KIT Mutations Research Articles

Clinical efficacy of avapritinib in gastrointestinal stromal tumors (GIST) with different KIT genotypes: Post hoc analysis of the phase 1 NAVIGATOR and phase 1/2 CS3007-101 trials.

11523 Background: Avapritinib, a novel KIT/platelet-derived growth factor receptor α (PDGFRA) kinase inhibitor, is approved in patients (pts) with GIST harboring PDGFRA activation loop (AL) exon 18 mutations, based on unprecedented clinical antitumor activity. Despite available treatments, there remains a great unmet medical need for pts with KIT-AL-mutant GIST receiving 2nd-line (2L) standard of care (SOC) sunitinib, and pts with primary KIT exon 9 ( KIT 9)-mutant GIST receiving 4th-line (4L) SOC ripretinib. This post hoc analysis assessed the clinical benefit of avapritinib in pts with KIT mutations, especially with AL exons 17 and 18, or primary KIT 9 mutations. Methods: Tumor tissue and liquid biopsy samples were collected and analyzed to determine baseline mutational status. KIT molecular subgroups and outcomes were determined in pts with primary KIT mutations treated with oral avapritinib 300 mg once daily (starting dose) enrolled in the phase 1 NAVIGATOR (NCT02508532) and phase 1/2 (China bridging) trials (NCT04254939, CS3007-101). Pts with PDGFRA mutations and PDGFRA- KIT co-mutations were excluded. Progression-free survival (PFS) and objective response rate (ORR) were compared using Cox and logistic regression, respectively. Results: A total of 160 pts with KIT-mutant GIST were evaluated (NAVIGATOR, n= 131; CS3007-101, n= 29). At data cutoff (NAVIGATOR: March 31, 2021; CS3007-101: June 30, 2021), median follow-up duration was 22.0 months (95% CI 18.3–27.4). KIT-AL mutations were more frequently detected (n = 74, 46.3%) than KIT ATP-binding pocket (ABP) mutations (n = 34, 21.3%). Sixty pts (37.5%) had KIT-AL mutations without KIT-ABP mutations (ALposABPneg group); the remaining 100 pts were designated as KIT OTHERS. Across all lines of therapy, the adjusted (inverse probability weighting of baseline characteristics) median PFS (mPFS) was longer for the ALposABPneg group than for the KIT OTHERS group (9.1 vs 3.4 months; HR 0.47, 95% CI 0.32–0.68; P< 0.0001), and the ORR was higher (31.4% vs 12.1%; odds ratio 3.31, 95% CI 1.44–7.58; P= 0.0047). mPFS and ORR in the KIT ALposABPneg group were 19.3 months and 38.5%, respectively, in the 2L setting (n = 13) and 11.0 months and 36.4%, respectively, in Chinese pts (3–9 lines, n = 11). In pts with KIT 9 mutations in the 4L (n = 14) and > 4L settings (n = 19), mPFS was 5.6 and 3.7 months, respectively. Conclusions: This post hoc analysis demonstrated significantly more robust avapritinib antitumor activity in pts with KIT ALposABPneg GIST versus pts with other KIT mutation profiles. The results suggest that avapritinib could confer meaningful clinical benefit in pts with GIST and specific KIT mutation types, especially KIT-AL or KIT 9 mutations. Avapritinib might be a potential 2L option for pts with KIT ALposABPneg GIST, and in later lines of therapy for pts with ALposABPneg or KIT 9 mutation profiles. Clinical trial information: NCT02508532 , NCT04254939 .

The genomic and transcriptomic landscapes of chemotherapy naïve vs post-chemotherapy germ cell tumors.

5007 Background: Cisplatin resistance occurs in up to 30% of patients with advanced germ cell tumors (GCTs). Despite effective salvage treatment regimen, there is a 50% risk of cancer-specific death. Previously, we identified molecular features, including TP53 mutations and MDM2 amplification, associated with cisplatin resistance (Bagrodia, 2016). Herein, we evaluate the genomic and transcriptomic landscapes of chemotherapy naïve vs post-chemotherapy GCT’s to uncover genetic factors that might drive cisplatin resistance. Methods: GCTs (N = 138) were tested at Caris Life Sciences (Phoenix, AZ) with next-generation sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Prevalence was calculated for pathogenic SNVs/indels and copy number amplifications (CNA≥6 copies). Primary (N = 65) and metastatic (N = 73) sites were defined based on the biopsy site. A specialized genitourinary pathologist blindly reviewed selected H&E-stained slides and designated tumors as chemotherapy naïve (N = 66) or post-chemotherapy (N = 17) based on treatment related changes. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Transcriptomic signatures predictive of response to immunotherapy (T cell-inflamed) and platinum sensitivity (PSS, high score suggests increased platinum sensitivity) were applied. Mann-Whitney U and χ² tests were applied, with P-values adjusted for multiple comparisons. Results: Primary and metastatic GCT had slight differences between putative drivers of platinum therapy resistance: KIT (15% vs 1), TP53 (10% vs 17), KRAS (13% vs 9) mutations and MDM2 CNA (4% vs 3), all p > 0.05. When comparing post-chemo vs chemo naïve GCTs, no significant differences in the genomic landscape were observed (p > 0.05). Chemo naïve tumors were shown to be enriched for gene sets associated with KRAS signaling and epithelial-to-mesenchymal transition. Additionally, they trended towards a higher proportion of T cell-inflamed tumors as compared to post-chemo samples (32% vs 18, p = 0.36). The average PSS for chemo naïve was slightly higher than post-chemo (CN: 0.07 Arbitrary Units (AU), N = 62 vs PC: -1.82, N =16, p = .52). Chemo naïve tumors with TP53, KRAS, or KIT mutation or MDM2 CNA had a lower PSS (-4.16 AU, N= 18) than tumors with none of those alterations (2.17, N = 38), p = 0.05. Finally, chemo naïve tumors with MDM2 CNA (N=2, -16.26 AU) had the lowest PSS followed by tumors with mutations in TP53 (N=6, -2.04), KIT (N = 2, -1.77) and KRAS (N=9, -1.05) (mutations were mutually exclusive except for a concurrent KRAS and TP53 mutation). Conclusions: This study provides evidence that chemo naïve GCTs with mutations in TP53, KRAS, KIT or MDM2 CNA have higher expression of genes associated with resistance to platinum-based chemotherapy. These findings contribute to a better understanding of the molecular characteristics of GCTs and may inform prognosis and treatment.

Longitudinal follow-up and outcomes of pediatric and adult patients with SDH-deficient GIST.

11542 Background: Gastrointestinal stromal tumor (GIST) are gastrointestinal non-epithelial neoplasms most commonly driven by somatic mutations in KIT or PDGFRA. Approximately ten percent of GIST are due to germline mutations in SDHx or epigenetic loss of expression of SDHC. While KIT and PDGFRa driven GIST respond to treatment with tyrosine kinase inhibitors, effective systemic therapies for SDH-deficient GIST have not yet been identified. SDH-deficient GIST are indolent tumors that typically progress slowly over time. A better understanding of the natural history of patients with these neoplasms is critical to identify effective treatments and improve patient care. A cohort of patients with SDH-deficient GIST is followed at the NIH Clinical Center and through the NIH Pediatric and Wild-type GIST Clinic. The aim of this study is to characterize the long-term outcome of this cohort of patients. Methods: Data from patients with SDH-deficient GIST enrolled in a study Natural History and Biospecimen Acquisition for Children and Adults with Rare Solid Tumors (NCT03739827) from January 2019 through January 2023 at the NIH were evaluated. In addition to review of medical records and imaging, when available, tumors were characterized by sequencing of SDH genes. Germline analysis of SDH genes was offered to consenting patients and families. Results: Clinical information and specimens were collected from 77 GIST patients (median age at diagnosis 21.5, [range 7-57] years; 72.7% (56) female, 21.3% (21) male) were classified by molecular subtypes: 33.8% SDHC epimutation, 28.6% SDHA, 22.1% SDHB, 14.3% SDHC and 1.3% SDHD. Median age at presentation of SDHC epimutation was younger (14.5 years, range: 8-56) when compared to SDHA (27.5 years, range: 7-55), SDHB (22 years, range: 8-54), SDHC (18 years, range: 10-57) and SDHD (39 years, N = 1). Most commonly, patients had at least one surgery (55.8%) while a lower proportion had four or more (7.8%). Primary tumors occurred in the stomach with 26% having metastases at presentation the most common location being the liver (10.4%). Overall, 64.9% of patients were treated with imatinib, 39% were treated with sunitinib and 15.6% received other additional systemic therapies. Within the cohort there were 13% of patients with paragangliomas and 6.5% with chondromas while only 9.1% had a family history of GIST. Conclusions: Longitudinal follow-up of an SDH-deficient GIST patient cohort will allow for better understanding of the natural history including treatment history and survival of patients with this rare disease and will help to optimize strategies for treatment and follow-up of these patients.

Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): Results from part 1 of the phase 3 Peak study.

11537 Background: Patients with GIST often relapse after first line therapy with imatinib due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct and complementary, when combined they inhibit a broad spectrum of secondary KIT mutations. In a prior Phase 1b/2a study (NCT02401815), the combination of the original formulation (Form. A) of bezuclastinib + sunitinib had an acceptable safety profile and was associated with clinical activity at the RP2D (Wagner, JAMA Oncol 2021;7(9):1343-50). An optimized formulation (Form. B) of bezuclastinib with improved bioavailability was developed to reduce pill burden for GIST pts. PK and safety results from the Part 1a lead-in of Peak (NCT05208047) have been previously presented (Wagner, CTOS 2022, P320). Herein we intend to report comprehensive clinical results from Part 1a including duration of therapy, initial response assessment and updated safety. Methods: Peak, a randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in pts with imatinib-resistant or intolerant GIST. In Part 1a of the 3-part study, bezuclastinib (Form. B) dosing was escalated in serial cohorts based on PK results until the target exposure, comparable to those achieved at the RP2D established in the Phase 1b/2a study, was achieved. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Results: Part 1a enrolled 19 pts. Five pts (Cohort 1) received the starting dose of once daily (QD) bezuclastinib 300 mg+ sunitinib 37.5 mg; dose was escalated to 600 mg with 14 pts receiving bezuclastinib 600 mg + sunitinib 37.5 mg. Median age - 60 yrs (range: 42-77); 68% male; 95% ECOG PS 0-1; 95% metastatic and 5% locally advanced. As of Sept 2022 data cutoff, the median (range) treatment duration was 6 weeks (3.1, 23.9). Due to AEs, one pt required dose reduction of bezuclastinib (Gr 3 diarrhea) and 1 pt discontinued (Gr 2 rash). The majority of TEAEs were low grade, with no ≥ Gr4. Most common TRAEs were diarrhea (37%), neutropenia (37%), ALT (32%) and AST (26%) increases. One pt experienced SAEs of Gr 2 neutropenia and pyrexia and Gr 3 thrombocytopenia. Steady state exposure in pts receiving QD doses of bezuclastinib 600 mg + sunitinib 37.5 mg in this study were similar to that at the RP2D established in the prior Phase 1b/2a study. Conclusions: Initial data from Peak shows an encouraging safety and tolerability profile with no unique safety signals when compared to the known safety profile for sunitinib monotherapy. A dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was confirmed for use in Peak study Part 2, for which enrollment is ongoing. Updated data from Part 1a, including response data, will be presented. Clinical trial information: NCT05208047 .

Initial results from the phase (ph) 1 portion of a ph 1/2 study of THE-630 in patients (pts) with advanced gastrointestinal stromal tumor (GIST).

e23508 Background: Activating mutations in KIT are found in most pts with GIST. First-line imatinib provides initial clinical benefit in advanced disease, but prognosis is poor for pts whose tumors progress, despite 3 other approved tyrosine kinase inhibitors (TKIs). Resistance is typically driven by secondary KIT mutations in the ATP-binding pocket (exons 13/14) or activation loop (exons 17/18). No approved drug has potent activity against both classes of resistance mutations, and many pts have polyclonal resistance after multiple lines of therapy. THE-630 is an investigational pan-variant KIT inhibitor. Based on preclinical models, an average plasma concentration (Cav) of 100 nM is predicted to have potent activity against all major classes of KIT-activating and resistance mutations. Here, we report initial data from a first-in-human study in pts with advanced GIST (NCT05160168). Methods: This ph 1/2 study is assessing the safety (including dose-limiting toxicities [DLTs] and recommended ph 2 dose [RP2D]), pharmacokinetics (PK), and antitumor activity of THE-630. Pts enrolled in the ph 1 portion were ≥18 y, had unresectable or metastatic GIST previously treated with imatinib and ≥1 additional TKI, and had ECOG performance status ≤2. Pts received THE-630 (QD; 28-day cycles) in a 3+3 dose-escalation design. PK was assessed on days 1 and 15 in cycle 1, antitumor activity was assessed by modified RECIST 1.1, and circulating tumor DNA (ctDNA) was assessed using Guardant360. Results: As of 13 Jan 2023, 19 pts had been treated in the ph 1 portion at THE-630 daily doses of 3 mg (n = 3), 4 mg (n = 7), 6 mg (n = 3), 9 mg (n = 3), and 12 mg (n = 3). Median age was 57 y (range 39–72); 13 pts had ≥4 prior TKIs. Median treatment duration was 55 days (range 1–252). PK analysis shows approximately dose-proportional increase in systemic exposure across doses tested. Mean steady-state Cav at 12 mg was 47 nM. There was 1 DLT at 4 mg (grade 5 myocardial infarction in a pt with 8 prior TKIs and hyperlipidemia where relationship to THE-630 could not be incontrovertibly ruled out). No other DLTs or related serious adverse events have occurred; 13 pts had treatment-related AEs (TRAEs), 91% of which were grade 1–2. The most common TRAEs were fatigue (n = 4), dry mouth (n = 3), anemia, ALT increase, AST increase, diarrhea, dyspepsia, dyspnea, and hypertension (n = 2 each). Reductions in select KIT-mutant allele fractions in ctDNA were observed, consistent with THE-630 levels achieved thus far. Stable disease (SD) was the best response in 1/7 pts at 4 mg, 1/3 pts at 6 mg, and 3/3 pts at 9 mg. Post data cut, SD was seen in 3/3 pts at 12 mg. Dose escalation continues to determine the RP2D. Conclusions: THE-630 had an acceptable initial safety profile, and escalation continues, as target exposure for pan-variant KIT activity is not yet reached. Reduction in KIT-mutant allele fractions in ctDNA and initial evidence of disease control were observed. Clinical trial information: NCT05160168 .

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 < 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 .

Mutational landscape of intracranial germ cell tumors.

e14060 Background: Intracranial germ cell tumours (GCTs) are relatively rare tumours of the central nervous system, which account for 1% to 3% of cases. The pathogenesis of intracranial GCTs is unknown, molecular diagnostic methods currently play only a minor role in the diagnosis of CNS germ cell tumours, which generally rest on histopathological and secretory features. The objective of this study was to explore the molecular profile associated with Chinese intracranial GCT patients. Methods: This study retrospectively analyzed the genomic features of 24 intracranial GCT patients. Next-generation sequencing (NGS) of 551-gene panel was performed to detect gene mutations in tumor and blood samples of the patients. Results: The tumors originated most frequently in the pineal region (41.6%, 10/24), followed by the sellar tumor (16.6%, 4/24). The average age of the patients was 14 years (range, 4-55years), There is a male preponderance of 2:1. The most common mutation genes were KIT (4.23%, n=6), KRAS (2.82%, n=4) and PTEN (2.11%, n=3). KIT mutations are mainly missense mutations concentrated in exon 17, exon 11 and exon 13. Exon 2 and exon 3 of KRAS gene were the main mutation hotspots, mainly G12X(2.08%) missense mutation. The co-mutation of KIT and KRAS was only in one patient. Unexpectedly, four patients (16.6%) carried germline deleterious mutations, in FANCA(n=1), FANCD2(n=1), FANCE(n=1), SDHA(n=1). Two of the patients with germline mutations co-mutated with KIT and KRAS, respectively. Conclusions: 16.6% of the intracranial GCT patients carry germline deleterious mutations, and 12.5% in Fanconi anemia (FA) gene. Overall, these findings indicate that the Fanconi anemia (FA) pathway and the PI3K/AKT pathway play a significant role in intracranial GCTs tumorigenesis.

Gestational trophoblastic neoplasia of intermediate trophoblasts: Epithelioid trophoblastic tumor and placental site trophoblastic tumor, a study of morphologic, immunohistochemical, and next generation sequencing.

Gestational trophoblastic tumors are very rare neoplasms. We determined the distinctive morphological, immunohistochemical, and clinical features of placental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) in our cohort. Nine cases of PSTT and four cases of ETT were retrieved from the archives. Histomorphologic, immunohistochemical, and clinical features were noted. A molecular study was performed on one PSTT and one ETT case using next-generation sequencing. While the nodular pattern, geographic necrosis, and extracellular eosinophilic globules were peculiar to ETTs, vessel wall affinity, marked pleomorphism, intranuclear pseudoinclusion, spindle tumor cell, and vacuolar degeneration were more specific for PSTTs in our series. An immunohistochemical panel of p63, hPL, and CD146 were helpful for the exact typing of the tumor. p63 positivity supports the ETT and diffuse staining of hPL and CD146 supports the PSTT diagnosis. Three of the patients with metastatic disease (lung and brain metastasis) except one have a high mitotic count (12 and 8) and a long interval between (8 and 10 years) antecedent pregnancy and diagnosis. While KIT and TP53 mutations were observed only in PSTT, amino acid changes in KDR, APC, and SMAD4 genes were detected both in the ETT and PSTT cases. In the prediction of metastasis, the long intervals between antecedent pregnancy and diagnosis, deep myometrial invasion, mitotic count, and Ki67 proliferation index were involved rather than other histomorphological parameters, but none of the parameters is an absolute predictor of the metastasis.

NeoPlus: A phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma.

9514 Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, ongoing phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566 .

Molecular profiling as a predictor of treatment response and survival in unresectable pancreatic ductal adenocarcinoma.

e16279 Background: To date, few targetable mutations have been found to enhance PDAC treatment. Next-generation sequencing (NGS) of somatic mutation profiles may help tailor cytotoxic chemotherapy selection and guide translational research. Methods: We analyzed NGS data from a retrospective cohort of 142 patients with unresectable biopsy-proven PDAC from August 2009 to December 2022. Individual mutations were grouped into 14 distinct signaling pathways: cell cycle, DNA damage repair, KIT, ErbB2, TP53, MAPK-RAS, PIK3, TGF-beta, NOTCH, ALK, FLT3, FGFR, and WNT. Treatment selection, duration of response, and survival were recorded. We stratified patients based on their first-line therapy, either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (GA). We present median time-to-first progression (PFS1) and overall survival (OS) based on the presence or absence of mutations in these pathways. The time-to-event endpoint was estimated by the Kaplan-Meier method. Results: Of 142 samples, 131 were analyzed for PFS1; 57 received FFX, and 60 received GA. In the FFX group, no pathway predicted PFS1 with statistical significance. In the GA group, KIT pathway mutations (n = 10) showed improved PFS1 vs. non-KIT mutated tumors (10.3 mos vs. 6.2 mos, p = 0.02). Similar improvement in PFS1 was seen for mutations in the PIK3 pathway (n = 25, 6.6 vs. 5.7, p = 0.02) and FLT3 pathway (n = 4, 13.1 vs. 6.2, p = 0.02). 125 samples were analyzed for OS. KIT pathway mutations (n = 21) showed a better OS vs. non-KIT mutated samples (21.3 mos vs. 12.2 mos, p = 0.04), as did NOTCH mutated samples (n = 44, 15 vs. 12.3, p < 0.01). FLT3 pathway mutations showed a trend toward improved OS (23.6 vs. 13, p = 0.3). PIK3 mutated tumors had no difference in OS. 8 samples were KRAS WT; removing these from the analysis did not change the results. Conclusions: In this sample, KIT, FLT3, and PIK3 pathway mutated tumors had improved PFS1 with GA (but not FFX) treatment. Tumors with KIT and NOTCH pathway mutations had an improved OS. This and similar analyses could help identify potential drivers of treatment response for unresectable pancreatic tumors. [Table: see text]

Multi-omic characterization of gastrointestinal stromal tumor (GIST) in a large real-world patient cohort.

11522 Background: Molecular knowledge of GIST is limited due to its rarity, few genes have been identified as relevant determinants of outcomes, tumor evolution and therapeutic targets. Therefore, we aimed to dissect the GIST molecular landscape in the largest series of real-world patients reported to date. Methods: 946 GIST patient samples (536 localized, 369 metastatic, 41 unknown) underwent next-gen sequencing of DNA (592-gene, N = 495; whole exome, N = 451) and RNA (whole transcriptome, N = 592) at Caris Life Sciences (Phoenix, AZ). Gene expression signatures of proliferation (Cristescu, 2021), cell cycle activation (CINSARC; Chibon, 2010), inflammation (T-cell inflamed; Ayers, 2017) and tumor microenvironments (MCP-counter; Becht, 2016) were examined. Statistical significance tested by χ2, Fisher’s exact, or Mann-Whitney U as appropriate. Results: GIST samples were comprised of 80% (N = 758) KITmut, 8.1% (N = 77) PDGFRAmut, and 11.7% (N = 111) KIT/PDGFRA wild-type (WT), with 14.8% (N = 140) samples harboring a secondary KIT variant suggestive of TKI resistance. Overall median TMB was 2 mutations/MB (range 0-13). WT GIST were identified with mutations in NF1 (33.7%), DNA repair genes (16.7%), SDHX (8.2%), BRAF (6.3%), and PTEN (1.9%), along with NTRK3 fusions (3.1%). Primary KIT variants occurred in exons 11 (83.5%), 9 (13.9%), and 13 (2.6%), and secondary KIT variants (14.6% of total KIT mutations) were distributed across the ATP binding pocket (36.8%) and activation loop (63.2%). Primary PDGFRA mutations were in exons 18 (62.4%), 12 (11.0%), 14 (4.6%) and other (16.5%). KIT/PDGFRAmut GIST infrequently harbored RB1, TP53, SETD2, ARID1A, PIK3CA, PTEN, TSC1, BRCA1, or CHEK2 co-mutations (1-5% each) . Copy number amplification (≥6 copies) was overall uncommon (≤2% for all genes). Proliferation and cell cycle activation signatures were higher in KIT exon 11 indels v. missense mut (1.2-fold, p < 0.05) and KIT resistant v. KIT primary (1.2-fold, p < 0.05), but not in KIT exon 11 557/558 v. others, nor between KIT v. PDGFRA v. WT subgroups. Deletion of tumor progression genes MAX (40.0%), CDKN2A (32.3%), and DEPDC5 (33.9%) was associated with increased proliferative gene expression (1.2-, 1.3-, and 1.2-fold, p < 0.05 each), while DMD deletion (52.5%) was not (1.1-fold, p = 0.37). Compared to KITmut and WT GIST, PDGFRAmut had increased abundance of several immune cell populations (range 1.2-3.7-fold, p < 0.05), along with enhanced inflammation signatures (1.1- and 1-2-fold, p < 0.05). Conclusions: This series provides unprecedented resolution of KIT/PDGFRAmut GIST with features of clinical aggressiveness associated with KIT exon 11 indels and resistance mutations, illustrating a specific cytogenetic genotype with more aggressive growth and malignant behavior. Identification of less common molecular alterations that drive kinase activation and impaired DNA damage repair warrant further investigation.

National overview of gastrointestinal stromal tumors: Experience from middle income setting.

e23515 Background: Gastrointestinal stromal tumors (GISTs) are mesenchymal malignancies representing 1-2% of all gastrointestinal cancers. There is a general shortage of reported data on GISTs from the Republic of Armenia (RA). This paper aims to conduct a national assessment of the epidemiological, diagnostic, and treatment approaches of the GISTs in RA. Methods: The study utilizes a cross-sectional design. Five-year retrospective data on patients with the moderate and high-risk group has been analyzed (from August 31, 2016, up to February 01, 2023). Data has been obtained through medical records. It was feasible to apply census sampling since each GIST patient receives Imatinib in the Hematology Center after prof. Yeolyan free of charge and all the medical records are centered in this facility. Descriptive analysis has been done to demonstrate patients’ demographic characteristics, the spread of the disease, pathological and genetic features of the tumor, and performed treatment. Results: In total 69 moderate and high-risk patients have been targeted. That counts for about 1% of all GI tumors diagnosed in Armenia in 2021. The mortality rate was 10%. The male-to-female ratio was 1.56:1. Age range was 30-81 years (median 58). Advanced disease was observed in 31.9% of cases. The primary site of the tumor (gastric vs non-gastric) was not significantly associated with the disease stage (p-value: 0.192). Expression of CD34, CD117, and DOG1 was positive in 97.3%, 100%, and 96.7% of cases respectively. However, it is worth mentioning that data on immunohistochemical (IHC) features are lacking due to the incompleteness of medical records and the absence of a joint e-health system in Armenia. Furthermore, significant under-testing of the tumor genetic profile was observed. Only 3 patients were tested for KiT mutation (positive in all cases) and no one for PDGFRA mutation. Under-testing is caused by the high cost of genetic profiling which is covered out-of-pocket in RA. All patients received first-line tyrosine kinase inhibitors (TKI). Adjuvant or palliative radiation therapy (RT) was not applied. The majority of patients (95%) underwent tumor resection for curative or palliative purposes. Conclusions: Demographic and epidemiological profile of GISTs in RA is similar to the reported international data. In contrast, the rate of advanced diseases is higher in RA, possibly due to diagnosis delays. [Table: see text]

Sex differences in localized gastrointestinal stromal tumor.

e23511 Background: Sex plays an important role in the incidence and prognosis of several cancer types. Male patients with gastrointestinal stromal tumors (GISTs) have inferior outcomes compared to women, but the reasons behind the sex differences are not well understood. This study aimed to investigate whether sex was a prognostic factor in localized GIST and to explore the relationship between sex and established clinical, molecular and histopathological characteristics. Methods: The study cohort is population-based and consisted of patients who underwent surgical resection of primary, non-metastatic GIST at Oslo University Hospital, Norway between January 2000 and September 2017. Recurrence-free survival (RFS) was the primary endpoint. Mutation analysis was performed by Sanger sequencing or by the AmpliSeq for Illumina Cancer Hotspot Panel version 2. Results: The study cohort comprised 409 patients, 202 women and 207 men. There were 275 gastric tumors (67.2%) and 134 non-gastric tumors (32.8%). Disease recurrence was recorded in 87 patients (21%) after a median follow-up of 64 months. Men with gastric tumors had inferior RFS compared to women (HR 2.18; 95% CI 1.07-4.45; P= 0.029), while there was no difference for non-gastric tumors (HR 0.77; 95% CI 0.44-1.33; P= 0.341). There was a substantial sex variation in the type of primary KIT mutation related to tumor location. Men with gastric tumors had a deletion or insertion-deletion that involved codons 557 and 558 (del557/558) more than twice as frequently as women (34% versus 16%; P= 0.008). Men also had slightly larger tumors (mean 6.6 cm versus 5.5 cm; P= 0.035) and more often tumors located in the upper third of the stomach, but there was no difference in mitotic count (23% versus 22% with > 5 mitoses per 5 mm2). There was no difference in adjuvant imatinib treatment between men and women. No sex differences in primary mutation, tumor size or mitotic count were observed for non-gastric tumors. When KIT del557/558 mutation was included in the Cox regression analysis for gastric tumors, sex was not significantly associated with RFS (HR 1.49; 95% CI 0.70-3.18; P= 0.303), while del557/558 mutation was a strong prognostic factor (HR 6.40; 95% CI 3.17-12.94; P< 0.001). Del557/558 mutation was not associated with RFS in non-gastric tumors (HR 0.67; 95% CI 0.33-1.35; P= 0.262). Conclusions: Women with localized, gastric GISTs had a lower risk of recurrence compared to men. There was no sex difference in outcome or baseline characteristics for non-gastric tumors. Men with gastric tumors more often had KIT del557/558 primary mutations, which may explain their inferior outcome. The observed sex difference in primary mutations in GISTs is unexplained and should be further explored.

Clinical utility of liquid-based comprehensive genomic profiling (CGP) in gastrointestinal stromal tumors (GIST).

11541 Background: GIST is the most common mesenchymal cancer of the digestive tract. Beyond surgery, treatment for GIST focuses largely on tyrosine kinase inhibitors (TKI), whose selection and potential resistance depend on select mutations. We present the molecular landscape of GIST utilizing tissue and liquid biopsies with emphasis on the clinical utility of liquid biopsy in advanced GIST. Methods: Liquid (FoundationOne Liquid CDx [F1LCDx]) and tissue (FoundationOne CDx) CGP was performed by hybrid capture, targeted NGS at Foundation Medicine Inc. Tissue and liquid samples from 2,198 and 147 patients, respectively, were analyzed. A cohort of 27 paired tissue and liquid samples were also evaluated. The levels of circulating tumor DNA (ctDNA) in liquid biopsies was quantified by tumor fraction (TF), with a TF algorithm incorporating aneuploidy, variant allele frequency, and canonical alterations detected on F1LCDx. Results: Tissue CGP (n = 2,198) revealed the following prevalence of primary driver alterations: KIT (77%), PDGFRA (8%), NF1 (6%), SDHA/B/C/D (SDHx, 3%) and BRAF (1%). Rates of molecular markers previously associated with worse prognosis included: CDKN2A (29%), RB1 (9%), TP53 (6%) and SETD2 (4%). 7% of cases had no reportable known pathogenic alterations in canonical GIST genes (wild-type GIST), while 2% of cases had a mutation in more than one driver. In a cohort of 147 liquid biopsies, TF was < 1% in 68.0%, 1-10% in 18.4%, > 10% in 13.6% of samples. In samples with elevated TF ( > 10%), the prevalence of targetable driver alterations in KIT (89%), PDGFRA (4%) , NF1 (4%) and BRAF (4%) was comparable to the tissue prevalence. In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration. In addition, 4/147 patients (3%) were predicted to harbor a germline KIT mutation, including one patient (0.6%) with a potential imatinib-resistant KIT D820G germline mutation and another with clinical suspicion of germline KIT L576P mutation due to the presence of multiple primary GISTs, hyperplasia of myenteric plexus and dysplastic skin nevi. In paired tissue/liquid samples, liquid detected 2/2 driver mutations found in tissue when liquid TF was > 10%, and 5/6 in specimens with TF > 1%. In the overall cohort, the relative prevalence of KIT exon 9 and 11 driver alterations was comparable in tissue vs liquid, while imatinib-resistance KIT exon 13 and 17 mutations were enriched in liquid samples. Conclusions: 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.

Genomic characterization in gastrointestinal cancer patients based on cfDNA sequencing.

e15507 Background: Gastrointestinal cancer (GIC) is one of the most prevalent cancers worldwide. Late stages diagnosis is one of the main reasons for poor prognosis of GIC. The invasive nature of endoscopy assay has greatly decrease the willingness for early screening, nearly 50% of patients diagnosed with GIC were in advanced stages. With the advanced of next-generation sequencing (NGS) technology, liquid biopsy has quickly gaining interest in early cancer screening. In order to address the poor prognosis of GIC, mutation features and potential biomarkers were investigated using NGS data from 169 Chinese GIC patients with blood derived cell-free DNA (cfDNA). Methods: Blood-derived cfDNA sampels were collected from Chinese patients with colorectal cancer (CRC) (n = 121) and gastric cancer (GC) (n = 48) and then performed pan-cancer sequencing panel targeting 680 cancer-related genes. Genomic alterations of single nucleotide variations, short indels and tumor mutation burden were analyzed. Two-sided Fisher’s exact test was used for all statistical analyses. COSMIC data was retrieved from COSMIC database version 97. Results: Among GC patients, the proportion of patients possessing mutations in TP53 (43.75% vs 37%, p = 0.49) and KRAS (10.42% vs 5.6%, p = 0.19) showed consistent distribution with COSMIC database. While KIT (14.58% vs 3.42%, p = 0.0014) and SYNE1 (10.42% vs 30.8%, p = 0.0021) showed varied distribution outcomes. CRC patient cohort also showed coherent distribution compared with COSMIC database. No significant difference was detected between the two cohorts in TP53 (51.5% vs 44.57%, p = 0.085), KRAS (36.53% vs 32.33%, p = 0.24), APC (44.91% vs 47.74%, p = 0.48) and PIK3CA (14.37% vs 14.10%, p = 0.91). However, the proportion of SYNE1 mutation is still significantly lower than in the COSMIC database (17.37% vs 29.31%, p = 0.0006). As all patients from the study cohort are Chinese, whether a lowered occurrence of SYNE1 mutation is specific to Chinese or certain region can be further studied. Conclusions: This study revealed that the mutational landscape of liquid biopsy cfDNA sequencing is highly consistent with existing database, which has consolidated the feasibility of liquid biopsy in early cancer detection. Besides, this study also revealed a lowered occurrence of SYNE1 and increased KIT mutation in the cohort. While increased KIT mutation can be explained by the proportion of recruited gastrointestinal stromal tumor patients, the lowered SYNE1 can provide new insights into region-specific diagnosis and treatment selection.

Fluorine-18 fluorodeoxyglucose (18FDG)-uptake assessment of PDGFRA mutant gastrointestinal stromal tumors (GIST): A retrospective multicenter Italian study.

11539 Background: D842V PDGFRA mutation identifies a molecular subtype of GIST, primarly resistant to imatinib and characterized by higher indolent behavior and a prominent immune profile. Although functional imaging with 18FDG-PET plays a proven role in GIST, especially in early assessment tumor response, less is known about 18FDG-uptake according to the GIST molecular subtypes. Taking into account of clinical and molecular features of D842V mutant GIST, we assumed that this subset of GIST could also have a different 18FDG-uptake. Therefore, the aim of the present study has been to investigate the degree of FDG uptake of PDGFRA mutant GIST, focusing on D842V ones, in order to better define the role of functional imaging in this rare and peculiar subset of GIST. Methods: Patients with PDGFRA mutant GIST underwent 18FDG-PET were retrospectively included from seven GIST Italian reference centers. Data on maximum standardized uptake (SUVmax) value of primary tumor or metastatic disease were collected. Results: 71 patients have been included: 37 (55.1%) with D842V PDGFRA mutant GIST (group A) and 34 (47.9%) with PDGFRA non-D842V mutant GIST (group B). Additionally, 30 patients with exon 11 KIT mutant GIST have been included, as control (group C). SUVmax values were obtained from primary tumor and metastatic lesions in 55 (54,4%) and 46 (45,6%) patients, respectively. Considering the whole population of 101 patients, the global median SUVmax was 3,7 (IQR 0-9.1), while the median SUVmax for group A, B, and C was 0, 3.6, and 10.4, respectively. The median SUVmax of PDGFRA mutant GIST was significantly lower than the median value of exon 11 KIT mutant GIST (p < 0.001). Notably, median 18FDG-uptake was significantly lower in D842V PDGFRA mutant GIST compared to PDGFRA non-D842V mutant ones (p = 0.021). Conclusions: PDGFRA D842V-mutant GIST present an overall lower 18FDG uptake compared to other GIST subgroups. This feature could be related to their specific molecular background and is consistent with their higher tendency to an indolent behavior. Therefore, the role of functional imaging with 18FDG-PET in this subset of GIST is limited. Finally, the prognostic value of the 18FDG-uptake degree within all PDGFRA mutant GIST will be investigated in the future.

Combination targeted therapy with avapritinib and sunitinib in patients with refractory gastrointestinal stromal tumors after failure of standard treatments: A small prospective pilot study.

11538 Background: There is currently no standard treatment after ripretinib beyond the fourth-line setting for refractory gastrointestinal stromal tumors (GISTs). A combination of tyrosine kinase inhibitors (TKIs) is rational to be potentially effective after failure of standard therapies. The objective of this study was to explore the efficacy and safety of avapritinib plus sunitinib in refractory GISTs. Methods: This was a prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. Participants received avapritinib 100–200 mg once a day (QD) combined with sunitinib 25–37.5 mg QD continuously in 28-day cycles until disease progression (PD) or discontinuation from January 2022 to January 2023. Clinical outcomes including objective response rate (ORR), survival and safety were assessed. Results: A total of 11 pts with a median age of 57 years were enrolled. Median follow-up duration was 4.1 months (range, 1.4–12.8 months). Median sum of target lesions was 28.2 cm (range, 6.6–47.0 cm). Four pts had primary KIT exon 11 mutation, 6 had exon 9 and one had exon 17, secondary mutation KIT exon 13 was in 2 pts, exon 14 in one, exon 16 in 2 and exon 17 in 7 pts. Seven pts received more than 4 lines of prior TKIs, three received 3 and one had 2 lines of prior TKIs. One patient (9.1%) achieved partial response (PR) with 48.7% lesion length reduction, 9 (81.8%) had stable disease (SD) with 8 out of 9 pts achieving tumor shrinkage (median sum of lesion reduction of 20.8% [range, 9.8–27.3%]), and one (9.1%) had PD according to mRECIST1.1. Eight pts (72.8%) achieved PR, one (9.1%) had SD, and 2 (18.2%) had PD according to the Choi criteria. Until last follow-up, 4 pts progressed, one withdrew from the study and one discontinued treatment after surgery. Five pts were still receiving treatment, one exceeded 1 year with 26.3% lesion reduction in the seventh line setting. Progression-free survival and overall survival results were immature. ORR and lesion reduction trended favorably in those with KIT activation loop (AL) mutations, but this was not statistically significant. The dose of avapritinib (100–150 mg/d) and sunitinib (25–37.5 mg/d) could be tolerated. Common adverse events (AEs) were anemia, leukopenia, diarrhea, fatigue, periorbital and face oedema, and memory impairment. Common grade ≥3 AEs included anemia (54.5%), leukopenia (36.4%), diarrhea (36.4%), tumor hemorrhage (27.3%) and gastrointestinal hemorrhage (18.2%). Conclusions: The preliminary results from this study demonstrated meaningful clinical benefit with avapritinib plus sunitinib, achieving significant lesion reduction in refractory GISTs, especial those with KIT AL secondary mutations. Further studies are warranted to determine the optimal dosing regimen of two targeted drugs. Clinical trial information: NCT05461664 .

SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib.

KIT is frequently mutated in gastrointestinal stromal tumors (GISTs), and the treatment of GISTs largely relies on targeting KIT currently. In this study, we aimed to investigate the role of sprouty RTK signaling antagonist 4 (SPRY4) in GISTs and related mechanisms. Ba/F3 cells and GIST-T1 cell were used as cell models, and mice carrying germline KIT/V558A mutation were used as animal model. Gene expression was examined by qRT-PCR and western blot. Protein association was examined by immunoprecipitation. Our study revealed that KIT increased the expression of SPRY4 in GISTs. SPRY4 was found to bind to both wild-type KIT and primary KIT mutants in GISTs, and inhibited KIT expression and activation, leading to decreased cell survival and proliferation mediated by KIT. We also observed that inhibition of SPRY4 expression in KITV558A/WT mice led to increased tumorigenesis of GISTs in vivo. Moreover, our results demonstrated that SPRY4 enhanced the inhibitory effect of imatinib on the activation of primary KIT mutants, as well as on cell proliferation and survival mediated by the primary KIT mutants. However, in contrast to this, SPRY4 did not affect the expression and activation of drug-resistant secondary KIT mutants, nor did it affect the sensitivity of secondary KIT mutants to imatinib. These findings suggested that secondary KIT mutants regulate a different downstream signaling cascade than primary KIT mutants. Our results suggested that SPRY4 acts as negative feedback of primary KIT mutants in GISTs by inhibiting KIT expression and activation. It can increase the sensitivity of primary KIT mutants to imatinib. In contrast, secondary KIT mutants are resistant to the inhibition of SPRY4.

Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line-Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST).

The majority of gastrointestinal stromal tumors (GIST) are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity toward the most relevant KIT mutations, in 4 GIST xenograft models. NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E), and the cell line-derived model GIST882 (KIT:p.K642E). Mice were treated daily with vehicle (control), imatinib (100 mg/kg), sunitinib (20 mg/kg), avapritinib (5 mg/kg), or IDRX-42 (10 mg/kg, 25 mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histologic response, and IHC. The Kruskal-Wallis and Wilcoxon matched-pairs tests were used for statistical analysis, with P < 0.05 considered as significant. IDRX-42 (25 mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882, and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3%, and 35.1% on the last day as compared with baseline, and tumor growth delay (160.9%) compared with control in UZLX-GIST9. Compared with controls, IDRX-42 (25 mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 histologic response with myxoid degeneration was observed in all IDRX-42 (25 mg/kg)-treated tumors. IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity, and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.

Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management.

Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs. The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations. Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients. Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.