized, primary gastric and small bowel GIST that had been surgically removed, and they investigated their recurrence-free survival outcomes and genomic profiles. In the setting of patients with localized GIST, where we’re trying to guide treatment decision-making regarding the role of adjuvant imatinib therapy, the risk-stratification models were developed in the pre-imatinib era and focused on clinical-pathologic parameters, such as tumor size, site, mitotic rate, and the presence or absence of tumor rupture at the time of surgery.

My colleagues have tried to incorporate genomic information from the baseline tumor to risk stratify. These data require validation. However, they highlight the potential role for genomic information, even beyond the known primary oncogenic alterations themselves. In the metastatic setting, [they indicate the use of] genomic information to predict efficacy for the individual therapeutics that are available.

What other ongoing trials for patients with GIST are important to highlight?

We’re very fortunate that there are several GIST-specific trials ongoing that patients can be considered for. At the 2024 ASCO Annual Meeting, we saw phase 1 data with 2 pan-KIT inhibitors presented, NB003 and IDRX-42. These appear to have safe toxicity profiles but also promising clinical activity across a broad range of the GIST genotype within the KIT-mutant population. We are excited to see the results that will come from ongoing expansions in both these phase 1 studies.

Going on the idea of evaluating broader coverage of the GIST genomic alterations we can observe, particularly in the KIT-mutant population, we have the ongoing Peak trial investigating sunitinib plus or minus bezuclastinib in patients with advanced GIST in the second-line setting [who have] progressed on or have been intolerant to imatinib. Data from part 1 of this study demonstrated promising activity, and the results of the randomized phase 3 [portion of the] study will be forthcoming, and we are excited to see those data. Also, the [phase 2] SARC044 trial [NCT06208748] will examine this combination in patients who have previously progressed on sunitinib, [providing] another potential option for patients who have progressed on both imatinib and sunitinib.

There is another ongoing phase 1 study [NCT05957367] in the GIST setting for patients with advanced disease who have not been exposed to ripretinib. It’s investigating ripretinib in combination with the novel therapeutic DCC-3116, a ULK1/2 kinase inhibitor. What’s been evident in preclinical data is that activation of ULK1/2 leads to activation of autophagy. This can be an adaptive stress response used by GIST cells in the setting of targeted therapeutics with receptor TKIs for RAS/MEK/MAPk pathway inhibition. DCC-3116 is an inhibitor of ULK1/2 kinases, which can ultimately lead to inactivation and suppression of autophagy. In a preclinical GIST model, the combination of ripretinib with DCC-3116 led to complete tumor regression. The phase 1 study is underway, and we are looking forward to seeing the data from this as a novel combination therapeutic approach to treating patients with advanced GIST.

There have been some studies in the SDH-deficient GIST population. We had the results of the [phase 2 study (NCT04595747) investigating] rogaratinib [(BAY 1163877) in this patient population], which were presented at the 2023 CTOS Annual Meeting, with promising activity and durable control for patients. The study met its primary end point. We also have the more recently presented [data with] olverembatinib [HQP1351] in an SDH-deficient GIST population, again, demonstrating promising activity. [These data will] hopefully lead to a larger phase 3 study to highlight [the efficacy of the agent] in a rarer GIST subtype.

On GIST Awareness Day, what is your message for colleagues about the way the GIST treatment arena has evolved and what the future looks like for improving outcomes for this patient population?

GIST is a rare cancer. It is important that patients are given the opportunity to meet a sarcoma specialist, because that may offer them the potential for clinical trials that are ongoing in this setting, that they may not otherwise be aware of. That is critical to how we manage GIST. There are also wonderful GIST patient advocacy groups that are doing excellent work in educating patients and providers, and using those resources is also of critical importance.

References

1. Heinrich MC, Jones RL, George S, et al. Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial. Nat Med. 2024;30(2):498-506. doi:10.1038/s41591-023-02734-5
2. Wagner AJ, Trent JC, Attia A, et al. Peak part 1 summary: A phase 3, randomized, open-label multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol. 2024;42(suppl 16):11533. doi:10.1200/JCO.2024.42.16_suppl.11533