Unresectable Gastrointestinal Stromal Tumors Research Articles

POSB342 Time Until Definitive Deterioration (TUDD) in Patient Reported Outcomes (PROS) in a Phase 3 Trial for Ripretinib in 4L Patients with Gastrointestinal Stromal Tumour (GIST)

Ripretinib is FDA-approved as a fourth-line therapy in unresectable GIST and is the only NCCN-recommended therapy. In the INVICTUS study, an international, multicenter, randomised, double-blind, placebo-controlled Phase 3 trial, ripretinib was shown to be an effective, and well-tolerated inhibitor of KIT and PDGFRA primary and secondary mutations, delaying disease progression in unresectable advanced 4L GIST. Ripretinib patients reported being able to maintain quality of life (QoL), health, and physical and role functioning in the INVICTUS study, while these measures declined sharply in the placebo arm.

Assessment of Adherence to Imatinib and Health-Related Quality of Life Among Patients with Gastrointestinal Stromal Tumor: A Cross-Sectional Study in an Oncology Clinic in Malaysia.

PurposeTo evaluate the rate and predictors of non-adherence to imatinib in gastrointestinal stromal tumor (GIST) patients, as well as to compare the difference in health-related quality of life (HRQOL) between adherent and non-adherent patients.Patients and MethodsA cross-sectional study at the Oncology Clinic, Hospital Kuala Lumpur was conducted from March to August 2018. All patients with metastatic and/or unresectable GIST aged ≥18 years old and on at least 3 months of imatinib were included. Adherence to imatinib was assessed using the 10-item validated Medication Compliance Questionnaire, with a score of <100% indicating non-adherence. Non-adherence predictors were determined by multiple logistic regressions. HRQOL was evaluated by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The difference in the mean HRQOL scores between adherent and non-adherent groups was determined by multivariate analysis of variance.ResultsA total of 89 patients were enrolled, of which 49 (55.1%) were considered non-adherent. The significant predictors of non-adherence were age (adjusted odds ratio [OR] 0.93; CI 0.89–0.98; P = 0.007), presence of nausea and vomiting (OR 5.63; CI 1.25–25.27; P = 0.024), and presence of comorbidities (OR 4.56; CI 1.44–14.40; P = 0.010). Patients who were in the adherent group showed significantly better score in overall HRQOL, F (15, 73) = 2.09, P < 0.02; Pillai’s trace = 0.3, partial eta squared = 0.30.ConclusionNon-adherence to long-term treatment with imatinib among patients with GIST should not be underestimated. Significant predictors of non-adherence among this population are younger age, presence of nausea and vomiting, as well as comorbidities. Patients with good adherence portrayed better HRQOL.

Avapritinib in unresectable or metastatic gastrointestinal stromal tumor with PDGFRA exon 18 mutation: safety and efficacy

ABSTRACT Introduction Avapritinib (formerly known as BLU-285) is an orally available type I tyrosine kinase inhibitor that, in 2020, obtained regulatory approval for the treatment of patients with gastrointestinal stromal tumors (GISTs) harboring a primary mutation in PDGFRA exon 18, including the PDGFRA D842V mutation. Areas covered Herein, we comprehensively review the available efficacy and safety data on avapritinib, with the final goal of providing practical knowledge to both sarcoma and community-based oncologists for the correct management of this rare GIST subpopulation with this novel therapy. Expert opinion The approval of avapritinib in GIST is a milestone in precision oncology, as this is the first agent ever demonstrating unequivocal antitumoral activity in GIST driven by the multi-resistant PDGFRA D842V mutation. The safety profile is manageable and tolerability-guided dose adjustment is recommended to manage treatment-related adverse events without compromising efficacy. Based on its unprecedented activity, avapritinib should be considered as first-line therapy for GIST patients harboring this mutation. We strongly recommend to determine KIT/PDGFRA genotype in order to identify the different GIST molecular subtypes and guide treatment decision.

New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor.

The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in "early treatment phase", new predicting factor in earlier stage is desired to work out the whole strategy of each patient.Early morphological change(EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer.The purpose of the present study was to verify the efficacy of EMC in predicting theoutcome in patients with GIST receiving imatinib at early evaluation. We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (-) group. We investigated the association between the presence of active MR and clinical outcomes. Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23months (P = 0.0039). The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor.

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.

Abstract 1482: M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST

Abstract Oncogenic mutations in cKIT in exons 9 and 11 are the main driver of gastrointestinal stromal tumors (GIST). Imatinib is standard of care in 1L in unresectable metastatic or recurrent GIST, yet secondary resistance mutations in exons 13/14 and 17/18 of the cKIT kinase domain frequently arise limiting efficacy. Currently approved 2L and 3L therapies sunitinib and regorafenib target these mutations only to some extent and show limited clinical benefit. Even with the recent approval of ripretinib as 4L treatment, a high unmet medical need remains for patients with imatinib resistance mutations in exon13/14. M4645 was designed to particularly inhibit the frequent V654A resistance mutation in exon 13 of cKIT. Based on cKIT inhibitor scaffolds identified within the Merck compound collection, a 3,5,6-substituted indazole-lead was discovered. Substituent optimization in the 5- and 6-positions of the core scaffold resulted in highly selective kinase inhibitors. Through variation at the 3-position, potency and physicochemical properties were optimized, resulting in the candidate molecule M4645 which combined potency, kinase selectivity, and solubility with a good safety profile. The excellent kinase selectivity could be rationalized by the crystal structure of cKIT V654A mutant kinase domain in complex with M4645. M4645 showed potent inhibition of cKIT autophosphorylation and of downstream P-ERK1/2 and P-AKT signaling in cell lines bearing activating and resistance mutations of cKIT. Dose-dependent inhibition of cKIT activation was demonstrated in a GIST xenograft model expressing the cKIT resistance mutation V654A in exon 13. Strong antitumor activity was observed in cell line and patient-derived GIST xenograft models with this imatinib resistance mutation. Compared to imatinib, M4645 induced prolonged anti-tumor response in a GIST model with a primary activating mutation of cKIT. In summary, the favorable profile and strong antitumor activity, particularly in GIST models expressing the V654A resistance mutation, suggests superiority of M4645 compared to currently available &amp;gt; 2L treatment options for unresectable metastatic or recurrent GIST patients. Citation Format: Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar. M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1482.

Ripretinib and MEK Inhibitors Synergize to Induce Apoptosis in Preclinical Models of GIST and Systemic Mastocytosis

The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells.

Clinicopathological features and treatment outcome of oesophageal gastrointestinal stromal tumour (GIST): A large, retrospective multicenter European study

BackgroundOesophageal gastrointestinal stromal tumours (GISTs) account for ≤1% of all GISTs. Consequently, evidence to guide clinical decision-making is limited. MethodsClinicopathological features and outcomes in patients with primary oesophageal GIST from seven European countries were collected retrospectively. ResultsEighty-three patients were identified, and median follow up was 55.0 months. At diagnosis, 59.0% had localized disease, 25.3% locally advanced and 13.3% synchronous metastasis. A biopsy (Fine Needle aspiration n = 29, histological biopsy n = 31) was performed in 60 (72.3%) patients. The mitotic count was low (<5 mitoses/50 High Power Fields (HPF)) in 24 patients and high (≥5 mitoses/50 HPF) in 27 patients. Fifty-one (61.4%) patients underwent surgical or endoscopic resection. The most common reasons to not perform an immediate resection (n = 31) were; unresectable or metastasized GIST, performance status/comorbidity, patient refusal or ongoing neo-adjuvant therapy. The type of resections were enucleation (n = 11), segmental resection (n = 6) and oesophagectomy with gastric conduit reconstruction (n = 33), with median tumour size of 3.3 cm, 4.5 cm and 7.7 cm, respectively. In patients treated with enucleation 18.2% developed recurrent disease. The recurrence rate in patients treated with segmental resection was 16.7% and in patients undergoing oesophagectomy with gastric conduit reconstruction 36.4%. Larger tumours (≥4.0 cm) and high (>5/5hpf) mitotic count were associated with worse disease free survival. ConclusionBased on the current study, enucleation can be recommended for oesophageal GIST smaller than 4 cm, while oesophagectomy should be preserved for larger tumours. Patients with larger tumours (>4 cm) and/or high mitotic count should be treated with adjuvant therapy.

Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.

BackgroundMost gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single‐arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.Materials and MethodsEligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.ResultsAs of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10–25). Median duration of response was 10.2 months (95% CI, 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI, 2.8–4.6).ConclusionAvapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations.Implications for PracticeIn the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.

Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial

BackgroundPDGFRA D842V mutations occur in 5–10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. MethodsNAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. ResultsBetween 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6–not reached [NR]); median PFS was 34.0 months (95% CI: 22.9–NR). Median OS was not reached. ConclusionTargeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules.

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

Unresectable gastrointestinal stromal tumor (GIST) liver metastases as a new indication for liver transplantation

Purpose: Liver metastases from gastrointestinal stromal tumors (GIST) can be found synchronously to a primary tumor and in the medium/long term after resection of a high-risk GIST. In these cases, treatment with tyrosine kinase inhibitors like imatinib has provided good results, but drug resistance is common after two years of treatment. Liver resection of potentially resectable metastases can improve the results of medical treatment. In cases of unresectability, the role of liver transplantation (LT) has not been well-studied. Method: A systematic review of the literature was undertaken from January 1995 to December 2020. Results: Fifteen cases were identified. In eight cases, the LT was carried out before 2000. Mutational status was only studied in seven cases. LT was performed in 12 cases with a deceased donor and in three cases with a living donor. After a mean follow-up of 52.4 months, overall survival was 86.6% with disease-free survival of 53.3%. Conclusion: LT in the management of unresectable GIST metastases has rarely been performed. Although its application has a solid theoretical basis, its use understood as a radical extension of a standard resection can only be recommended within prospective studies by groups with considerable experience in both GIST and transplantation care.

Financial Implications of Avapritinib for Treatment of Unresectable Gastrointestinal Stromal Tumors in Patients With a PDGFRA Exon 18 Variant or After 3 Previous Therapies in a Hypothetical US Health Plan

With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. The model compared scenarios with and without avapritinib in a formulary. Annual, total, and per member per month (PMPM) budget impact. In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

Research advance of liquid biopsy in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Surgical resection is the only curative treatment, while imatinib is the first-line therapy for recurrent, metastatic, and unresectable GIST. However, more than half of GIST patients suffer from secondary resistance to imatinib within 2 years after treatment initiation. Therefore, early diagnosis, drug resistance and recurrence surveillance are critical for GIST patients. Liquid biopsy is a new method which utilizes the detection of tumor biomarkers in peripheral blood for early diagnosis and therapeutic efficacy assessment. In recent years, liquid biopsy has achieved significant research progress in several kinds of malignancy. This review aims at presenting an overview on research advance of liquid biopsy in GIST and may provide a new method for early diagnosis and therapeutic efficacy assessment of GIST.

Recent advances in the management of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is a rare but an important clinical entity seen in our clinical practice. It is the most common mesenchymal tumor of the gastrointestinal tract and most common malignancy of the small intestine. Although the exact prevalence of GIST is not known, the incidence of GIST has been increasing. GISTs arise from interstitial cells of Cajal. Most of the GISTs occur due to mutation in c-kit gene or platelet derived growth factor receptor alpha gene. 15% of GISTs do not have these mutations and they are called wild-type GISTs. Almost all GISTs express KIT receptor tyrosine kinase. Histologically, GISTs look like spindle cell tumors most of the time but they can be epitheloid or mixed type. The median size of GISTs varies from 2.7 cm to 8.9 cm. Clinically, patients with small GISTs remain asymptomatic but as the GIST size increases, patients present with various symptoms depending on the location of the GIST. Most of GISTs are located in the stomach or small bowel. Diagnosis is suspected on imaging and endoscopic studies, and confirmed by tissue acquisition with immunohistochemical staining. The aggressiveness of GISTs depends on the size, mitotic index and location. Surgical resection is the treatment of choice. But various endoscopic modalities of resection are increasingly being tried. Tyrosine kinase inhibitors are extremely useful in the management of large GISTs, unresectable GISTs and metastatic GISTs. Treatment options for metastatic GISTs also include radiotherapy, chemotherapy, hepatic artery embolization, chemoembolization and radiofrequency ablation.

Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib.

Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

Preliminary safety, pharmacokinetics, and efficacy results from an open-label, multicenter, Phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors (GIST).

e23526 Background: More than 85% of GIST patients (pts) have tumors associated with KIT or PDGFRA mutations. Avapritinib is a potent, selective, small-molecule inhibitor that targets KIT/PDGFRA activation loop mutants. Recently FDA approved avapritinib for pts with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations based on a robust ORR (84%) in the NAVIGATOR study. This abstract reports preliminary results from the dose escalation part of the bridging study in Chinese pts with advanced GIST. Methods: Adult pts with unresectable or metastatic GIST that progressed after imatinib and ≥ 1 other tyrosine kinase inhibitor, or could not tolerate the standard treatment or had PDFGRA D842V mutation were enrolled and treated with avapritinib once daily (QD) in continuous 28-day cycles following a modified 3+3 dose escalation design. Primary objectives included determination of Recommended Phase II dose (RP2D) and assessment of safety. PK parameters and response per mRECIST v1.1 for GIST were also assessed. Results: As of 25 Dec 2019, 12 pts were treated with avapritinib QD at a starting dose of 200 mg or 300 mg (6 per group). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were Grade (G) 1-2, most commonly blood creatine phosphokinase increased (n = 9) and blood bilirubin increased (n = 8). There were no G4-5 TEAEs. The most frequent G3 treatment-related TEAE was anaemia (n = 2). Serious adverse events were observed in 1 pt (renal hydrocele) in 200 mg group and 2 pts (abdominal distension and anaemia) in 300 mg group, all were G3 and considered unrelated to avapritinib. No AEs leading to drug discontinuation occurred. Avapritinib was rapidly absorbed (median Tmax 2.0-4.0 h) and the exposure increased proportionally with doses at the steady state. The mean half-life of avapritinib ranged 42.2-44.4 h, supporting QD dosing. Of the 3 pts with PDGFRA D842V mutation (all in the 300 mg group), 2 pts achieved PR, and 1 had SD, as assessed by investigators at the first tumor assessment. Conclusions: Avapritinib appears generally tolerable at 200 mg and 300 mg QD and shows clinical activity in Chinese pts with PDGFRA D842V mutation. Based on the safety profile in Chinese pts and dose selection results in NAVIGATOR study, 300 mg QD was determined to be the RP2D for Chinese pts. The preliminary safety, PK, and efficacy data support further investigation of avapritinib in Chinese pts with GIST. Clinical trial information: NCT04254939 .

Lower-dosing ponatinib in pre-treated GIST: Results of the POETIG phase II trial.

11536 Background: Despite long-lasting responses to imatinib most metastatic gastrointestinal stromal tumors (GIST) eventually progress and subsequent treatments are associated with limited duration of disease control. Ponatinib is a potent KIT inhibitor with a strong activity against secondary mutations in exon 17, including the highly resistant D816 mutations of KIT. Based on the dose-depending toxicity profile we sought to evaluate the safety and activity of lower dosing (30mg) ponatinib in pretreated patients with KIT-mutant GIST. We here report safety data for the whole cohort and first efficacy data for the last line cohort within a planned interim analysis. Methods: This multicenter phase 2 trial (NCT03171389) recruited patients with advanced, unresectable GIST progressing after imatinib (Cohort A/B: absence/presence of KIT Exon 13/14 mutations by plasma sequencing) or imatinib, sunitinib and regorafenib (Cohort C). Patients were treated with 30mg oral ponatinib daily in 4-week-cycles. The primary endpoint was the clinical benefit rate at 16 weeks as measured by mRECIST1.1 criteria. Results: At the cutoff date of 31st Jan 2020, 39 patients were evaluable for safety analysis (25 male, 14 female, median age 60 (38-86) years). Median duration of treatment was 65 (14-699) days. 66.7% of all patients observed Grade 3/4 adverse events (AEs), most common were pain (10/39), hypertension (6/39), GGT or lipase increase (both 5/39), and fever (3/39). One AE of special interest was observed (myocardial infarction, rated not related to study drug) and 20/39 patients experienced at least 1 severe AE (6/39 possibly related to ponatinib). Within the last line cohort, 20 patients were evaluable for efficacy. Clinical benefit rate was 35% (CI 15.4-59.2%). Median progression-free survival was 86 days with single patients yielding long-lasting responses (75% quartile 210 days, maximum: 420 days). Conclusions: Treatment with ponatinib was tolerable at a dose of 30mg qd with a toxicity profile comparable to other TKIs used in GIST. The majority of grade 3/4 AEs were hypertension or asymptomatic increases of laboratory values and thromboembolic events were rare. In a heavily pretreated patient population that lacks alternative treatment options the clinical activity was notable. An updated analysis including predictive biomarkers will be presented. Clinical trial information: NCT03171389 .

Avapritinib: First Approval.

Avapritinib (AYVAKIT™) is a potent and selective tyrosine kinase inhibitor of platelet-derived growth factor receptor alpha (PDGFRA) and KIT activation loop mutants. It is being developed by Blueprint Medicines for the treatment of gastrointestinal stromal tumours (GIST), solid tumours and systemic mastocytosis. Avapritinib is approved in the USA for PDGFRA exon 18 (including D842V) mutant GIST and is undergoing regulatory assessment in the USA as a 4th-line treatment for GIST. Avapritinib is also undergoing regulatory assessment in the EU for PDGFRA D842V mutant GIST. This article summarizes the milestones in the development of avapritinib leading to this first approval for the treatment of adults with unresectable or metastatic GIST harbouring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Clinical development of avapritinib is also underway for the treatment of systemic mastocytosis and late-stage solid tumours in several countries.

A retrospective cohort study of 304 patients with gastrointestinal stromal tumors in mackay memorial hospital

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs often occur in middle-aged and older individuals. The main morphologic type of GISTs is the spindle cell type. Immunohistochemistry and genotyping can help to identify GISTs from other subgroups of sarcoma. Materials and Methods: This retrospective study collected 304 patients over a 10-year period (from January 2009 to June 2019) who were diagnosed with GISTs based on the pathological database of our hospital. We retrospectively analyzed the clinical manifestations and treatment strategies. Results: Anemia or gastrointestinal bleeding was the most common symptom (36.5%), followed by gastrointestinal discomfort (32.6%) and incidental findings (21.4%). Ruptured tumors with hollow organ perforation increased the mortality risk. Liver metastasis and peritoneal seeding were the most two common patterns of recurrence. GISTs arising in adults are characterized by the near-universal expression of CD117/KIT antigen. Early surgery with margin-free resection is the best strategy for GISTs without metastasis. Routine lymph node dissection is not recommended. Laparoscopic surgery is feasible and safe for GISTs in the gastrointestinal tract. Endoscopic submucosal dissection to treat GISTs is suitable for small tumors with very low-to-intermediate risk in the stomach. Postoperative treatment with tyrosine kinase inhibitors can prolong recurrence-free survival after surgery. Conclusion: Surgical resection is the preferred treatment for patients without metastasis. Administration of tyrosine kinase inhibitors such as imatinib is recommended for unresectable, metastatic, or recurrent GISTs. Postoperative follow-up by computed tomography to detect early recurrence is recommended.