In a bridging study of INTRIGUE, second-line ripretinib demonstrated comparable progression-free survival (PFS) and favorable safety versus sunitinib in Chinese patients with advanced gastrointestinal stromal tumor. Overall survival (OS) was highly immature at the time of primary analysis. This updated analysis assessed long-term OS of ripretinib versus sunitinib.
This phase 2, multicenter, randomized, open-label study in China enrolled patients with gastrointestinal stromal tumor previously treated with imatinib, randomized (1:1) to ripretinib 150 mg once daily by continuous dosing in 42-day cycles or sunitinib 50 mg once daily in 42-day cycles (four weeks on/two weeks off). The updated analysis assessed OS and PFS on third-line therapy in all-patient intention-to-treat and KIT exon 11-mutated intention-to-treat (Ex11 ITT) populations.
Of 108 patients randomized, 54 received ripretinib and 54 sunitinib; 70 had a primary KIT exon 11 mutation (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT). By December 30, 2024, in all-patient intention-to-treat population, median OS was 43.3 months with ripretinib and 29.9 months with sunitinib (hazard ratio, 0.681; 95% CI, 0.411–1.126; nominal p = .134). In the Ex11 ITT population, median OS was 43.3 months with ripretinib and 28.6 months with sunitinib (hazard ratio, 0.552; 95% CI, 0.291–1.047; nominal p = .065). PFS on third-line therapy was comparable between treatment arms in both populations.
After two additional years of follow-up, ripretinib showed a trend toward clinically meaningful OS benefit versus sunitinib in the Ex11 ITT population. Second-line ripretinib does not appear to affect third-line treatment efficacy.
Accurate prediction of the recurrence risk of localized primary gastrointestinal stromal tumors (GISTs) after complete surgical resection is crucial for determining adjuvant treatment and surveillance strategies. Traditional risk-stratification schemes often exhibit heterogeneity and may not provide sufficient prognostic information. Therefore, the authors' objective was to develop a pathomics nomogram that integrates digital pathology and machine-learning algorithms to improve predictive accuracy. The authors enrolled 421 eligible participants (253 in the training cohort, and 168 in the external validation cohort) from four medical centers. Four distinct machine-learning methods were evaluated, and the one that demonstrated optimal performance in the validation cohort was selected to develop the pathomics model. Subsequently, stepwise multivariate Cox regression analysis was performed to construct a machine-learning–based pathomics nomogram (the MLPNom). The MLPNom exhibited superior predictive performance compared with traditional risk criteria (concordance index values: training cohort, 0.892; validation cohort, 0.964). The time-dependent area under the curve values for the MLPNom were notably higher than those for traditional risk criteria (5-year area under the curve values: training cohort, 0.919; validation cohort, 0.959). Calibration curves and Brier scores confirmed the excellent calibration of the MLPNom. Decision curve analysis further underscored the utility of the MLPNom in clinical decision making for GISTs. Furthermore, the MLPNom identified three distinct prognostic subgroups that retained their significance after stratification based on diverse clinicopathologic factors. The MLPNom demonstrates robust discrimination and calibration in predicting recurrence-free survival in localized primary gastric and small intestinal GISTs after complete surgical resection. This may complement traditional risk criteria and aid in selecting patients for adjuvant imatinib therapy.
Tyrosine kinase inhibitors (TKIs) are the primary therapeutic agents for patients with gastrointestinal stromal tumors (GISTs). Imatinib has demonstrated efficacy as a first-line treatment for intermediate- and high-risk localized GISTs, as well as for relapsed or metastatic progressive GISTs. However, some patients develop resistance to imatinib, which leads to accelerated progression, complex genetic mutations, and high spatiotemporal heterogeneity. The efficacy of the second-, third-, and fourth-line standard treatments recommended by the latest National Comprehensive Cancer Network guidelines is limited, and no unified treatment protocol after the failure of fourth-line therapy exists. Therefore, exploring new treatment modalities is crucial. This article reviews recent research on treatment strategies after the failure of standard treatments for progressive GISTs, including the alternating or combined use of different TKIs, radiotherapy, and immunotherapy. It also discusses relevant advances presented at international conferences, which provide new evidence-based support for clinical decision-making.
Although therapeutic drug monitoring is crucial for the comprehensive management of gastrointestinal stromal tumors (GISTs), the relationship between plasma concentration of ripretinib and its therapeutic efficacy is unknown. This study aimed to explore the relationship between ripretinib plasma trough concentration (R-Ctrough) and clinical efficacy and between ripretinib concentration and the incidence of adverse reactions among Chinese patients with advanced GIST.
The authors analyzed patients with GIST treated continuously for ≥1 month with a consistent daily dose ripretinib in a real-life setting. Peripheral venous blood samples were collected 24 h after the previous dose to measure R-Ctrough and 4 h after the current dose to identify the maximum concentration (R-C4). The plasma concentrations of ripretinib and its metabolites were quantified using liquid chromatography-tandem mass spectrometry.
Between June 2021 and October 2024, 102 patients receiving ripretinib were evaluated. Ripretinib treatment resulted in higher mean R-Ctrough values in the nonprogression group than in the progression group (p < .05). Patients exhibiting an R-Ctrough above the threshold (R-Cmin, 475 ng/mL) demonstrated a significant improvement in median progression-free survival from 12.8 to 22.6 months (p < .05). A correlation was observed between ripretinib blood concentration and the occurrence of alopecia, fatigue, hand-foot syndrome, and rashes (p < .05). Moreover, variability in blood–drug concentrations was observed among patients with different KIT genotypes.
Ripretinib and its metabolites maintained consistent plasma concentrations in Chinese patients with advanced GIST. Furthermore, a trough ripretinib concentration >475 ng/mL was associated with extended survival.
Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcomas of the gastrointestinal tract, with most cases harboring oncogenic driver mutations in the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor α (PDGFRA). The advent of targeted therapy, notably the first tyrosine kinase inhibitor (TKI) imatinib, has revolutionized the treatment landscape for GISTs. Recent advancements and emerging evidence in the diagnosis, treatment, and assessment of treatment response to TKIs in GISTs have led to updates to major clinical practice guidelines, including the latest guidelines from the Chinese Society of Clinical Oncology (CSCO, 2024), the US National Comprehensive Cancer Network (NCCN, version 1.2025), and the European Society for Medical Oncology (ESMO, 2022). Although these guidelines align on fundamental principles, some key differences in recommendations exist. This commentary highlights discrepancies in the recommendations for managing GISTs as outlined in these major guidelines. Based on emerging new evidence from recent studies, the authors propose recommendations to be considered for inclusion in future guideline updates to optimize management strategies and ultimately improve the outcomes of patients with GISTs.
Targeted therapy with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of unresectable advanced gastrointestinal stromal tumors (GISTs), significantly prolonging the survival and improving the quality of life of affected patients worldwide. However, resistance to TKIs inevitably occurs. Surgery following TKI therapy has been investigated for its clinical benefits in patients with advanced GISTs. Recent advancements have enhanced our understanding of using TKIs to create opportunities for and facilitate subsequent surgical interventions. These interventions appear feasible for highly selected cases and demonstrate survival benefits. Current evidence primarily comes from combining first-line treatment with imatinib and surgery, with limited clinical studies on second- and later-line TKIs. When formulating optimal treatment strategies, key factors such as surgical timing, factors influencing surgical benefit (including treatment response, disease extent at the time of surgery, and completeness of surgery), surgical morbidity, and TKI selection should be carefully assessed. Multidisciplinary care involving targeted therapy with suitable TKIs and appropriate surgical modalities may extend the duration of TKI treatment and improve associated clinical outcomes. Therefore, further studies, particularly randomized trials, on a global scale, are warranted. This commentary review offers insights for treatment decision-making in clinical practice, aiming to optimize patient-centered care for individuals with advanced GISTs and ultimately enhance survival benefits and quality of life for these patients.
Emerging evidence suggests that circadian timing influences the efficacy of immune checkpoint inhibitors (ICI), with morning infusions associated with improved therapeutic outcomes across various malignancies. However, the impact of ICI infusion timing on extensive-stage small cell lung cancer (ES-SCLC), a disease with poor prognosis and limited therapeutic advancements, remains unexplored.
This retrospective study (LungTime-R02) analyzed 397 patients with ES-SCLC who received first-line anti–PD-L1 (atezolizumab or durvalumab) plus chemotherapy at our center between May 2019 and October 2023. The time of day of administration (ToDA) was calculated as the median infusion time for each patient’s first four ICI treatment cycles. To assess its prognostic relevance, hazard ratios (HRs) of earlier progression or death were estimated across multiple ToDA thresholds (11:00–16:30). Propensity score matching (1:2) was applied to balance baseline characteristics.
Of the 397 patients, the optimal ToDA cutoff for maximizing progression-free survival (PFS) benefit was identified as 15:00, with the lowest HR for PFS observed at this threshold. Patients who received immunochemotherapy before 15:00 exhibited significantly longer PFS and overall survival compared to those treated later, with results consistent across pooled and propensity score matching cohorts. Multivariable analysis confirmed early ToDA as an independent prognostic factor for both PFS (adjusted HR, 0.483; 95% CI, 0.357–0.654) and overall survival (adjusted HR, 0.373; 95% CI, 0.265–0.526).
This study provides real-world evidence supporting the survival benefit of earlier immunochemotherapy administration in patients with ES-SCLC. These findings add to the growing body of knowledge on the clinical relevance of circadian timing in cancer treatment.
Not applicable
Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is characterized by poor response to traditional chemotherapy but heightened sensitivity to immune checkpoint inhibitors (ICIs). However, it is unclear whether envafolimab, a subcutaneous programmed death-ligand 1 inhibitor, provides comparable efficacy and safety as a neoadjuvant treatment in these patients compared to programmed cell death-1 inhibitors.
This open-label, single-arm phase 2 trial enrolled patients with locally advanced dMMR CRC. Participants received subcutaneous envafolimab (300 mg every 3 weeks) for three to four cycles. Tumor response was assessed using computed tomography/magnetic resonance imaging and endoscopy, with pathological response evaluated postsurgery. The primary end point was the complete response rate (CR), including clinical complete response (cCR) and pathological complete response (pCR). The secondary end points included R0 resection rate, 3-year disease-free survival, 5-year overall survival, and treatment-related adverse events (AEs).
Between August 22, 2022, to August 22, 2024, 15 patients were enrolled and received at least one dose of envafolimab. Two patients were excluded from efficacy analyses due to loss of follow-up or patient refusal. Of the remaining 13 patients, seven (53.8%) achieved a complete response (two, cCR; five, pCR). The median time to CR was 3.1 months. Eleven patients underwent radical surgery, with no disease recurrence observed during follow-up. Treatment-related AEs were mild and of low incidence (28.6%), with only one patient experiencing a grade 3 fever. Subcutaneous administration of envafolimab demonstrated high patient convenience and satisfaction.
This preliminary study suggests that envafolimab is a promising effective and safe neoadjuvant option for locally advanced dMMR CRC; confirmation in larger cohorts is awaited.
Fludarabine with melphalan (FM) or busulfan (FB) is among the most widely used reduced-intensity conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The authors conducted a systematic review and meta-analysis comparing these regimens in adult patients with hematologic malignancies.
A comprehensive search of Ovid MEDLINE, Embase, and the Cochrane Library from inception through July 22, 2025, identified 17 eligible studies involving 10,396 patients. Pooled analyses were performed using a random-effects model, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.
In the overall analysis, FM was associated with improved progression-free survival (PFS) (HR, 0.90; 95% CI, 0.82–0.98), driven by lower relapse rates (HR, 0.69; 95% CI, 0.62–0.78) but increased treatment-related mortality (TRM) (HR, 1.44; 95% CI, 1.10–1.89). There were no significant differences in overall survival (OS), grade 3–4 acute graft-versus-host disease (GVHD), or chronic GVHD. In subgroup analyses, FM significantly improved OS and PFS, primarily driven by a significant reduction in relapse risk in acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) and elderly patients aged ≥60 years without significant differences in TRM. In contrast, for lymphoma patients, FM was associated with worse OS and higher TRM compared with FB, and no advantage in PFS, but significantly lower relapse.
These findings suggest that FM may be a preferred reduced-intensity regimen for AML/MDS and elderly patients, whereas lower intensity regimens may be needed for lymphoma to reduce TRM and optimize long-term survival after allo-HSCT.
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