Unresectable Gastrointestinal Stromal Tumors Research Articles

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1.

Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

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 .

Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2-3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.

Phase 1/1b first-in-human study of IDRX-42, a novel oral tyrosine kinase inhibitor (TKI), in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs).

TPS483 Background: The majority of GISTs are driven by constitutively activated kinases, either KIT or platelet-derived growth factor-alpha ( PDGFRA), and respond to TKI treatment (eg, imatinib, sunitinib, regorafenib, ripretinib). Most GISTs develop heterogeneous resistance to TKI during treatment, usually driven by secondary mutations in the primary kinase oncogene ( KIT or PDGFRA). Novel therapies are needed to prevent emergence of resistant subclones or to treat TKI-resistant GISTs. IDRX-42 (formerly M4205) is a potent, highly selective, orally administered small-molecule TKI targeting disease-specific oncogenic drivers and a range of clinically relevant resistance mutations of KIT. Nonclinical studies of IDRX-42 have demonstrated robust antitumor activity in patient and cell line-derived GIST xenograft models, including models with relevant KIT mutations and TKI resistance mutations (De Sutter et al AACR 2022). Methods: IDRX-42-001 is a phase 1/1b, first-in-human, open-label, multicenter study to evaluate single-agent IDRX-42 in participants with metastatic and/or surgically unresectable GISTs. Phase 1 dose escalation utilizes a 3+3 design to evaluate safety, tolerability, PK, and preliminary antitumor activity of IDRX-42 to establish the MTD and RP2D. Phase 1b will consist of exploratory cohorts with selected lines of prior therapy to assess the antitumor activity of IDRX-42 and further characterize its safety profile at RP2D. Eligible participants are ≥18 yr old with ECOG PS 0–1, documented pathogenic mutation in KIT or any PDGFRA mutation other than exon 18 mutations, and ≥1 measurable lesion per mRECIST v1.1 by investigator assessment. Phase 1 dose-escalation participants must have documented progression on at least imatinib. For phase 1b exploratory cohorts, cohort 1 participants must have progressed on imatinib only (2nd line); cohort 2 participants must have progressed on imatinib and sunitinib (3rd line) or progressed on imatinib, sunitinib, and an additional agent (ie, regorafenib or ripretinib; 4th line); cohort 3 participants must have progressed on imatinib, sunitinib, regorafenib, and ripretinib (≥5th line). IDRX-42 will be initiated at 120 mg PO QD in 28-d cycles until disease progression, unacceptable toxicity, or other reason. Primary endpoints are to determine the nature, incidence, & severity of IDRX-42 TEAEs and DLTs (phase 1), and to evaluate safety and determine ORR per investigator assessed mRECIST v1.1 (phase 1b). Secondary efficacy endpoints include PK parameters, DoR, PFS, and time to response related to IDRX-42. Exploratory endpoints will evaluate potential predictive and pharmacodynamic markers using ctDNA, as well as changes in KIT, PDGFRA, and other relevant gene mutant allele fractions and their correlation with clinical outcomes. Enrollment is ongoing (NCT05489237). Clinical trial information: NCT05489237 .

Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors.

In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit BCR-ABL in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.

NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022.

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

The Role of Regorafenib in the Management of Advanced Gastrointestinal Stromal Tumors: A Systematic Review.

Regorafenib, a multi-kinase inhibitor, has been widely used to treat patients with gastrointestinal stromal tumors (GIST) who failed the initial treatment with imatinib and sunitinib. This systematic review aims to demonstrate the efficacy and safety of regorafenib for patients with metastatic and/or unresectable GIST. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform this systematic review. We searched PubMed, Science Direct, and Cochrane databases to identify relevant articles based on predefined selection criteria. The implication of the search strategy results in 776 records from all databases. We excluded conference abstracts, discussion articles, case reports, case series, systematic reviews, and other observational non-intervention studies from the study, along with the articles published in languages other than English. After the screening and quality assessment, 10 studies were selected for final review - two randomized controlled trials and eight non-randomized prospective and retrospective review articles of intervention. Regorafenib improved the survival rates of patients after the failure of imatinib and sunitinib treatment, with an acceptable safety profile. Close monitoring of the patients may be needed to detect and manage the grade 4 or higher adverse events.

Liver transplantation combined with tyrosine kinase inhibitors for the treatment of hepatic metastatic giant gastrointestinal stromal tumors: A case report and literature review

BackgroundSurgical resection combined with oral tyrosine kinase inhibitors(TKI) is the most effective treatment for gastrointestinal stromal tumor(GIST) liver metastases. Liver transplantation (LT) is the last resort for the treatment of terminal liver malignancy. Whether it can be a potential treatment option for liver metastases from unresectable GIST is worth exploring.Case presentationWe report a 38-year-old woman who underwent jejunal stromal tumor resection and TKI(imatinib) therapy 15 years ago for jejunal stromal tumor liver metastases. During the period from 2015 to 2018, the liver metastases continued to grow after the patient stopped taking imatinib voluntarily, and the patient subsequently underwent multiple interventional surgeries and drug treatments, which were still poorly curative. The tumor was deemed unresectable because it filled the entire liver, and the patient subsequently underwent LT and was treated with imatinib post-operatively, which resulted in no recurrence of the tumor within 18 months of follow-up.Literature reviewThere are few reports in the literature on LT for the treatment of liver metastases from GIST. A systematic review and summary of the current literature by literature search revealed that LT as a last resort for metastatic GIST of the liver remains a major challenge.ConclusionsLT combined with TKI-targeted therapy is a potential therapy worth exploring for patients with unresectable metastatic GIST.

Abstract 495: Outcomes of an expanded access program for patients with gastrointestinal stromal tumors in low- and middle-income countries

Abstract Background: Gastrointestinal Stromal Tumors (GIST) treatment was revolutionized by the introduction of the tyrosine kinase inhibitor imatinib. More recently, sunitinib, has prolonged survival in patients (pts) with metastatic disease resistant to imatinib. 10-year survival for high-risk pts treated with adjuvant imatinib is 79%. Median overall survival for pts with unresectable or metastatic GIST is 4.8 years. In order to bring access to these life-saving medications to pts in low- and middle- income countries (LMICs), The Max Foundation (TMF) developed its Max Access Solutions (MAS) program in 2017, after administering Novartis’ imatinib (Glivec) International Patient Assistance Program (GIPAP) since 2002. We analyzed the outcomes of pts enrolled in these programs from 2002-2020 for both adjuvant (n=2100) or metastatic (n=9,867) GIST across 67 countries. Methods: Demographic data and treatment indications were reported by treating physicians. The clinical status of each enrolled pt was reviewed with TMF every 3-4 months. Pts who were lost to follow-up (LTFU) (n=2282) with metastatic or unresectable disease were presumed to be deceased. Alternatively, for patients treated in the adjuvant setting an imputation based informed censoring model was used to estimate events for LTFU patients (n=477). Kaplan-Meier analysis was used to estimate the distribution of progression-free (PFS) and overall survival (OS). Results: The median age at diagnosis was 54 and 55 years in the adjuvant and metastatic groups, respectively. Males comprised 59.5% of all metastatic/unresectable cases and females 51.3% of adjuvant cases. Median OS for pts treated with imatinib for unresectable or metastatic disease was 5.8 years (CI: (5.6, 6.1)) and PFS was 3.5 years (CI: (3.5, 3.7)). Pts treated with imatinib in the adjuvant setting had a 10-year OS of 72% and PFS of 70%. Median OS of pts with metastatic disease treated with sunitinib was 2 years (CI: (1.5, 2.5)); PFS was 1.2 years (CI: (0.9, 1.6)). Multivariate analysis showed that male sex was a negative prognostic factor in both the metastatic and adjuvant setting. Other variables including World Bank Income groups and frequency of contact were not associated with increased mortality or progression in any group. Discussion: This is the largest known cohort of GIST outcomes and the first study to present outcomes from predominantly low- and middle-income countries. Additionally, studies in LMICs are challenged by high rates of lost to follow-up which can falsely prolong or shorten survival times due to censoring. Therefore, we employed an informed censoring model to better reflect survival in the adjuvant setting. We demonstrate that access to a targeted oral anti-cancer therapy results in outcomes similar to those in high resource countries and provides a model to help close the global gap in cancer outcomes. Citation Format: Edward Lloyd Briercheck, J. Michael Wrigglesworth, Philip Stevenson, Alicia A. Annamalay, Pat Garcia-Gonzalez, Michael Wagner. Outcomes of an expanded access program for patients with gastrointestinal stromal tumors in low- and middle-income countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 495.

A systematic review on unresectable gastrointestinal stromal tumor (GIST) liver metastases as a new indication for liver transplantation: Has its time arrived?

A systematic review on unresectable gastrointestinal stromal tumor (GIST) liver metastases as a new indication for liver transplantation: Has its time arrived?

Gastrointestinal Stromal Tumors: What Is the Best Sequence of TKIs?

In our practice, we evaluate the mutation status of advanced unresectable disease to guide decisions on use of tyrosine kinase inhibitor (TKI) therapy. This review focuses on management of GIST with KIT and PDGFRA mutations. Imatinib is first-line treatment for unresectable gastrointestinal stromal tumors (GISTs) unless they harbor a PDGFRA D842V mutation; it is recommended to escalate imatinib to twice daily dosing for KIT exon 9 mutant tumors. When patients progress on first-line treatment, treatment is changed to sunitinib followed by regorafenib; while the spectrum of activity against resistance mutations varies with these agents, routine biopsies provide data on one area of disease and ctDNA has not been validated prospectively. For those with a PDGFRA D842V mutation, avapritinib is the first TKI to lead to tumor response and disease control. Ripretinib is approved in the 4th line setting, with limited data on its benefit for PDGFRA D842V GIST. Avapritinib can be considered for treatment beyond ripretinib for KIT mutant disease. The efficacy of other TKIs tested in GIST is reviewed. Ongoing therapy provides palliative benefit and should be continued given rapid decline observed off of treatment.

Imatinib-associated skin rash is related to treatment outcome in patients with unresectable and/or metastatic gastrointestinal stromal tumor.

Imatinib-associated skin rash in gastrointestinal stromal tumor (GIST) patients is one of the most troublesome adverse effects, and can reduce imatinib adherence and persistence. However, the relationship between skin rash and adherence is unknown, and there are few published studies on the clinical outcomes of patients with severe skin rash. Adult patients (≥18 years) who were treated with 400 mg/day imatinib for unresectable or metastatic GIST were enrolled in this retrospective study. The skin rash was graded by physicians according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Progression-free survival (PFS) was compared using the Kaplan-Meier method between groups with and without skin rash. The risk factors for GIST progression were investigated by Cox regression analysis. A total of 125 GIST patients were finally included. Among them, 43 (34.4%) patients developed skin rash during imatinib treatment. Serial blood eosinophil levels were associated with skin rash and severity (P<0.001). Patients with skin rash tended to have poorer PFS than patients with no rash (P=0.035). Moreover, patients with rash had a significantly higher prevalence of non-adherence compared with patients without rash [odds ratio (OR): 3.42, 95% confidence interval (CI): 1.36-8.61, P=0.009 for grades 1-2; OR: 6.07, 95% CI: 1.42-26.11, P=0.015 for grades 3-4). Cox regression analysis indicated that the independent risk factors for GIST progression were non-adherence (OR: 4.20, 95% CI: 1.57-11.25, P=0.004) and medium- and high-risk GIST (OR: 5.38, 95% CI: 1.15-25.09, P=0.032). Non-adherence and medium- and high-risk GIST are independent risk factors for GIST progression. Skin rash can be associated with treatment adherence, which can in turn be associated with poor outcomes of GIST treatment. Measuring the blood eosinophil levels could be helpful in predicting risk of skin rash during imatinib treatment.

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.