Therapy For Gastrointestinal Stromal Tumors Research Articles

DCC-3116 in combination with ripretinib for patients with advanced gastrointestinal stromal tumor: A phase 1/2 study.

TPS11587 Background: Advanced cancers driven by mutations at or downstream of receptor tyrosine kinases (RTKs), including KIT- and PDGFRA-mutant gastrointestinal stromal tumor (GIST), activate autophagy as an escape mechanism in response to RTK pathway inhibitors. ULK1/2 kinases are key regulators that initiate autophagy in response to stress, such as KIT/PDGFRA inhibition in KIT- and PDGFRA-mutant GIST. Therefore, ULK1/2 inhibition represents a potential targeted approach to selectively inhibit autophagy and is an attractive strategy for combination with RTK pathway inhibitors, including ripretinib. Ripretinib is a switch-control KIT/PDGFRA tyrosine kinase inhibitor approved as a ≥fourth-line therapy for advanced GIST. In the INTRIGUE trial, ripretinib demonstrated comparable efficacy and more favorable safety compared with sunitinib in second-line advanced GIST. DCC-3116 is an investigational, selective, potent, switch-control kinase inhibitor of ULK1/2 in development for combination with targeted therapies that activate autophagy, such as ripretinib. In a GIST xenograft model, animals treated with ripretinib demonstrated stable tumor burden while treatment with ripretinib + DCC-3116 resulted in complete regressions. Here, we describe the design of a phase 1/2, multicenter, open-label study evaluating the safety, recommended phase 2 dose (RP2D), and preliminary efficacy of DCC-3116 in combination with ripretinib in advanced GIST (NCT05957367). Methods: This phase 1/2 study includes safety/dose-finding (part 1) and expansion (part 2). In part 1, patients (pts) ≥18 years must have pathologically confirmed GIST with a KIT or PDGFRA mutation and disease progression on or intolerance to ≥1 systemic regimen. Escalating doses of DCC-3116 will be assessed with ripretinib 150 mg once daily. Part 1 will use safety, pharmacokinetics, pharmacodynamics, preliminary efficacy, and a Bayesian optimal interval design to identify the RP2D for part 2 and the maximum tolerated dose. In part 2, second-line pts with confirmed GIST with a KIT exon 11 mutation and disease progression on or intolerance to first-line imatinib will be enrolled. Part 2 will use a two-stage design with non-binding futility and efficacy analyses after stage 1 to explore efficacy of the combination dose selected in part 1. Exclusion criteria for both parts include use of other anticancer treatments, such as ripretinib, and any investigational therapies within 14 days, use of moderate or strong inhibitors or inducers of cytochrome P450 3A4 or P-glycoprotein, symptomatic central nervous system metastases or leptomeningeal disease, and active infections. Primary objectives in part 1 are to identify adverse events and the RP2D. The primary objective of part 2 is to determine the objective response rate per modified Response Evaluation Criteria in Solid Tumors version 1.1. The study is currently enrolling. Clinical trial information: NCT05957367 .

A systematic review and meta-analysis of neoadjuvant imatinib use in locally advanced and metastatic gastrointestinal stromal tumors.

Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection, and long-term survival outcomes. This manuscript provides a comprehensive review on neoadjuvant imatinib treatment outcomes and facilitate evidence-based decision-making for the use of imatinib therapy in GISTs. Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to September 9, 2023. Meta-analyses of proportions were performed for the outcomes of R0 resection, disease responses, and 1-year, 3-year, and 5-year overall survival (OS) as well as 1-year, 3-year, and 5-year disease free survival (DFS). Sensitivity analyses in the form of leave-one-out analyses, meta-regression, and subgroup analyses were performed for outcomes with substantial statistical heterogeneity. The search yielded 1254 articles, and 36 studies were included in our analysis. Meta-analysis of proportions revealed that 1-year, 3-year, and 5-year OS was 100%, 94%, and 88%, while 1-year, 3-year and 5-year DFS was 99%, 89%, and 79%, respectively. An R0 resection rate of 89% and a disease response rate of 67% was achieved after a mean duration of treatment of 8.41±0.367months. KIT exon 9 mutation was significantly associated with poorer 5-year DFS. This study quantified key outcomes for neoadjuvant imatinib in locally advanced and metastatic or recurrent GIST. Patients with gastric and rectal tumous stand to benefit from neoadjuvant imatinib with an optimal treatment duration of 8months. Furthermore, the potential utility of mutational analysis in guiding treatment with neoadjuvant imatinib was demonstrated.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with KIT exon 11 + 17/18 mutations.

TPS767 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib.1 Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P <0.0001).2 Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study aiming to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. 1. Bauer S et al. J Clin Oncol. 2022. 2. Bauer S et al. J Clin Oncol. 2023; abstract 397784. Clinical trial information: NCT05734105 .

A retrospective analysis of the efficacy and safety of imatinib in elderly patients with advanced gastrointestinal stromal tumor.

730 Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising from the gastrointestinal tract, characterized by a high predominance of the elderly population. Imatinib is the standard first-line therapy for advanced GIST with a median survival of around 4 years in pivotal clinical trials. However, clinical data for the elderly population is not known well. The aim of this study is to evaluate the efficacy and safety of imatinib for advanced GIST in the elderly population in comparison with the non-elderly population. Methods: We extracted clinical data of patients with advanced GIST treated with imatinib as first-line therapy at our institution between January 2010 and July 2023. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs) were assessed and compared between the elderly group (age: ≥ 70 years, E group) and the non-elderly group (age: < 70 years, NE group). Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of age groups. Results: A total of 91 patients were included in this analysis with 32 patients in the E group and 59 patients in the NE group with a median follow-up duration of 39.8 months. Patient characteristics were as follows (the E group vs. the NE group): median age 76 (70–90) vs. 54 (29–69) years, male: 50% vs. 56%, performance status 0: 19% vs. 63%, disease status (: 47% vs. 44%), stomach primary 44% vs. 34%, KIT mutation (exon 11: 50% vs. 61%), and maximum tumor diameter (≥8cm: 66% vs. 51%). The proportion of patients with a reduced starting dose of imatinib was significantly higher in the E group (34% vs. 2%, p <0.0001). Median PFS in the E group and the NE group were 29.4 months and 60.0 months (HR=2.04, log-rank p=0.035). Median OS in the E group and the NE group were 91.5 months and not reached (HR=2.74, log-rank p=0.02). ORR was 53% in the elderly group and 66% in the non-elderly group (p=0.32). In for OS, age was not an independent prognostic factor (HR=2.09, p=0.14) with a significant independent prognostic factor of disease status (unresectable/initially metastatic vs. recurrent (reference): HR=3.58, p=0.03). The occurrence of ≥ grade 2 non-hematologic AEs was more common in the elderly group compared to the non-elderly group (78% vs. 32%, p<0.001). Conclusions: The elderly population with advanced GIST may achieve a survival period comparable to that observed in pivotal trials with imatinib. Even with reduced doses of imatinib, careful monitoring is necessary because of the high frequency of non-hematologic ≥ grade 2 AEs in the elderly population.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

Long-term survival outcomes of endoscopic therapy vs. surgical resection in patients with cardia gastrointestinal stromal tumor.

The ideal surgical approach for treating cardia gastrointestinal stromal tumor (GIST) is not clearly established. This study aimed to assess the long-term survival results among patients who received endoscopic therapy (ET) or surgical resection (SR) for cardia GIST. Cardia GIST patients from 2000 to 2019 were selected from the surveillance, epidemiology, and end result (SEER) database. Multiple imputation (MI) was applied to handle missing data, and propensity score matching (PSM) was carried out to mitigate selection bias during comparisons. Demographic and clinical characteristics' effects on overall survival (OS) and cancer-specific survival (CSS) were assessed using Kaplan-Meier analyses and multivariate Cox proportional hazard models. A total of 330 patients with cardia GIST were enrolled, including 47 (14.2%) patients with ET and 283 (85.8%) patients with SR. The 5-year OS and CSS rates in the ET and SR groups were comparable [before PSM, (OS) (76.1% vs. 81.2%, P = 0.722), (CSS) (95.0% vs. 89.3%, P = 0.186); after PSM, (OS) (75.4% vs. 85.4%, P = 0.540), (CSS) (94.9% vs. 92.0%, P = 0.099)]. Moreover, there was no significant difference between ET and SR in terms of long-term OS (hazard ratio [HR] 0.735, 95% confidence interval [CI] 0.422-1.282) and CSS (HR 1.560, 95% CI 0.543-4.481). Our study found no significant disparity in long-term survival outcomes between ET and SR in cardia GIST patients, implying that ET could be a valid surgical strategy for treating cardia GIST.

Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors.

The discovery of the constitutive activation of KIT/PDGFRA tyrosine kinases in gastrointestinal stromal tumors (GISTs) led to the development of the targeted drug imatinib. However, the inevitable development of imatinib resistance remains a major issue. Ripretinib is a novel targeted drug that inhibits the activity of a broad spectrum of drug-resistant KIT/PDGFRA mutants. It was approved in 2020 and is currently recommended in major international guidelines as fourth-line and beyond therapy for advanced GISTs. Emerging evidence shows that ripretinib is superior to sunitinib as second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the precision of targeted GIST treatment. This article is protected by copyright. All rights reserved.

Liver resection for metastatic GIST tumor improves survival in the era of tyrosine kinase inhibitors: a systematic review and meta-analysis.

Survival for gastrointestinal stromal tumor (GIST) has been increasing over the years after the introduction of tyrosine kinase inhibitors. However, the role of metastasectomy for GIST is still controversial. Patients are currently treated with imatinib or sunitinib in case of imatinib failures as optimal medical therapy for metastatic GIST. The Pubmed, EMBASE, and Cochrane Library were systematically searched. Overall survival following liver resection ± tyrosine kinase inhibitor treatment for metastatic GIST was compared to treatment with tyrosine kinase inhibitors alone. Eleven studies including both randomized control trials and retrospective cohort studies were included in the final analysis with a total of 988 patients. Seven studies encompassed data on 556 patients with isolated liver metastases (219 surgery ± drug groups and 337 drug-only groups) were included. Overall survival was significantly improved in patients undergoing liver resection ± drug therapy in comparison to drug therapy alone. [HR (95%CI) = 2.10 (1.58, 2.79); p<0.00001]. Subgroup analysis showed that patients also had improved progression free survival based on 4 studies. [HR (95%CI) = 1.92 (1.43, 2.56); p<0.00001]. In case of concurrent liver and peritoneal metastases, patients showed improved overall survival with aggressive surgical approaches based on 10 studies. [HR (95%CI) = 1.90 (1.56, 2.31); p<0.00001]. This meta-analysis found that liver resection for patients with metastatic GIST regardless of peritoneal metastases improved progression free and overall survival in conjunction with tyrosine kinase inhibitors as compared with medical therapy alone. Furthermore, liver resections did not have any immediate detrimental impact on survival in the group of patients selected.

Cytoreductive surgery for metastatic gastrointestinal stromal tumors treated with ripretinib: A single-center experience

BackgroundCytoreductive surgery (CRS) has been advocated as an additional treatment with survival benefits for advanced gastrointestinal stromal tumor (GIST), especially in patients with responsive disease or focal progression after treatment with imatinib. Ripretinib is a fourth-line therapy for advanced GIST. This single-center pilot study investigated the short-term safety and efficacy of CRS after treatment with ripretinib in selected patients with recurrent or metastatic GIST. MethodsMedical records of patients with recurrent or metastatic GIST who underwent CRS after ripretinib in the First Affiliated Hospital of Sun Yat-sen University between June 1st, 2020 and June 1st, 2022 were retrospectively reviewed. Patients’ clinicopathological characteristics, preoperative treatment and general condition, surgical information, and postoperative management were recorded. ResultsThis study included 7 patients who underwent CRS after ripretinib. Radiographic response to ripretinib included partial response (n ​= ​1), stable disease (n ​= ​5), and progressive disease (n ​= ​1). The cumulative size of targeted lesions shrank by 4.8%–45.3% in 5 patients. R0/R1 resection was achieved in 6 (85.7%) patients. Postoperative complications (IId) were reported in 2 (28.6%) patients. There were no delayed post-operative complications. Median follow-up was 11.8 months. Median time-to-progression and median post-operative progression-free survival were not reached. Four patients who did not progress before surgery had no evidence of disease. ConclusionRipretinib combined with CRS is safe and effective in select patients with advanced GIST despite extensive prior therapy.

Immunotherapy of gastrointestinal stromal tumors: current view and future directions

Gastrointestinal stromal tumors (GIST) are most common mesenchymal tumors in gastrointestinal tract which originate from interstitial cells of Cajal and characterized by the mutations in the KIT or PDGFRA tyrosine kinase receptors. Thus, the common therapeutic approach for GIST therapy (including metastatic, recurrent and non-resectable forms) is based on inhibiton of activities of receptor tyrosine kinases indicated above by corresponding receptor tyrosine kinase inhibitors, including first-line therapeutic agent imatinib mesylate – Gleevec. Despite of high efficacy of IM-based therapy, most of GIST patients acquire resistance to this receptor tyrosine kinase inhibitor, which in turn requires second-, third- and fourth-line therapies. The review also describes the common molecular and genetic variants of GIST and the mechanisms of primary and secondary GIST resistance to the targeted-based therapies. In addition, the role of immune microenvironment in GIST and its relationship with tumor’s mutational burden are discussed in detail, thereby illustrating the immunotherapy as one of the attractive future directions for GIST therapy. Lastly, the manuscript provides the information about the ongoing clinical trials of GIST immunotherapy.

P-264 The effect of preoperative imatinib therapy in gastrointestinal stromal tumors: A multicenter study

P-264 The effect of preoperative imatinib therapy in gastrointestinal stromal tumors: A multicenter study

INSIGHT: A phase 3, randomized, multicenter, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib harboring KIT exon 11 + 17 and/or 18 mutations.

TPS11582 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST develop disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib (Bauer S et al. J Clin Oncol. 2022). Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17 and/or 18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR = 0.22, 95% CI 0.11 to 0.44, nominal P &lt; 0.0001; Bauer S et al. J Clin Oncol. 2023; abstract 397784). Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17 and/or 18 mutations. Methods: INSIGHT is a phase 3, randomized, open-label study that aims to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17 and/or 18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17 and/or 18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group Performance Status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation via ctDNA at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. Clinical trial information: NCT05734105 .

Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors (GIST) as ≥4th line therapy: Long-term update from a single-arm, phase 2 trial.

11543 Background: In INVICTUS study (NCT03353753), ripretinib as ≥4th line (4L) GIST therapy significantly improved median progression-free survival (mPFS) versus placebo (hazard ratio 0.15, 95% confidence interval [CI] 0.09–0.25; mPFS 6.3 vs 1.0 months) with a satisfactory safety profile. In the primary analysis (data cut-off: 26 Feb 2021) of the bridging study (NCT04282980) of INVICTUS, ripretinib as ≥4L therapy showed consistent efficacy and safety profiles in Chinese GIST patients to those in INVICTUS, with mPFS of 7.2 months and objective response rate (ORR) of 18.4% (7/38 patients). The overall survival (OS) data was immature at the primary analysis. Here we report the long-term updates of this bridging study. Methods: Patients received ripretinib 150 mg once daily continuously in 28-day cycles until progressive disease or other protocol-specified events for treatment discontinuation. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 GIST-Specific Standard. Secondary endpoints included ORR by IRR, time to best response (TBR), duration of response (DOR), OS and safety. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Results: Overall, 39 patients were enrolled. Thirty-eight patients received continuous ripretinib treatment and were included in the efficacy analysis set. All 39 patients received at least one dose of ripretinib and were included in the safety set. The updated data cut-off was 23 Aug 2022. The overall median follow-up (90% CI) was 23.00 (11.99, 24.87) months. In the efficacy analysis set, mPFS (90% CI) by IRR was 6.44 (2.89, 8.31) months and ORR was 21.1% (8/38 patients). Median TBR and median DOR for the 8 patients with confirmed partial response were 2.25 and 8.57 months, respectively. The median OS (95% CI) in the efficacy analysis set was 25.56 (11.73, not evaluable) months. In the safety set, 20.5% of patients experienced ≥1 grade 3/4 treatment-related treatment-emergent adverse events (TRAEs). Compared to the primary analysis, the increase in TRAEs and new TRAEs leading to dose modification were minimal after 18 months of additional follow-up. Conclusions: After long-term follow-up, the more mature results continued to support the clinically meaningful benefit in PFS and also demonstrated clinically meaningful benefit in OS in Chinese ≥4L GIST patients, while the safety profile remained satisfactory. Clinical trial information: NCT04282980 .

Ripretinib inhibits polyclonal drug-resistant KIT oncoproteins: the next step forward in gastrointestinal stromal tumor therapy

Ripretinib inhibits polyclonal drug-resistant KIT oncoproteins: the next step forward in gastrointestinal stromal tumor therapy

Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib.

Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot. We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors.

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.

TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors.

Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.

N6-methyladenosine-modified USP13 induces pro-survival autophagy and imatinib resistance via regulating the stabilization of autophagy-related protein 5 in gastrointestinal stromal tumors.

Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including autophagy, correlate with IM resistance. Regulation of autophagy-related protein 5 (ATG5) by the ubiquitin-proteasome system is critical for autophagic activity, although the molecular mechanisms that underpin reversible deubiquitination of ATG5 have not been deciphered fully. Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. USP13 preferentially is induced in GIST cells by IM and interacts with ATG5, which leads to stabilization of ATG5 through deubiquitination. Activation of PAK1 promoted phosphorylation of ATG5 thereby enhancing the interaction of ATG5 with USP13. Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2. Moreover, an inhibitor of USP13 caused ATG5 decay and co-administration of this inhibitor with 3-methyladenine boosted treatment efficacy of IM in murine xenograft models derived from GIST cells. Our findings highlight USP13 as an essential regulator of autophagy and IM resistance in GIST cells and reveal USP13 as a novel potential therapeutic target for GIST treatment.

Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Background: Systemic mastocytosis (SM) is characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. NonAdvSM is characterized by the lack of mast cell-related organ damage (e.g., C-findings) and other features of advanced SM such as associated hematologic neoplasms. NonAdvSM includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). ISM affects nearly 85% of the general SM population and is characterized by symptoms related to mast cell degranulation/mediator release. SSM is characterized by higher mast cell burden in the absence of organ damage or an associated hematologic neoplasm. There are currently no approved therapies for the treatment of the underlying causes of ISM or SSM, and anti-mediator therapies are used for symptom control with variable efficacy and tolerability due to disease heterogeneity. In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17; therefore, agents targeting this mutated kinase have been used to treat advanced SM variants. However, off-target activity of these agents may lead to toxicities that limit dosing and thus efficacy in this population. Therefore, an unmet need remains for safe and effective treatments for patients with NonAdvSM. Bezuclastinib inhibits KIT D816V mutations with high potency and specificity while avoiding other kinases with potential off-target liabilities such as PDGFRα, PDGFRβ, VEGFR2, and CSF1R. Bezuclastinib has demonstrated minimal brain penetration and no central nervous system toxicities were observed in preclinical studies. In an ongoing Phase 2 study (Apex) of patients with AdvSM, early data indicate that bezuclastinib was generally well tolerated and is associated with a meaningful reductions in serum tryptase levels, bone marrow mast cell burden, and KIT D816V variant allele fraction. Additionally, bezuclastinib was safely administered in a completed phase 1/2 clinical study in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST), in which activating KIT mutations are found in a majority of patients. In that study, bezuclastinib led to a reduction in KIT exon 17 mutational burden, which was associated with a reduction in tumor burden. These results support the investigation of bezuclastinib as a potential therapy in GIST as well as AdvSM and NonAdvSM. Study Design and Methods: The Summit study (NCT05186753) is a multi-center, Phase 2, double-blind, placebo-controlled, 3-part clinical trial to evaluate the safety, efficacy, and biomarker correlates (e.g., bone marrow mast cell burden, serum tryptase level, and KIT D816V mutation burden) of bezuclastinib in patients with NonAdvSM. Patients diagnosed with ISM or SSM who have inadequate control of their symptoms despite treatment with at least 2 anti-mediator therapies will be included in this trial. Multiple patient-reported outcome measures (PROMs) will be used to follow symptom scores while on treatment. Part 1 of the study will assess the safety profile of bezuclastinib and will determine the recommended dose for Part 2 through the assessment of changes from baseline of a disease specific PROM. Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo through the evaluation of the PROMs and changes in clinical activity markers such as serum tryptase, bone marrow mast cell burden, and KIT D816V mutation allele burden. All patients will continue to receive their baseline anti-mediator treatments throughout the trial. Serial photographic evaluation will assist in the determination of changes of disease in the skin. Part 3 allows patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, to participate in a long-term extension study and receive open label bezuclastinib. Conclusions: There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.