This review discusses the current and future landscape of advanced gastrointestinal stromal tumor (GIST) treatment. It covers the role of tyrosine kinase inhibitors (TKIs), specifically imatinib, and further treatment options, such as sunitinib, regorafenib, and ripretinib, as well as avapritinib for platelet-derived growth factor receptor alpha D842V mutations. In addition, this review emphasizes individualized treatment strategies within multidisciplinary expert teams, including surgery and other locoregional therapies, together with the importance of mutation-guided approaches, particularly for wild-type GISTs. Finally, it explores the potential of next-generation KIT inhibitors, combination therapies, and other investigational approaches.

2025-07-02·MOLECULAR CANCER THERAPEUTICS

M4205 (IDRX-42) Is a Highly Selective and Potent Inhibitor of Relevant Oncogenic Driver and Resistance Variants of KIT in Cancer

Article

作者: Grädler, Ulrich ; Dorsch, Dieter ; Ross, Edith ; Petersson, Carl ; Leuthner, Birgitta ; Sherbetjian, Eva ; Drechsler, Christine ; Linde, Nina ; Blum, Andreas ; Blaukat, Andree ; Esdar, Christina ; Schieferstein, Hanno

Abstract:

Primary activating mutations in KIT (exon 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small-molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for patients with unresectable metastatic or recurrent GIST, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared with imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to the registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a phase I first-in-human study in participants with GIST.

2025-06-01·Maedica

Innovative Therapeutic Approaches in Systemic Mastocytosis: an Updated Review.

Article

作者: Leru, Poliana ; Bumbea, Horia ; Soare, Delia

Introduction:

Systemic mastocytosis (SM) is a heterogeneous clonal disorder characterized by the accumulation of abnormal mast cells in various tissues, predominantly the bone marrow. Given the rarity of the disease, the available data in Romania are extremely limited. It is estimated that the total number of diagnosed patients is approximately 170. In recent years, significant advances have been made in understanding the molecular pathogenesis of SM, leading to the development of targeted therapies that have transformed the management of this condition. The approval of tyrosine kinase inhibitors (TKIs), particularly midostaurin and avapritinib, has provided new therapeutic options for patients with advanced SM, demonstrating significant improvements in overall survival (OS) and symptom control.

Objective:

To conduct a systematic review of clinical trials, observational studies and international or national guidelines published since 2000 to evaluate the efficacy, safety and mechanistic rationale of innovative therapeutic approaches for SM - including KIT inhibitors, monoclonal antibody-based therapies, stem cell transplant - and to compare the impact of these interventions with conventional cytoreductive and symptomatic treatments on overall response rate, survival, mediator-related symptom burden, quality of life and treatment-related adverse events.

Materials and methods:

A comprehensive search was performed in MEDLINE ( via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science from 1 January 2000 to 1 May 2025. ClinicalTrials.gov, WHO ICTRP. Search strings combined controlled vocabulary ( e.g. , "Mastocytosis") and free-text terms for the disease (systemic mastocytosis, advanced SM, indolent SM) with key innovative interventions (KIT inhibitors, avapritinib, midostaurin, monoclonal antibodies, stem cell transplant). No language limits were set at the search stage; non-English full texts were excluded only if an accurate translation could not be obtained. As the review relied exclusively on published or publicly available data, ethical approval and informed consent were not required.

Conclusion:

The present review provides an updated overview of the evolving therapeutic landscape of SM, emphasizing recent clinical trial data, novel targeted therapies and emerging treatment paradigms. We discuss the implications of this progress on patient outcomes and future directions for personalized medicine in SM.

项与 KIT Inhibitor (PeptiDream) 相关的新闻（医药）

2025-08-20

·FierceBiotech

Celldex ends esophageal program despite hitting primary endpoint in phase 2 trial

Investors sent Celldex’s share price down by 18% to $19.72 in premarket trading.\n Celldex has stopped development of barzolvolimab in eosinophilic esophagitis (EoE) despite meeting its primary endpoint in a phase 2 trial. The biotech showed the candidate depletes mast cells in the gastrointestinal tract, but that positive finding was overshadowed by the antibody\'s failure to improve clinical outcomes.EoE is a chronic inflammatory condition of the esophagus characterized by the infiltration of eosinophils and mast cells, two types of white blood cells. Yet, efforts to treat the condition by targeting white blood cells have floundered. Allakos’ lirentelimab reduced eosinophils in a phase 2/3 trial but showed no significant effect on a dysphagia scale that assessed patients’ ability to swallow food, a key symptom of EoE.Now, Celldex has suffered a similar setback. The biotech randomized 65 patients to receive the anti-KIT antibody barzolvolimab or placebo. After 12 weeks, mucosal mast cell levels in the gastrointestinal tract had fallen significantly in the barzolvolimab cohort compared to placebo, achieving the trial’s primary endpoint. Previously, Celldex had shown the antibody can deplete cutaneous mast cells.Yet, the mucosal mast cell primary endpoint was just one of two key areas of focus for Celldex. The biotech also wanted to show that depleting mast cells improves symptoms, as Celldex CEO Anthony Marucci explained on a Tuesday call with investors to discuss the data.“We have repeatedly said that we needed to not only see profound impact of cell depletion, but we also [needed] a reduction of dysphagia scores that would be clinically meaningful and compare favorably to the current standard of care,” Marucci said. “These results did not meet our internal hurdle rate, and we will not advance development in this indication.” Scores on the Dysphagia Symptom Questionnaire were no better for patients on barzolvolimab than placebo, the biotech reported. Equally, Celldex saw no significant improvement in endoscopic scoring of EoE-related inflammation and fibrosis in the treatment group. After Celldex reported the trial findings and program discontinuation, investors sent the biotech’s share price down by 18% to $19.72 in premarket trading.Celldex is continuing to test barzolvolimab in two phase 3 trials in chronic spontaneous urticaria as well as in phase 2 studies in atopic dermatitis and prurigo nodularis. The biotech advanced in those settings on the strength of evidence that barzolvolimab depletes cutaneous mast cells. The discovery in the EoE trial that barzolvolimab also depletes mucosal mast cells could open up other indications for KIT inhibitors. The EoE trial suggests Celldex could expand beyond skin conditions to target gastrointestinal conditions where mast cells play a role. One possibility is that Celldex will apply its bispecific approach, rather than barzolvolimab, to gastrointestinal indications. Engaging two targets may unlock diseases where depleting mast cells is beneficial but insufficient to significantly improve clinical outcomes. The failures of Allakos and Celldex in EoE have thinned the field of late-stage programs in this indication. Amgen and AstraZeneca are still in the running, with a phase 3 trial of the partners’ anti-TSLP antibody Tezspire now fully enrolled. Tezspire reduces blood eosinophil counts but works in severe asthma patients irrespective of their starting levels of the white blood cells.

临床3期临床2期临床结果免疫疗法细胞疗法

2025-07-07

·FierceBiotech

Cogent’s phase 3 hits primary endpoint, building case for filing to challenge Blueprint’s Ayvakit

Shares in Cogent climbed 14% to $8.65 in premarket trading.\n A phase 3 trial of Cogent Biosciences’ bezuclastinib has hit its primary endpoint, teeing the biotech up to seek FDA approval for a potential rival to Blueprint Medicines’ Ayvakit.Cogent randomized 179 patients with non-advanced systemic mastocytosis to receive the KIT inhibitor bezuclastinib or placebo. After 24 weeks, total symptom scores fell 24.3 points on bezuclastinib and 15.4 points on placebo. The 8.91-point difference between the two arms was big enough for the trial to hit its primary endpoint.The biotech said the trial established new benchmarks for placebo-adjusted and absolute symptomatic improvement for the patient population. Blueprint’s Ayvakit is the current treatment for patients with indolent systemic mastocytosis. Cogent’s trial enrolled people with indolent or smoldering forms of the disease.Blueprint used a different scoring system than Cogent as the primary endpoint of its phase 3 trial. However, Cogent has argued (PDF) that the scales are highly analogous and showed the results for the two scoring systems were nearly identical in the first part of its study. Blueprint reported (PDF) a placebo-adjusted difference of 5.69 points on its scoring system. One-quarter of patients on Ayvakit had a 50% or greater improvement in symptoms, compared to 10% of their peers on placebo. Cogent’s press release lacks comparable data for bezuclastinib, with the biotech only providing a statistically significant p value for the secondary endpoint.Almost 54% of patients on Ayvakit had a 50% or greater reduction in serum tryptase, a marker of mast cell degranulation. Cogent said 87.4% of patients on bezuclastinib experienced such a reduction. Nobody on placebo in either trial had a 50% or greater reduction in the biomarker.Almost 6% of patients on bezuclastinib stopped treatment because of elevated liver enzymes that fully resolved. The most common treatment-emergent adverse events on the study drug were changes in hair color and altered taste, which affected 69.5% and 23.7% of patients, respectively. One person permanently stopped taking Ayvakit in Blueprint’s trial because of an adverse reaction.Cogent plans to file for FDA approval of bezuclastinib this year. The biotech has a current cash balance of $237 million and access to up to $350 million more via a debt facility. Shares in Cogent climbed 14% to $8.65 in premarket trading.

临床3期临床结果上市批准

2025-06-02

·FiercePharma

With Opella proceeds burning a hole in its pocket, Sanofi snaps up Blueprint for $9.1B

Sanofi has made its largest acquisition in seven years, buying up Massachusetts rare disease specialist Blueprint Medicines for $9.5 billion. In late April, when Sanofi revealed that it was selling a controlling stake in its consumer health business Opella for 10 billion euros ($11.4 billion), chief financial officer Francois Roger said that the French drugmaker would “explore external growth opportunities for bolt-on acquisitions.”Just five weeks later, Sanofi has made a deal few would describe as “bolt-on,” as it has bought out Massachusetts-based Blueprint Medicines for up to $9.5 billion.With the deal, Sanofi gains Blueprint’s portfolio of rare immunological disease treatments, including systemic mastocytosis (SM) pill Ayvakit, which generated sales of $479 million last year and has peak sales potential of $2 billion, the 14-year-old company projected last year.Blueprint also brings a next-generation SM candidate in elenestinib, a KIT D816V inhibitor which is the subject of a phase 2/3 study, and an early-stage KIT inhibitor BLU-808. KIT plays a central role in mast cell activation, Sanofi said, which is implicated in a broad range of inflammatory diseases.Sanofi is paying $129 per share for the drugmaker, which is a 27% premium over Blueprint’s closing price on May 30 and 34% above its average price over the previous 30 days.The acquisition includes contingent value rights (CVRs) tied to the advancement of BLU-808, which could expand payments to Blueprint shareholders by $2 and $4 per share, bringing the total equity value of the deal from $9.1 billion to $9.5 billion.The Blueprint buyout "complements recent acquisitions of early-stage medicines that remain our main field of interest,” Sanofi CEO Paul Hudson said in a release. “Sanofi still retains a sizeable capacity for further acquisitions.”While Blueprint’s shares jumped by 26% on Monday, Sanofi’s dropped by less than 1%.It is Sanofi’s largest acquisition since its 2018 buyout of hemophilia specialist Bioverativ for $11.8 billion. The Blueprint deal comes after Sanofi made an unsuccessful play in 2022 for another rare disease specialist, Horizon Therapeutics. In that case, Amgen took the prize with its $27.8 billion offer. Sanofi said it anticipates completing the deal in the third quarter and that it will not impact its 2025 financial guidance. The company said in April that it expects (PDF) sales to increase by mid-to-high single digits this year on top of a 9% year-over-year increase in 2024 to 41.1 billion euros ($44.5 billion).The acquisition will help revitalize Sanofi’s portfolio, which has taken a few hits recently. Last week, Sanofi and Regeneron reported the failure of a phase 3 trial of their chronic obstructive pulmonary disorder (COPD) candidate itepekimab. In February, Sanofi revealed a phase 3 trial of its invasive E. coli vaccine came up short. The candidate had been acquired from Johnson & Johnson for $250 million. Sanofi has been active in the M&A market this year, picking up Dren Bio’s clinical-stage bispecific antibody, DR-0201, for $600 million upfront and another $1.3 billion in milestones. Last month, Sanofi spent $470 million for Vigil Neuroscience and its investigative Alzheimer’s disease candidate. And in January, Sanofi paid $2.2 billion for Inbibrx and its human recombinant protein rare disease drug.Other recent Sanofi deals include a $3.2 billion acquisition of Translate Bio in 2021 and a $2.9 billion buyout of Provention Bio in 2023.