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Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2–8·2) in the ripretinib group and 1·6 months (1·1–2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6–6·9) with ripretinib compared with 1·0 months (0·9–1·7) with placebo (hazard ratio 0·15, 95% CI 0·09–0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. Deciphera Pharmaceuticals.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis ( N  = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing–based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n  = 21; sunitinib, n  = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n  = 27; sunitinib, n  = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501. Exploratory ctDNA analyses from the phase 3 INTRIGUE trial indicate that ripretinib may provide benefits in patients with advanced gastrointestinal stromal tumors with KIT exon 11 + 17/18 mutations

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases 1 , 2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease 3 . Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn’s disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner’s glands. Although previously linked to mucosal healing 4 , we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases. The study provides a comprehensive transcriptomic atlas of the human gastrointestinal tract across the lifespan, highlighting inflammation-induced changes in epithelial stem cells that alter mucosal architecture and promote further inflammation.

The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8–236·6) after the 1-year randomisation, 200·9 months (190·2–208·4) after the 3-year randomisation, and 164·5 months (134·4–176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5–10·1) versus 27·8 months (19·5–37·9; hazard ratio [HR] 0·36 [95% CI 0·20–0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5–11·7) versus 67·0 months (48·8–85·6; 0·15 [0·07–0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0–16·6) versus not reached (NR; NR–NR; 0·13 [0·03–0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1–39·1) versus 90·6 months (25·3–156·1; HR 0·93 [95% CI 0·51–1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0–89·6) versus 127·3 months (15·0–239·7; 0·35 [0·17–0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0–167·4) versus NR (NR–NR; 0·24 [0·05–1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3–82·9) versus 105·0 months (20·6–189·6; HR 0·84 [95% CI 0·46–1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7–118·7) versus 134·0 months (89·7–178·3; 0·40 [0·20–0·82], log-rank p=0·0096), and after 5 years was NR (NR–NR) versus 110·4 months (82·7–154·1; 1·28 [0·41–3·99]; log-rank p=0·67), Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Background Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival. Methods We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria. Results Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%). Conclusions About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture. Clinical Trial Registration NCT00116935.

BackgroundIn a tertiary center setting we aimed to study the diagnostic accuracy and clinical impact of EUS-guided biopsy sampling (EUS-FNB) with a reverse bevel needle compared with that of fine needle aspiration (EUS-FNA) in the work-up of subepithelial lesions (SEL).MethodsAll patients presenting with SELs referred for EUS-guided sampling were prospectively included in 2012–2015. After randomization of the first pass modality, dual sampling with both EUS-FNB and EUS-FNA was performed in each lesion. Outcome measures in an intention-to-diagnose analysis were the diagnostic accuracy, technical failures, and adverse events. The clinical impact was measured as the performance of additional diagnostic procedures post-EUS and the rate of unwarranted resections compared with a reference cohort of SELs sampled in the same institution 2006–2011.ResultsIn 70 dual sampling procedures of unique lesions (size: 6–220 mm) the diagnostic sensitivity for malignancy and the overall accuracy of EUS-FNB was superior to EUS-FNA compared head-to-head (90 vs 52%, and 83 vs 49%, both p < 0.001). The adverse event rate of EUS-FNB was low (1.2%). EUS-FNB in 2012–2015 had a positive clinical impact in comparison with the reference cohort demonstrated by less cases referred for an additional diagnostic procedure, 12/83 (14%) vs 39/73 (53%), p < 0.001, and fewer unwarranted resections in cases subjected to surgery, 3/48 (6%) vs 12/35 (34%), p = 0.001.ConclusionsEUS-FNB with a reverse bevel needle is safe and superior to EUS-FNA in providing a conclusive diagnosis of subepithelial lesions. This biopsy sampling approach facilitates a rational clinical management and accurate treatment.

Seegene Medical Foundation, one of the major clinical laboratories in South Korea, developed SeeDP, an artificial intelligence (AI)-based postanalytic daily quality control (QC) system that reassesses all gastrointestinal (GI) endoscopic biopsy (EB) slides for incorrect diagnoses. To review the operational records and clinical impact of SeeDP since its launch in March 2022. Operational records of SeeDP were retrieved for the period of March 1, 2022, to February 28, 2023. Among cases scanned during 40 working days (March 10, 2022, to May 4, 2022), all discordant cases encountered by 2 pathologists were reviewed. Cases of SeeDP-assisted revised diagnoses were collected and compared with cases recognized using conventional methods. Occasional scanner failures and various types of aberrant errors compromised QC coverage, resulting in the scanning of only 67.7% (572 254 of 844 906) of all EB slides submitted and 0.8% of the scanned slides being further excluded from the AI analysis. The AI predictions differed from the pathologists' diagnoses in 42 760 of the 557 672 gastrointestinal EB slides (7.7%) successfully assessed by the AI models; however, a detailed review of discordant slides revealed that true misdiagnosis accounted for only 5.5% (25 of 454) of the disagreements. Compared with conventional error recognition methods, SeeDP detected more misdiagnoses (7 versus 14) within a significantly shorter time (average, 3.6 versus 38.7 days; P < .001), including 1 signet ring cell carcinoma initially diagnosed as gastritis. AI-based daily QC systems are plausible solutions to guarantee high-quality pathologic diagnosis by enabling rapid detection and correction of misdiagnosis.

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in and . Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501

BackgroundSunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance.MethodsThis single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships.ResultsSix patients were enrolled with median (range) age of 14 (13–16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3—not reached). There were no serious adverse events.ConclusionsThe tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Recent research has shown that small intestinal GISTs exhibit more aggressive features than gastric GISTs. To compare the clinical features of gastric and small intestinal GISTs for the further prediction of different prognoses, we conducted a retrospective study. 43 patients in the small intestine group and 97 in the gastric group were collected between January 2016 and December 2017. Data on demographics, preoperative lab results, clinicopathological results and surgical management were compared between groups. Significant elements were subsequently included in logistic regression analysis for further identification. The Kaplan-Meier method and log-rank test were used to calculate the relapse-free survival (RFS) rate and cumulative survival rate. Univariable analysis demonstrated that underlying disease, gastrointestinal (GI) bleeding, lymphocyte count, haemoglobin (Hb), albumin (ALB), platelet-to-lymphocyte ratio (PLR), thrombin time (TT), National Institutes of Health (NIH) category, Dog1, surgical procedure types and postoperative hospitalization were different between the two groups. Among these factors, logistic regression analysis identified that patients in small intestinal group exhibited significantly higher GI bleeding rate (p = 0.022), NIH category (p = 0.031), longer postoperative hospitalization time (p = 0.001) with lower TT value (p = 0.030) than those in gastric group. The log-rank test indicated that the location of the GIST (p = 0.022), GIST with GI bleeding (p = 0.027) and NIH category (p = 0.031) were independent prognostic predictors for poor outcome regarding RFS. Regarding cumulative survival, only the location of the GIST (p = 0.027) was an independent prognostic predictor for poor outcome. Thus, we concluded that small intestine GISTs were associated with lower TT, recurrent GI bleeding, advanced NIH category and extended postoperative hospitalization. Nevertheless, future multicentre prospective study are expected to validate our results.