Twenty Years of Waiting: How ASCO 2026 Is Rewriting the Playbook for GIST Treatment

For two decades, oncologists treating patients with gastrointestinal stromal tumors have worked with the same two drugs. Imatinib, approved by the FDA in 2002, and sunitinib, approved in 2006, have defined the standard of care for metastatic GIST since the early years of the targeted therapy era. They have saved lives. They have also, for most patients, eventually stopped working. At the 2026 American Society of Clinical Oncology annual meeting in Chicago, two separate datasets arrived that together suggest the long wait for something better may finally be ending.

A Disease Defined by Its Mutations

GIST is the most common soft tissue sarcoma, with an estimated 80,000 to 120,000 new cases diagnosed globally each year. Roughly 80 percent of cases are driven by mutations in the KIT gene, which encodes a tyrosine kinase receptor that, when mutated, drives uncontrolled tumor cell growth. Imatinib works by inhibiting KIT at the primary mutation sites, most commonly in exons 9 and 11. The problem is that approximately 90 percent of patients treated in the first line eventually develop secondary resistance mutations, predominantly in exons 13 and 17, that imatinib cannot effectively inhibit. Sunitinib addresses some of those secondary mutations but is hampered by its broad activity profile, hitting targets beyond KIT and generating side effects that limit tolerability. No approved tyrosine kinase inhibitor has been able to inhibit the full spectrum of clinically relevant primary and secondary KIT mutations simultaneously. That gap is precisely what both programs presented at ASCO are designed to close.

Cogent Biosciences: A Phase 3 Win That Changes the Conversation

The more immediately consequential of the two datasets came from Cogent Biosciences, whose PEAK Phase 3 trial of bezuclastinib in combination with sunitinib versus sunitinib alone in imatinib-resistant or intolerant GIST patients delivered results that the field has not seen before. Median progression-free survival in the bezuclastinib combination arm reached 16.5 months, compared to 9.2 months for sunitinib monotherapy, a hazard ratio of 0.50 with a p-value below 0.0001. The objective response rate in the combination arm was 46 percent, against 26 percent for sunitinib alone. Cogent's CEO Andrew Robbins described the result as the first treatment ever to demonstrate a statistically significant advantage against an active comparator in GIST patients, and the data support that characterization.

What makes the PEAK result particularly notable is its consistency across patient subgroups. The benefit held regardless of whether patients carried primary or secondary KIT mutations, which matters clinically because the mutational landscape of GIST at the time of second-line treatment is heterogeneous. A drug that works only in a narrow mutational subset has limited utility in a disease where resistance evolves unpredictably. Bezuclastinib targets KIT exon 17 mutations, including the D816V variant, which are among the most common secondary resistance mutations that emerge after imatinib failure. By combining it with sunitinib, which addresses other resistance mutations, the combination achieves broader mutational coverage than either agent alone.

The FDA has granted bezuclastinib Priority Review, with a PDUFA date of November 30, 2026. Cogent has also established an expanded access program for eligible patients and announced the initiation of a new cohort investigating the combination in first-line GIST patients with KIT exon 9 primary mutations. The commercial trajectory, if the approval proceeds on schedule, would make bezuclastinib the first new second-line GIST standard of care in twenty years.

GSK's Velzatinib: A Different Approach to the Same Problem

Where bezuclastinib is designed to work in combination, GSK's velzatinib is built around a different premise: a single molecule that inhibits the full spectrum of clinically relevant KIT mutations, both primary and secondary, without requiring a partner drug. The compound, acquired through GSK's $1 billion purchase of IDRx in January 2025, presented its first clinical data at ASCO from the Phase 1/1b StrateGIST 1 trial.

The numbers from a limited cohort are encouraging. Among 24 first-line patients, velzatinib produced a tumor response in 61 percent. Among 49 second-line patients, the response rate was 38 percent, with a median progression-free survival of approximately 17 months, a figure that compares favorably to historical sunitinib data in the same setting. GSK's head of oncology R&D, Hesham Abdullah, noted at ASCO that response rates with sunitinib in second-line GIST are typically in the teens, making the velzatinib signal meaningful even at this early stage.

The Phase 1 data also showed substantial clearance of circulating tumor DNA across clinically meaningful KIT mutations, providing a molecular correlate for the clinical responses observed. GSK has used these results to accelerate the initiation of StrateGIST Frontline, a Phase 3 trial that will pit velzatinib against imatinib in newly diagnosed patients, as well as StrateGIST 3, which will compare velzatinib to sunitinib in the second-line setting. The FDA has granted velzatinib both Fast Track designation and Orphan Drug designation for GIST.

Two Strategies, One Unmet Need

The convergence of these two programs at the same medical meeting in the same week is not coincidental. It reflects a field that has spent years building toward a moment when the biology of KIT resistance is finally yielding to more precisely engineered tools. The approaches are complementary rather than directly competitive in the near term. Bezuclastinib, if approved in November, will address the second-line population immediately. Velzatinib, still in Phase 1 for first-line use, is targeting a longer-term opportunity to replace imatinib as the initial treatment of choice.

The distinction matters for patients. A drug that can inhibit both primary and secondary KIT mutations from the outset of treatment could, in theory, delay or prevent the emergence of resistance that currently makes GIST a disease of sequential treatment failures. Whether velzatinib can deliver on that hypothesis in a randomized Phase 3 trial against imatinib is the central question the StrateGIST Frontline trial will answer. The Phase 1 data are not sufficient to draw conclusions about first-line superiority, and GSK has been appropriately measured in its characterization of the results as a basis for accelerating the Phase 3 program rather than as evidence of a definitive clinical advance.

What the Field Has Been Waiting For

GIST occupies an unusual position in oncology. It was one of the first solid tumors to be treated with a targeted therapy, and imatinib's approval in 2002 was a landmark moment for the field. But the subsequent two decades have seen relatively modest progress in moving beyond the initial breakthrough. The disease has remained a niche within oncology, affecting a patient population small enough that large commercial incentives have not always driven sustained investment in next-generation approaches.

What ASCO 2026 suggests is that the investment is now arriving. Two well-resourced programs, one with Phase 3 data strong enough to support an imminent FDA approval and one with Phase 1 data compelling enough to accelerate a Phase 3 program, are converging on a disease where the standard of care has been static for a generation. For the roughly 15,000 Americans diagnosed with GIST each year, and the far larger global population living with the disease, the data presented in Chicago this week represent the most credible signal of meaningful progress in two decades. The question now is not whether the standard of care will change, but how quickly, and in which direction the field will ultimately move.