A rare cancer can form in the wall of the stomach or intestines: gastrointestinal stromal tumor, or GIST. More than 20 years ago, the introduction of Gleevec revolutionized the treatment of this disease, but the therapeutic paradigm has remained largely static ever since. Over time, most GIST patients develop resistance to Gleevec, and subsequent treatment options have offered only limited clinical benefit.
However, that long-standing stasis showed definitive signs of fracturing at the American Society of Clinical Oncology annual meeting (ASCO 2026), held in Chicago from May 29 to June 2. Developers of next-generation therapies, each vying to deliver a "second Gleevec," presented a succession of compelling clinical data. The breakthrough results have fueled widespread expectations that the standard of care for GIST is on the precipice of its first major shift in two decades.
The Landmark Breakthrough That Defined Precision Medicine
Gleevec, launched by Novartis in 2001, stands as a historic landmark in modern oncology. Initially approved with chronic myeloid leukemia (CML) as a main indication, its therapeutic scope quickly expanded after studies confirmed its profound effectiveness against GIST. As an early targeted anticancer therapy designed to precisely block specific genetic mutations that drive cancer, it is widely credited with helping usher in a new era of cancer treatment.
Its impact on CML remains a classic example of transforming a rapidly fatal diagnosis into a manageable chronic condition, lifting the five-year survival rate from roughly 30% in the early 1990s to over 90%. At its commercial peak in 2015, Gleevec generated $4.7 billion (approximately 6 trillion won) in annual global sales. While patent expirations and the influx of generic competitors around 2015 caused revenue to decline sharply, the drug remains a breakthrough that helped define the era of precision medicine.
Overcoming the Inevitability of Drug Resistance
GIST is a rare malignancy, affecting approximately 10 to 20 individuals per million globally each year. In the United States, between 4,000 and 6,000 people are newly diagnosed annually, while the Korean GIST Study Group estimates that South Korea sees between 500 and 1,000 new cases per year. Because GIST develops within the muscular layers of the gastrointestinal wall—unlike conventional gastric or colorectal cancers that originate in the mucosa—it requires an entirely distinct therapeutic approach.
In the vast majority of patients, the disease is driven by mutations in the KIT gene. The KIT gene produces a protein (c-KIT) that regulates cell growth signals; when abnormalities occur, cancer cells can proliferate uncontrollably. While localized, non-metastatic tumors can be surgically resected, systemic targeted drug therapy becomes critical if the cancer recurs or spreads.
Gleevec became the cornerstone of first-line therapy following its regulatory approval for metastatic GIST in 2002. For patients who progress past frontline treatment, sequential options narrow significantly: Pfizer’s Sutent (sunitinib) was established as the standard second-line therapy in 2006, followed by Bayer’s Stivarga (regorafenib) as the standard third-line treatment in 2013.
The primary culprit behind treatment failure is acquired drug resistance. While Gleevec powerfully suppresses the initial KIT signaling, prolonged exposure induces secondary mutations within the KIT gene, causing the drug's effect to wane and forcing clinicians to shift patients to later-line therapies.
Next-Generation Tyrosine Kinase Inhibitors Enter the Arena
Velzatinib, showcased by British pharmaceutical giant GSK at this year’s meeting, is a next-generation therapy specifically engineered to overcome these resistance mechanisms. Designed to suppress resistance mutations that newly emerge while patients are taking Gleevec and Sutent, the drug was originally developed by Boston-based biotech IDRx, which GSK acquired in January 2025 in a transaction valued at approximately $1 billion.
Early clinical results demonstrated remarkable efficacy: velzatinib achieved an objective response rate of 61% in frontline patients. Among the 49 second-line patients evaluated, 38% experienced tumor shrinkage. Given that the historical response rate for standard second-line Sutent typically hovers in the teens, velzatinib's performance represents a significant clinical leap. For patients who had received second-line or later treatment, the median time without cancer worsening extended up to 17 months.
Velzatinib may also offer a superior safety and tolerability profile due to its extreme precision. While older multi-kinase inhibitors like Sutent hit a broad array of targets beyond KIT—leading to a heavy burden of systemic side effects—velzatinib focuses tightly on KIT mutations alone, raising hopes for a much-improved quality of life for patients.
A High-Stakes Regulatory Race to Redefine the Playbook
To solidify its clinical momentum, GSK highlighted its ongoing StrateGIST 3 Phase 3 trial, which directly compares velzatinib monotherapy against standard-of-care Sutent in patients with imatinib-resistant GIST. Concurrently, the company is preparing to launch a global Phase 3 frontline trial pitting velzatinib head-to-head against Gleevec in newly diagnosed patients, aiming to completely rewrite the GIST treatment playbook much like Gleevec did more than 20 years ago.
Meanwhile, U.S.-based Cogent Biosciences presented full Phase 3 data from its PEAK trial for bezuclastinib, another potent KIT inhibitor. Originally licensed from Plexxikon (now part of Japan's Daiichi Sankyo group), bezuclastinib was evaluated in combination with Sutent for patients who developed resistance to Gleevec. The results were striking: the dual-therapy combination delivered a median time without cancer worsening of 16.5 months, more than seven months longer than the 9.2 months achieved by the Sutent monotherapy control group.
These frontrunners utilize fundamentally different therapeutic strategies. Bezuclastinib is a highly selective inhibitor targeting specific KIT mutations, meaning it must be paired with another agent like Sutent to block multiple mutations simultaneously. Conversely, velzatinib operates as a pan-KIT inhibitor, aiming to capture a wider range of KIT mutations within a single molecule.
As these next-generation strategies mature, other players continue to explore niche opportunities. Deciphera Pharmaceuticals (now a subsidiary of Japan's Ono Pharmaceutical) noted that while its drug Qinlock previously failed to prove superiority over Sutent in the second-line setting, significant clinical utility was confirmed within specific patient subgroups, prompting further targeted exploratory development.
For GIST patients who have navigated a virtually unchanged treatment sequence for more than two decades, the sheer volume of positive data at ASCO 2026 marks an extraordinary turning point. While full Phase 3 readouts and long-term safety profiles are still required to secure definitive regulatory entries, the momentum toward a historic shift in the standard of care is officially undeniable.
