KIT exon 9 mutation

Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

P2, N=23, Active, not recruiting, Asan Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

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.

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.

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.

Approximately 70% and 77% of patients develop secondary resistance to first-line imatinib or at least three lines of treatment. The prevalence of secondary mutations among patients with primary exon 11 mutations seemes higher than those with exon 9 mutations. Ripretinib demonstrated promising mPFS and mOS benefit for patients with both primary and secondary KIT mutations, which was numerically superior to previously reported mPFS for sunitinib and regorafenib in patients with any secondary mutations.

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.

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.

Little evidence for OS benefit is available from randomized trials for patients whose GIST harbors KIT exon 9 mutation, KIT insertion mutation, PDGFRA D842V mutation, or lacks KIT and PDGFRA mutations. Adjuvant imatinib improves OS substantially if high-risk GISTs can be identified, treatment duration is long enough, and GISTs harbor an imatinib-sensitive mutation.

The radiomics nomogram model based on CE-CT can effectively predict the KIT exon 9 mutation status of GISTs and may be used for selective gene analysis in the future, which is of great significance for the accurate treatment of GISTs.

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.

The patient was submitted to adjuvant treatment with imatinib mesylate 800 mg/day...It is possible that DOG-1 will supplant KIT as the leading marker in the future. The scarcity of knowledge on omental EGISTs implies a close monitoring of these patients to detect local relapse or distant metastasis.

Compared to 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.

P2, N=23, Active, not recruiting, Asan Medical Center | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

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.

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.

Despite the small-sized cohort, our data suggests that for patients with severe imatinib-toxicity, nilotinib may represent a well-tolerated alternative – particularly in the context of its imminent patent expiration. We show for the first time a secondary mutation in exon 9 as mechanism of resistance to a highly specific KIT inhibitor that lacks activity against primary exon 9 mutations. Additional analyses are currently being performed to gain insight into the properties of nilotinib and imatinib to support the observations from clinical and in vitro settings.

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.

The majority of patients with imatinib-associated skin rash in GIST could resume imatinib in well toleration in a personalized dosage, after active management by desensitization therapy under plasma concentration monitoring. Compared with moderate rash, severe rash appeared earlier. Prednisone period should be appropriately extended to avoid rash recurrence.

This case provides evidence that MCL can have wide spectrum of genetic abnormalities as well as accumulation of mutations in various genes including BRAF. This finding may have significant implications for the understanding of pathogenesis, diagnosis, as well as targeted therapy of MCL.

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.

These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior.

The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.

Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians' individualized diagnosis and treatment. Our results have important implications for clinical management.

Pts with KIT resistance mutations received 2L+ therapy with avapritinib, dose-escalated imatinib, nilotinib, pazopanib, ponatinib, regorafenib, ripretinib, or sunitinib. ctDNA is a noninvasive tool for detecting driver and resistance mutations in pts with advanced GIST. GIST pts with KIT exon 13 V654 resistance mutations had superior outcomes in the 2L+ setting with sunitinib. Regorafenib was not superior to other 2L+ TKIs in pts with KIT exon 17 resistance mutations, possibly due to their own activity against exon 17 resistance alterations.

Imatinib is first-line treatment for unresectable gastrointestinal stromal tumors (GISTs) unless they harbor a PDGFRA D842V mutation; it is recommended to escalate imatinib to twice daily dosing for KIT exon 9 mutant tumors. When patients progress on first-line treatment, treatment is changed to sunitinib followed by regorafenib; while the spectrum of activity against resistance mutations varies with these agents, routine biopsies provide data on one area of disease and ctDNA has not been validated prospectively...Avapritinib can be considered for treatment beyond ripretinib for KIT mutant disease. The efficacy of other TKIs tested in GIST is reviewed. Ongoing therapy provides palliative benefit and should be continued given rapid decline observed off of treatment.

Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11-positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.

Gene phenotypes of mucosal melanoma in different locations has differences. Lesions in the nasal cavity and paranasal sinus should be assessed separately from other parts such as the nasopharynx.

We demonstrated the mechanism by which KIT secondary mutations on exon 13/17 cause Imatinib resistance to GIST, and validated that several novel TKIs were valuable therapeutic options against Imatinib-resistance for both secondary- and primary-KIT mutations.

Here, we review the unique and often poorly recognised molecular, biological and clinical characteristics that differentiate KIT exon 9-mutant GISTs from other GIST subtypes. In particular, KIT exon 9 mutations are associated to KIT mutants with retained sensitivity to stimulation by stem cell factor and localisation to the cell membrane. Moreover, KIT exon 9-mutant GISTs display significant activation of KIT-independent oncogenic pathways. These characteristics may explain the limited activity of the tyrosine kinase inhibitor imatinib in the adjuvant setting in KIT exon 9-mutant GISTs, as well as their lower sensitivity to standard dose imatinib in the advanced setting. In contranst, the multi-tyrosine kinase inhibitor sunitinib displays better activity in KIT-exon 9 mutant GISTs compared to others. Key Messages. KIT exon 9-mutant GISTs represent a subtype of GIST disctinct from others GISTs, including the more common KIT exon 11-mutant GISTs. A better understanding of the molecular biology and clinical behaviour of KIT exon 9-mutant GISTs may help identify more improved treatment options.

Objective: Despite an initial response, most patients with metastatic gastrointestinal stromal tumor (GIST) will ultimately be refractory to all current therapies, including imatinib, sunitinib, and regorafenib. Similar to the sub-analysis of the INVICTUS and phase I clinical trial, real-world data shows that dose escalation of ripretinib leads to objective responses in patients whose tumors progressed after standard dose. In our cohort, dose escalation also was also well tolerated with similar toxicity profile than then daily dose. Future studies are needed to assess when dose escalation would be most appropriate: after progression on the standard dose, as a ripretinib re-challenge after a different agent, or even initially in a subset of patients harboring specific mutations or clinical characteristics.

In this multi-institutional retrospective case series analysis of 185 KIT exon 9-mutated GIST patients who received adjuvant imatinib either at 400 mg/d or 800 mg/d, depending on institutional policies and/or physician’s choice, we did not find any statistically significant and/or relevant difference between the two cohorts in terms of RFS, mRFS, IFFS and OS. Higher mitotic count and non-gastric primary tumor site were associate to survival outcomes. The very fact that up to 30% of these patients are treated in expert centers with a dose of 800 mg/d despite the lack of any prospective study underscores how evidence based medicine is difficult to implement in the field of rare tumors.

P2, N=122, Recruiting, First Affiliated Hospital of Zhejiang University | Not yet recruiting --> Recruiting

In this retrospective series of KIT exon 9-mutated GIST patients treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.

Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit vs placebo regardless of mutation status (hazard ratio 0.16) and in all assessed subgroups in Kaplan-Meier PFS analysis (exon 11, P <0.0001; exon 9, P=0.0023; exon 13, P <0.0001; exon 17, P <0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2-23 months for ripretinib vs 0.9-10.1 months for placebo Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with 3 or more TKIs.

Imatinib therapy was applied in 81% of the patients with high risk or metastatic disease without patient’s refusal or adverse characteristics, e.g. comorbidities or resistance mutations... In conclusion, nationwide real-world data show that over 81% of the eligible high risk or metastatic disease patients with GIST receive targeted therapy, which was tailored to the mutation status as recommended in guidelines in 88% of cases. Therefore, still 27% of these GIST patients misses out on mutation-tailored treatment. The reasons for suboptimal uptake of testing and treatment require further study.

P2, N=23, Active, not recruiting, Asan Medical Center | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021

P1/2, N=41, Recruiting, Asan Medical Center | Trial completion date: Aug 2020 --> Aug 2022 | Trial primary completion date: Aug 2020 --> Aug 2022