ASCO 2026 Breakthrough: Two Decades of Stagnation Ended as GIST Therapy Enters a New Paradigm

Jun 03, 2026 14:11 CST Updated 14:11

GSK

Pharmaceutical R&D Manufacturer

Gastrointestinal stromal tumors (GIST): No breakthrough in the standard clinical treatment regimen has been achieved over the past two decades. At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, two next-generation KIT inhibitors unveiled impressive clinical data, holding promise to break the long-standing therapeutic impasse and drive a comprehensive paradigm shift in the treatment of this rare gastrointestinal malignancy.

A 20-Year Unresolved Dilemma: The Dual Burden of Drug Resistance and Side Effects

GIST is a rare malignant tumor originating from the interstitial cells of Cajal in the gastrointestinal tract,KIT Gene Mutationare the core drivers of its occurrence and development. In 2002, Novartis’ imatinib and, in 2006, Pfizer’s sunitinib were successively approved, establishing the standards for first-line and second-line targeted therapy for metastatic gastrointestinal stromal tumors (GIST). Over the subsequent nearly two decades, there has been no iteration of entirely new core treatment regimens in this field.

However, the clinical limitations of two classic targeted drugs are becoming increasingly apparent. Dr. Suzanne George, a renowned oncology expert at the Dana-Farber Cancer Institute, pointed out that tumor cells produceSecondary KIT Resistance Mutations, is the core mechanism of imatinib treatment failure and disease progression in patients, and also a core challenge that has long been faced in clinical practice.

For patients with imatinib resistance, sunitinib, the conventional second-line therapy, faces the dual challenges of limited efficacy and poor safety, with a clinical response rate only in the low double digits. Meanwhile, due to its broad target profile, it inadvertently affects key signaling proteins such as VEGF, leading to a high incidence of adverse reactions. Furthermore, the subsequent third-line regorafenib and fourth-line ripretinib offer limited clinical benefits, far failing to meet the long-term treatment needs of resistant patients. There is an urgent clinical need for a new generation of highly effective and safe targeted therapies.

GSK Velzatinib: Broad-Spectrum Coverage as Monotherapy, Phase I Data Impresses Across the Board

At this year’s ASCO Annual Meeting, GSK publicly disclosed the preliminary Phase I clinical data for its core candidate drug, velzatinib, for the first time. Acquired through GSK’s January 2025 acquisition of IDRx, velzatinib is a novel precision-targeted therapy. As a next-generation tyrosine kinase inhibitor (TKI), it not only precisely targets primary KIT mutations driving gastrointestinal stromal tumors (GIST) but also effectively covers secondary mutations that confer resistance to earlier-generation TKIs, thereby addressing the therapeutic limitations of traditional TKIs.

Hesham Abdullah, Head of Oncology R&D at GSK, stated that velzatinib has the potential to replicate the landmark significance of imatinib and reshape the global standard of care for metastatic gastrointestinal stromal tumors (GIST).

The data released this time shows:

In24 Treatment-Naïve (First-Line) PatientsIn China, the tumor response rate of velzatinib reached61%
At49 Cases of Imatinib-Resistant Second-Line Patients, the response rate was38%, significantly higher than the historical data for sunitinib
For Patients in Second-Line and BeyondMedian Progression-Free Survival (PFS) Reached 17 Months, this figure far exceeds that of existing standard-of-care treatments

Compared with traditional multi-target TKIs, velzatinib features high target specificity, acting precisely on the KIT target alone, thereby effectively avoiding toxic side effects associated with off-target effects and demonstrating a significantly superior safety profile. Dr. George highly endorsed the drug, noting that its Phase I clinical data exhibited an excellent objective response rate and durability of efficacy, indicating substantial potential for clinical application.

Currently, GSK has officially launched the pivotal Phase III StrateGIST 3 trial, a head-to-head comparison of velzatinib versus sunitinib in patients with second-line resistant gastrointestinal stromal tumors (GIST). Meanwhile, the Phase III trial pitting this drug against imatinib in the first-line setting is also in preparation, aiming to comprehensively reshape the therapeutic landscape across the entire continuum of GIST care.

Cogent’s Bezuclastinib: Breakthrough in Combination Therapy, Expected Approval by Year-End

In the race for next-generation KIT inhibitors, in addition to GSK, Cogent Biosciences also prominently announced the complete Phase III clinical data of its self-developed drug bezuclastinib at this year’s ASCO conference, providing a new combination therapy approach for patients with resistant GIST.

Data show that, in imatinib-resistant GIST patients,Median PFS with bezuclastinib plus sunitinib reached 16.5 months, whereas the sunitinib monotherapy group had a median of only 9.2 months, with benefit observed across all mutation subgroups.

Currently, the New Drug Application for bezuclastinib has been submitted to the U.S. Food and Drug Administration (FDA), with the official approval decision expected to be announced on November 30, 2026. Andrew Robbins, CEO of Cogent Biosciences, stated that the company has completed all preparations for the drug’s commercial launch and is awaiting regulatory approval. Upon approval, bezuclastinib will be rapidly introduced into clinical practice, providing a novel therapeutic option for patients with resistant gastrointestinal stromal tumors (GIST).

However, this drug has clear application limitations: it targets only specific subtypes of KIT mutations and cannot cover all pathogenic mutation types alone. It must be used in combination with other KIT inhibitors to achieve comprehensive antitumor efficacy. This also means that it cannot replace imatinib as the first-line treatment and is only suitable for second-line combination therapy scenarios.

Intense Competition: GIST Treatment Poised for Comprehensive Transformation

Meanwhile, Deciphera, a subsidiary of Ono Pharmaceutical, is actively positioning itself in the second-line treatment landscape for gastrointestinal stromal tumors (GIST), focusing on expanding the indications for ripretinib, its established fourth-line therapy. Although the previous head-to-head Phase II trial comparing ripretinib with sunitinib in the second-line setting did not meet its primary endpoint, subsequent subgroup analyses confirmed that certain specific patient populations derived significant benefit. The company is currently advancing targeted follow-up studies to further explore its clinical value.

As a key contributor to the development of sunitinib, Dr. George currently serves on the steering committee for multiple Phase III clinical trials of velzatinib. She acknowledges that the field of gastrointestinal stromal tumor (GIST) treatment, which has remained stagnant for two decades, is now entering a window period for disruptive paradigm shifts.

Looking ahead, the treatment of gastrointestinal stromal tumors (GIST) will completely move away from the traditional model of single-agent therapy, evolving into a diversified precision medicine framework characterized by “monotherapy with next-generation KIT inhibitors combined with multi-target combination regimens.” The concentrated breakthroughs and rapid market approval of multiple innovative drugs are poised to fundamentally disrupt the therapeutic stagnation that has persisted for two decades, offering global GIST patients new, more efficient, safer, and more precise comprehensive treatment solutions throughout their disease course.

References:https://www.fiercebiotech.com/biotech/asco-2026-paradigm-shift-rare-gut-cancer-looms

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