KIT exon 17 mutation

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts. Previously presented at the 2024 ESMO Sarcoma and Rare Cancers Congress.

55% (42/77) of liquid samples with a KIT -driver mutation had a co-occurring imatinib-resistant alteration, and a minority of cases harbored non- KIT mechanisms of resistance such as FGFR2 fusion, BRAF or EGFR alterations... Known driver and TKI-resistant mutations are identified in liquid biopsies of patients with GIST, with high concordance to tissue in the presence of elevated TF. Liquid biopsy may be valuable in the molecular classification of GIST during the medical management of advanced disease.

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was favorable for pts with KIT exon 11 + 17/18 mutations in the ripretinib arm.

Not available.

Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA.Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts.

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. 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.

For all patients in our cohort, age > 60 years, KITD816 mutations and BCOR mutations were showed to be independent unfavorable predictors for OS and EFS. Our results revealed that SM-t(8;21) AML shared more similar clinical characteristics, molecular features and clinical outcomes with KITD816 t(8;21) AML.

2 patients did not achieve continuous RUNX1: : RUNX1T1 negative after preemptive therapy with Decitabine (DAC) and donor lymph infusion (DLI), and then was treated with Avapritinib, one's RUNX1: : RUNX1T1 fusion achieved continuously negative after 1 month treatment of Avapritinib, the other's achieved continuous negative after 7 months treatment of Avapritinib. Avapritinib is safe and effective in the prophylactic and preemptive treatment of AML with KIT mutation after allo-HSCT in children, which provides a clinical drug for the prevention of relapse after transplantation.

Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ³4 line settings.

P3, N=54, Recruiting, Deciphera Pharmaceuticals LLC

Exon 17 KIT mutations serve as an important predictor of relapse in RUNX1::RUNX1T1 pediatric AML. In addition, a high KIT VAF may predict poor outcomes in these patients. These results emphasize the need to incorporate KIT mutational analysis into risk stratification for pediatric CBF-AML.

Patients with both non-mutated KIT exon 17 and negative MRD have the best prognosis, while positive MRD and KIT exon 17 mutations are associated with poorer outcomes. These findings indicated that integrated analysis of flow-MRD and KIT exon 17 status enables optimal risk assignment strategies in pediatric AML with RUNX1::RUNX1T1.

Our results suggest that short read NGS-based assays may miss a significant number of clinically actionable KIT variants, and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.

P1/2, N=67, Recruiting, Blueprint Medicines Corporation | Initiation date: Apr 2023 --> Sep 2023

One model is characterized by an imatinib-resistant PDGFRA exon 18 p.D842V mutation... We are expanding our established platform of well-characterized GIST PDX models, that were proven to serve as an excellent tool for preclinical drug testing and tumor biology studies. The platform is available for cooperative projects with academic and commercial partners.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

While KIT ATP-BP mutations were associated with clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of KIT mutations to predict the clinical benefit of second-line therapy in pts with advanced GIST. These data were presented in part at the Jan 2023 ASCO plenary session.

P2, N=48, Recruiting, University of Miami | Trial completion date: Jul 2028 --> Dec 2028 | Trial primary completion date: Jul 2026 --> Dec 2026

She had an aggressive clinical course following initiation of cytarabine-based induction chemotherapy. The underlying mutational landscape may significantly influence the biological behaviour of otherwise favourable risk of CBF-AML cases.

This study represents a one of the most comprehensive analyses of the genomic landscape and integration of genomic features with clinicopathologic attributes and survival outcome in GIST.

As sunitinib and regorafenib are only effective against certain secondary mutations, ripretinib can broadly inhibit a wide range of primary and secondary KIT mutations. The proportion of secondary mutations in KIT Exon 11 primary mutations is significantly higher than that in KIT Exon 9 primary mutations following progression on first-line imatinib treatment. Furthermore, the main resistance mechanism of KIT Exon 11 mutant GISTs continues to rely on complex secondary mutations in KIT signaling. Differences in resistance mechanisms among various primary mutations imply that subsequent treatment should take into account both the patient 's primary and resistance mutations.

Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.

uPARAP is highly expressed in several GIST xenograft models across multiple passages of ex-mouse tumors. Considering its preferential expression in GIST and other mesenchymal tumors and the recycling character of this molecular target, uPARAP may serve as a powerful emerging target for systemic treatment of GIST beyond traditional kinase inhibitors or in combination with the latter. uPARAP positive xenograft models can be used for in vivo evaluation of such anti-uPARAP treatment.

Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501.

In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration... Known driver and TKI-resistant mutations of both somatic and potential germline origin are identified in peripheral blood ctDNA of GIST patients. Liquid biopsy shows high concordance to tissue in identifying driver mutations in the presence of elevated TF and may exhibit TKI-resistant specific alterations. This study indicates that liquid biopsy may be useful in the molecular classification of GIST during the medical management of advanced GIST patients.

P1/2, N=67, Recruiting, Blueprint Medicines Corporation | Not yet recruiting --> Recruiting

P2, N=48, Recruiting, University of Miami | Trial completion date: Apr 2028 --> Jul 2028 | Initiation date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2026 --> Jul 2026

P1/2, N=67, Not yet recruiting, Blueprint Medicines Corporation | N=108 --> 67 | Trial completion date: Nov 2027 --> Nov 2029 | Initiation date: Dec 2022 --> Apr 2023 | Trial primary completion date: Nov 2027 --> Nov 2029

P2, N=15, Completed, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Completed | N=39 --> 15

P2, N=48, Recruiting, University of Miami | Trial completion date: Jan 2028 --> Apr 2028 | Initiation date: Jan 2023 --> Apr 2023 | Trial primary completion date: Jan 2026 --> Apr 2026

P1/2, N=39, Completed, Asan Medical Center | Recruiting --> Completed

Ripretinib has acceptable tolerability, with the most common drug-related grade 3 or 4 adverse events being lipase increases, hypertension, fatigue and hypophosphataemia. Ripretinib is therefore a valuable additional line of therapy available for the management of gastrointestinal stromal tumours.

There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.

Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

The first case is a 28-year-old female who developed multiple gastric GISTs with widespread abdominal metastases that were resistant to imatinib...Next-generation sequencing revealed a germline KIT exon 17 mutation (NM_000222.3, c.2459A > T, p.D820V). These cases highlight the diverse clinical presentations of patients with germline variants and raise several important points about the diagnosis and management of these patients, in particular: mutation in the SDH family of genes (somatic or germline) should be suspected in KIT and PDGFRA wild-type tumors; germline testing should be considered in patients with multiple GISTs or those who present with disease at a young age; and somatic next-generation sequencing cannot only help identify optimal therapy in all patients with GISTs but also help guide referral to Medical Genetics for appropriate patients.

There remains a high unmet need for more effective and better tolerated second- and later-line treatments for patients with GIST. Phase 1/2 bezuclastinib data in advanced solid tumors, including GIST, were encouraging and support further clinical investigation of co-targeting the complementary conformational states of the same kinase with bezuclastinib and sunitinib. The Peak Study aims to assess the efficacy and safety of bezuclastinib in combination with sunitinib as second-line treatment in adult patients with imatinib-resistant, or intolerant, GIST.

Standard treatment for metastatic or unresectable GISTs includes tyrosine-kinase inhibitors (TKIs) such as imatinib as first-line therapy followed by sunitinib, regorafenib and ripretinib as second-, third- and fourth-line therapies, respectively (2). This case report is a microcosm of the latest GIST treatments. It provides the evidence that combination therapy of ripretinib with sunitinib or imatinib can be an efficacious therapeutic option for arresting GIST progression in selective patients, who are refractory to current standard therapies.

Taken together, the inactivity of imatinib on KIT exon 17 mutations, the general low clinical efficacy of immunotherapy, as well as the consequent formal lack of standard available and active second line systemic treatments in both mucosal melanoma and thymic carcinoma, support the implementation of avapritinib in the therapeutic armamentarium, even though further prospective evidence is warranted.

Background & objectives: A 73-year-old man with a history of metastatic small bowel gastrointestinal stromal tumour (GIST) who have undergone liver and small bowel resections was found to have recurrent peritoneal nodules on follow-up despite being on Imatinib... This case demonstrated the utilization of Quantumcyte Oncomask, a novel tissue masking technology in detection of heterogeneous resistant subclones in a treatment resistant GIST. It enables the sampling of targeted areas in a tumour section to increase the cellular purity for molecular sequencing especially for the analysis of tumour heterogeneity which is known to be associated with therapeutic resistance. The presence of different mutation subclones in GIST is also important in guiding oncologists on the treatment choices.

They also function as predictive markers for response to imatinib... Overall Ckit mutation rate was lower (73%) than reported in literature, thus concluding that incidence of ckit muta-tions could be lower in Indian population. Ckit exon 9 mutations had consistent duplication while deletions and substitutions were found in in exon 11. Exon 9 mutations guided treatment decisions.

P2, N=48, Recruiting, University of Miami | Not yet recruiting --> Recruiting