The Drug That Could Dethrone a 24-Year-Old Cancer King
For 24 years, no drug has been able to knock Gleevec off its throne as the go-to treatment for GIST. GSK just showed up at ASCO 2026 with early data on velzatinib that has oncologists using the words "paradigm shift" — but the phase 3 gauntlet is just beginning.
The Longest Winning Streak in Oncology
In the year 2002, a drug called Gleevec turned one of the deadliest gastrointestinal cancers into something patients could live with for years. Before Gleevec (imatinib), patients with metastatic GIST (gastrointestinal stromal tumors, a rare cancer of the digestive tract) survived about 18 months. After it, median survival stretched past five years. Some patients hit the ten-year mark.
For nearly a quarter century, nobody could build anything better for first-line treatment. Not for lack of trying. Drug after drug entered the ring, and drug after drug got sent to later lines of therapy, mopping up what Gleevec left behind rather than replacing it outright. Sunitinib took second line. Regorafenib got third. Ripretinib picked up fourth.
Gleevec just sat on the throne, unchallenged.
At ASCO 2026, GSK walked up to that throne with early data on a drug called velzatinib and made a case that the reign might finally be ending.
A $1 Billion Bet on One Molecule
Velzatinib didn't start at GSK. It was originally discovered by Merck KGaA (EMD Serono) as M4205, and was later licensed by a small Boston biotech called IDRx, where it went by the code name IDRX-42. GSK liked what it saw enough to pay $1 billion upfront in January 2025 to acquire the company, with another $150 million tied to a regulatory approval milestone. That's a serious check for a drug still in early-stage testing.
What made it worth the price? Velzatinib is a highly selective KIT inhibitor, meaning it targets the specific protein (KIT) that drives most GIST tumors. But unlike Gleevec, which covers KIT's original mutations well but struggles with the secondary mutations that pop up later, velzatinib was engineered to hit essentially all clinically relevant KIT mutations: the primaries and the secondaries.
Think of it like this: Gleevec is a lock that fits most of the front doors in a neighborhood. Velzatinib is a master key that fits the front doors and the back doors that cancer sneaks through when it develops resistance.
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The Numbers That Turned Heads
The data GSK presented came from the phase 1/1b StrateGIST 1 study, and the crowd at ASCO paid attention.
In first-line GIST (patients who hadn't been treated before), velzatinib produced a 61% tumor response rate. That's striking for an early-phase study with a small group, and it showed activity across different KIT mutations.
In second-line patients (those who had already failed or couldn't tolerate Gleevec), the response rate was 38% among 49 evaluable patients at the recommended dose. For context, this population has been stuck with sunitinib for two decades, and new options have been frustratingly slow to arrive.
Safety looked clean, too. Grade 3 or higher treatment-related adverse events showed up in about 33% of patients overall. At the recommended dose, nobody dropped out due to side effects. That tolerability profile matters enormously in GIST, where patients often stay on treatment for years.
Why Two Decades of Challengers Failed
To appreciate why oncologists are excited, you need to understand the graveyard of drugs that tried and failed to unseat Gleevec.
The fundamental problem is biological. Gleevec works really well in most newly diagnosed GIST patients, with response rates historically ranging from about 45% to 71%. It transformed a disease where chemo barely worked (response rates around 0 to 10%) into one where most patients respond. That's an incredibly high bar to clear.
Every subsequent drug development effort essentially said: "Gleevec is too good in first line; let's focus on patients who've already failed it." That's how sunitinib, regorafenib, and ripretinib ended up stacked as second, third, and fourth-line options respectively. The one drug that did carve out a frontline niche, avapritinib, only works in a small molecular subgroup (PDGFRA D842V mutations) where Gleevec was never effective in the first place. That's not displacing the king; it's governing a province the king never visited.
No one has run a successful phase 3 trial showing a different drug beating Gleevec as universal first-line therapy. Until now, nobody's had the biological rationale to justify trying.
GSK Is Going Straight for the Crown
What's different this time is that GSK isn't settling for a later-line consolation prize. The company announced two phase 3 trials that amount to a full-frontal assault on GIST's established order.
StrateGIST 3 will pit velzatinib directly against sunitinib in second-line GIST, with progression-free survival as the primary endpoint. And the bigger swing: StrateGIST Frontline will compare velzatinib head-to-head against Gleevec itself in first-line patients, with progression-free survival as the primary endpoint.
GSK's oncology R&D head, Hesham Abdullah, has framed the ambition explicitly: redefining the standard of care in GIST the same way imatinib did two decades ago. GIST expert Suzanne George of Dana-Farber put it even more bluntly, saying "GIST is ripe for a really strong paradigm shift."
The fact that GSK accelerated the start of the frontline trial based on the early data signals real internal confidence.
The Competition Is Already in the Room
Velzatinib isn't the only drug trying to rewrite the GIST playbook at ASCO 2026. A combination of bezuclastinib plus sunitinib (the PEAK trial) showed phase 3 results cutting the risk of progression or death by 50% compared to sunitinib alone in second-line GIST. Investigator Andrew Wagner called the results "dramatic" and suggested the combo would become the new second-line standard if approved.
That creates a fascinating competitive dynamic. Velzatinib is a single agent trying to replace the entire first- and second-line sequence. PEAK is a combination aiming to upgrade second line specifically. By the time velzatinib's phase 3 data arrive, the second-line benchmark might not be sunitinib anymore; it might be bezuclastinib plus sunitinib.
What This Means for a Billion-Dollar Market
GIST is rare (roughly 5,000 new U.S. cases per year), but the market is surprisingly lucrative because patients cycle through multiple expensive drugs over years of treatment. Analysts estimate the global GIST therapeutics market was approaching $1 billion by 2025, growing at nearly 10% annually.
A drug that captures both first-line and second-line GIST would dominate the most valuable real estate in that market. And velzatinib already has FDA Fast Track designation for post-imatinib GIST, plus Orphan Drug status, both of which could speed its path to approval.
But the "paradigm shift" label comes with a massive asterisk: this is still phase 1 data in small patient groups. Phase 3 trials will need to prove that velzatinib actually extends lives compared to Gleevec, not just shrinks tumors in a few dozen people.
Gleevec has survived 24 years of challengers for good reason. It works, it's tolerable, and it's now available as a cheap generic. Beating it will require not just better efficacy, but better efficacy by enough of a margin to justify switching the entire treatment paradigm for a cancer that, for most patients, is already well-managed.
The early returns look promising. The real test starts now.
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