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PURPOSE OF REVIEW: This review explores the role of circulating tumor (ct)DNA as a biomarker for clinical decision-making and monitoring purposes in metastatic gastrointestinal stromal tumor (GIST) patients. We discuss key insights from recent clinical trials and anticipate the future perspectives of ctDNA profiling within the clinical landscape of GIST. RECENT FINDINGS: The identification and molecular characterization of KIT/platelet-derived growth factor receptor alpha (PDGFRA) mutations from ctDNA in metastatic GIST is feasible and reliable. Such identification through ctDNA serves as a predictor of clinical outcomes to tyrosine-kinase inhibitors (TKIs) in metastatic patients. Additionally, conjoined ctDNA analysis from clinical trials reveal the evolving mutational landscapes and increase in intratumoral heterogeneity across treatment lines. Together, this data positions ctDNA determination as a valuable tool for monitoring disease progression and guiding therapy in metastatic patients. These collective efforts culminated in the initiation of a ctDNA-based randomized clinical trial in GIST, marking a significant milestone in integrating ctDNA testing into the clinical care of GIST patients. SUMMARY: The dynamic field of ctDNA technologies is rapidly evolving and holds significant promise for research. Several trials have successfully validated the clinical utility of ctDNA in metastatic GIST, laying the foundations for its prospective integration into the routine clinical management of GIST patients.

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INTRODUCTION: Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED: In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION: The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

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Immune checkpoint blockers (ICB) act by reverting the immunosuppressive phenotype of cancer cells, thus allowing host immune system to generate an immune response to the tumor. One of the key mechanisms targeted by ICB is the PD-1/PD-L1 axis, which lies onto the interaction between the programmed-cell death protein 1 and its ligand, overexpressed in several tumor types. This interaction leads to the inhibition of T-cell proliferation and their apoptosis and exhaustion. Anti-PD-1/PD-L1 monoclonal antibodies are now the mainstay of treatment for several advanced stage tumors. Dostarlimab is a novel IgG4 anti-PD-1 antibody which has yielded remarkable results in mismatch-repair deficient endometrial cancer and locally advanced rectal cancer. This product review will illustrate the preclinical development of dostarlimab and its pharmacological characteristics, the clinical trials published so far and the ongoing clinical investigations.

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Metastatic urothelial carcinoma (mUC) is a lethal disease for which platinum-based chemotherapy represents the standard of care; however, long-term survival is achieved only in a minority of patients. Recently, along with important advances in the comprehension of the biology of this disease, the treatment paradigm of mUC has undergone a rapid expansion with the approval of several immune-checkpoint inhibitors (ICIs) and targeted agents in both first- and second-line settings. Cisplatin-based chemotherapy remains the backbone of first-therapy for mUC; nevertheless, for those patients who do not progress after the full course of first-line chemotherapy, maintenance treatment with the anti-PD-L1 avelumab showed to prolong overall survival compared observation alone. Moreover, the disappointing results of chemotherapy in pre-treated patients have led to the investigation and the subsequent approval of the anti-PD-1 pembrolizumab, which showed an unprecedented survival benefit when compared to second-line chemotherapy. Recently, target therapy with the antibody-drug conjugate (ADC) enfortumab vedotin, directed against Nectin-4, showed outstanding results in patients treated with both chemotherapy and immunotherapy. The FGFR inhibitor erdafitinib and sacituzumab govitecan, an ADC targeting Trop-2, demonstrated encouraging activity in phase II studies and are currently under investigation in randomized phase III trials. ICIs and targeted therapies also demonstrated promising results as first-line treatment of cisplatin-ineligible patients; randomized trials of ICIs alone or in combination with targeted agents are ongoing and may broaden the therapeutic armamentarium for this category of patients. In this review, we describe the current state of art for the treatment of mUC; in addition, we present the latest evidences from the most recent literature and congress presentations. Finally, we illustrate the key ongoing clinical trials, focusing on ICIs and target therapies.

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Lurbinectedin is an antitumor agent belonging to the natural marine-based tetrahydroisoquinoline family which has shown very promising clinical activity with a favorable safety profile in many types of cancer. Preclinical evidence showed that lurbinectedin inhibits active transcription and binds to GC-rich sequences, leading to irreversible degradation of RNA polymerase II and generation of single- and double-strand DNA breaks and, as a consequence, apoptosis of tumor cells. In addition, lurbinectedin has demonstrated modulation of the tumor microenvironment and activity against cancer cells harboring homologous recombination DNA repair deficiency. Although considerable improvements have been made in the treatment of epithelial ovarian cancer, most patients with advanced disease experience recurrence with a dismal prognosis due to chemotherapy (mainly platinum) resistance. Platinum-resistant/refractory ovarian cancer remains a difficult-to-treat setting of disease, and currently, the exploration of new therapeutic approaches represents a main field of interest. Although the CORAIL phase III study did not meet its primary endpoint, the results suggest that lurbinectedin might be a valid alternative for patients that have exhausted therapeutic options. This article will focus on the clinical evidence, the most recent investigations, and the future perspective regarding the use of lurbinectedin in ovarian cancer.

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Among liver vascular tumours, hepatic small vessel neoplasm (HSVN) has been recently identified as a rare infiltrative vascular neoplasm whose malignant potential is yet to be fully ascertained. About 30 cases of HSVN have been described so far. The most common clinical presentation is an asymptomatic solitary liver lesion. Multifocal disease has been described in literature; however, to date, there are no reports of disease dissemination to other organs. Here we report a case of multifocal HSVN with synchronous spleen secondary lesions.

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