Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

Rationalising Optimal Dosing of Phytotherapeutics For Use In Children: Current Status - Potential Solutions - Actions Needed.

"Children are not small adults with respect to the treatment with medicinal products." This statement of the WHO was the basis for the initiative of the European Commission for the establishment of a paediatric regulation in 2007 to improve the health of children by facilitating the development of medicines for children and adolescents. Seventeen years later, in the field of herbal medicinal products, results are still sobering. Therefore, the Foundation Plants for Health, Society for Medicinal Plants and Natural Products Research, and German Society for Phytotherapy organised a symposium to assess the status quo for the paediatric use of herbal medicinal products (HMPs), to analyse the causes of the current situation, and to discuss strategies for establishing the proof of safe and efficacious HMPs for children.The current situation for HMPs and their use in children is not fulfilling the requirements of legislation. HMPs in paediatrics are effective and safe, but considering the needs of children is necessary. In European countries, the use, registration, and marketing of HMPs are different, depending on the respective national regulations and specific traditions. EU herbal monographs are the best common denominator for such procedures. Emerging safety discussions must be considered. New approaches with real-world data might be a solution. The regulatory framework is to be adapted. Defining rationalised dosing for HMPs can be achieved by the extrapolation of data from adults, by using existing clinical data for children, and by using RWD. Therefore, a strong need for revising restrictions for the use of HMPs in children and rationalising defined dosage regimes is obvious.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

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.

Quality variation of maidong (Ophiopogon japonicus and Liriope spicata) - A HPTLC-based approach.

The tuberous roots of Ophiopogon japonicus and Liriope spicata are used for the same therapeutic purpose in traditional Chinese medicine and are collectively referred to as maidong medicine. Interestingly, it was observed that the price of tuberous roots varies depending on their location on the plant, and fibrous roots are usually discarded post-harvest. Mislabeling might be of concern due to similarities in morphological features between the two species. Moreover, paclobutrazol has been observed to be heavily applied during the production, and therefore might be of health concern. Overall, maidong might suffer from quality inconsistencies while its metabolomic complexity is influenced by growing region and cultivation practices, botanical species, and plant parts. To address these challenges, this study employed High-Performance Thin Layer Chromatography (HPTLC) approach, in which sample preparation and derivatization procedure were optimized to enable to capture more detailed and comprehensive metabolomic fingerprints. By integrating with rTLC algorithm and Multivariate Data Analysis (MVDA), an improved quality assessment was achieved. Samples were collected from four production regions and supplemented with commercial products from markets. The optimized HPTLC analysis recognized species- and region-specific metabolomic patterns of maidong, uncovering a 4% of mislabelled cases. Moreover, findings highlight the underexplored therapeutic potential of fibrous roots, and comparable therapeutic efficacy between different root types. Additionally, complemented by Liquid Chromatography-Mass Spectrometry (LC-MS) for paclobutrazol residue evaluation, 24.66% of the commercial maidong samples surpassed maximum residue limits of paclobutrazol, raising safety concerns. This research represents a significant analytical advancement, offering a robust, cost-effective, and comprehensive method for maidong quality control, and paving the way for more strict residue regulation and updates to herbal pharmacopoeias and monographs.

Avapritinib treatment of aggressive systemic mastocytosis with a novel KIT exon 17 mutation.

Background: Systemic mastocytosis is a rare hematologic malignancy that leads to the accumulation of neoplastic mast cells in the bone marrow, visceral organs, and skin. Mutations in the receptor tyrosine kinase, KIT are seen in most patients with systemic mastocytosis. The most common mutation is a gain of function mutation in KIT D816V. Avapritinib is a highly selective KIT D816V inhibitor approved for the treatment of advanced systemic mastocytosis. Recent studies have also suggested that avapritinib is active across other KIT mutations located in exon 11 and exon 17. Case Presentation: A 68 year old woman was referred for a history of lymphadenopathy and diarrhea and was ultimately found to have systemic mastocytosis with involvement in her bone marrow, gastrointestinal tract, liver, and spleen. The bone marrow biopsy reveled a novel KIT p.D816-N822delinsMIDSI mutation in exon 17. The patient was started on avapritinib leading to significant decrease in the frequency of her diarrhea and a significant reduction in her tryptase levels. Her course was complicated by arthralgias leading to a decrease in her avapritinib dose and ultimately a degranulation episode requiring hospitalization. Following dose re-escalation, patient has remained clinically stable without any further adverse events. Conclusion: We report a case of aggressive systemic mastocytosis with a novel KIT mutation on exon 17 treated with avapritinib leading to a sustained response. While avapritinib is known as a potent inhibitor against the D816V mutation, our case suggests that it may also be effective against other rare KIT mutations in systemic mastocytosis offering more potential treatment options in patients with rare mutations.

Active natural compounds perturb the melanoma risk-gene network.

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds.

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies.

PURPOSE: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS: 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 ≥4 line settings.

From the CONSORT to the ConPhyMP statement and beyond-how to ascertain best practice.

With the implementation of the ConPhyMP reporting tool as an element of peer review in Frontiers in Pharmacology, Section Ethnopharmacology and in other journals, this short perspective paper highlights the use of a new tool available via the website of the Society for Medicinal Plant and Natural Product Research (https://ga-online.org/best-practice/) and how to use it. The ConPhyMP guidelines and the tool cover the relevant aspects which need to be reported when studying a plant extract using pharmacological, toxicological microbiological, clinical and other approaches. In our vision, science will only remain impactful if it is based on a drive for best practice, i.e., on a sound conceptual and methodological basis.

Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor.

PURPOSE: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. PATIENTS AND METHODS: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. RESULTS: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P = .0006) and 0.0% (P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. CONCLUSION: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Avapritinib treatment of KIT D816V-mutant atypical chronic myeloid leukemia.

Background: Atypical chronic myeloid leukemia (aCML) is a rare myelodysplastic/myeloproliferative neoplasm. There is no proven standard of care treatment and the only curative option available is hematopoietic stem cell transplant. In addition to traditional chemotherapy, targeted therapy has shown to be a promising. Avapritinib is a selective type 1 tyrosine kinase inhibitor with high potency for KIT D816V and was recently approved for treatment of systemic mastocytosis. Here we present a case of aCML with novel D816V mutation treated with avapritinib for 17 months leading to clonal extinction of the driver mutation. Case presentation: An 80 year old man initially presented for evaluation of aCML. A bone marrow biopsy was completed, and next generation sequencing was notable for a novel KIT D816V mutation. Patient was started on avapritinib leading to significant improvement in leukocytosis and extinction of the D816V mutation over 17 months of treatment. The extinction was followed with serial next generation sequencing. Conclusion: We present the first case of aCML with KIT D816V driver mutation. We also demonstrate two novel management strategies. First, we show that treatment with avapritinib does not need to be limited to cases of systemic mastocytosis and could be useful in other hematologic malignancies with this driver mutation. Furthermore, with the use of serial next generation sequencing we were able to identify new emerging clones. While none of the clones noted in this study were targetable, they could be in other patients with aCML and help guide treatment.

A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor.

PURPOSE: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. RESULTS: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. CONCLUSIONS: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

Single botanical drugs in the Ayurvedic Pharmacopoeia of India-A quantitative ethnobotanical analysis.

Developing evidence-based uses of herbal medicines and natural product-based drug discovery are two core aims of ethnopharmacology. This requires an understanding of the medicinal plants and the traditional medical knowledge associated with them which is a basis for cross-cultural comparison. The botanical drugs of traditional medical systems are still not understood well, even for well-known and widely respected traditions like Ayurveda. In this study, a quantitative ethnobotanical analysis was performed on the single botanical drugs included in the Ayurvedic Pharmacopoeia of India (API), presenting an overview on the medicinal plants of Ayurveda from perspectives of plant systematics and medical ethnobotany. Part-I of API includes 621 single botanical drugs, which are sourced from 393 species (323 genera in 115 families). Of these, 96 species yield two or more drugs, together accounting for 238 drugs. Taking the traditional concepts, biomedical uses and the pragmatic disease classification into account, therapeutic uses of these botanical drugs are sorted into 20 categories, which meet primary health demands. The therapeutic uses of the drugs sourced from the same species may differ considerably, but 30 of the 238 drugs are used in highly similar way. The comparative phylogenetic analysis identifies 172 species with high potential for specific therapeutic uses. This medical ethnobotanical assessment for the first time provides a comprehensive understanding on the single botanical drugs in API from the perspective of medical botany using an "etic" (scientist-oriented) approach. This study also highlights the importance of quantitative ethnobotanic methods in understanding traditional medical knowledge.