For patients with a rare cancer that arises in the gut wall, standard treatment hasn’t changed in the last 20 years. At the American Society of Clinical Oncology meeting in Chicago, GSK shared a first look at its attempt to change that.
GSK bought the precision medicine biotech IDRx in January 2025 to secure a small molecule that targets a type of enzyme called a tyrosine kinase inhibitor (TKI). By specifically homing in on multiple mutations of the tyrosine kinase c-KIT, GSK hopes that the molecule, called velzatinib, can improve on the earlier TKIs Gleevec (imatinib) and Sutent (sunitinib).
Novartis first garnered approval for Gleevec in metastatic gastrointestinal stromal tumors (GISTs) in 2002, and Pfizer followed with Sutent in 2006. Mutations in KIT cause GIST to develop in rare, specialized cells called interstitial cells of Cajal, which serve as the gut’s pacemaker.
Non-metastatic GISTs can be removed surgically, but when the disease metastasizes, medicine must enter the conversation.
“Imatinib is a very potent inhibitor of KIT,” Suzanne George, M.D., a medical oncologist at Dana-Farber Cancer Institute, told Fierce at ASCO. “But we've learned over time that the primary mechanism of resistance to imatinib is the development of secondary mutations in KIT that imatinib does not work against.”
For these secondary mutations, Sutent is deployed, with Bayer’s Stivarga (regorafenib) and Deciphera’s Qinlock (ripretinib) following in the third and fourth lines.
Velzatinib is designed to not only attack the main mutations in KIT that drive the formation of GISTs, but also the subsequent mutations that the tumors develop in order to combat Gleevec and Sutent, Hesham Abdullah, M.D., GSK’s head of oncology R&D, explained to Fierce at the pharma’s conference booth.
In its ASCO debut, velzatinib was confirmed to shrink tumors in 61% of 24 first-line patients, GSK presented, and 38% of tumors among 49 second-line patients.
While acknowledging that the first-line data come from a “limited cohort of patients” from IDRx’s phase 1 trial, Abdullah said the results provide “the first look of what this drug can do.”
“The preliminary data from the phase 1 is very promising in terms of response rate and initial duration,” George agreed.
In the second-line setting, velzatinib’s response rates trump those of Sutent, Abdullah added.
“You would typically expect response rates with Sutent to be in the teens,” Abdullah said, “and we're looking at a median progression-free survival of about 14 months in second-line-plus patients, which is quite impressive.”
In addition to cancer being able to evolve resistance to it, Sutent is also hampered by side effects caused by its broad activity—in addition to KIT, the drug also hits other targets, most notably the signaling protein VEGF. By homing in just on KIT, velzatinib should be gentler on patients, George said.
GSK also used the poster session at ASCO to share details of a phase 3 trial for velzatinib in second-line patients who have already developed resistance to Gleevec. That trial, StrateGIST 3, is testing GSK’s upstart inhibitor against Sutent, and the British pharma is also planning a first-line phase 3 trial pitting velzatinib against Gleevec.
The aim is to “redefine what the potential standard of care is,” Abdullah said, much as Gleevec did for GIST patients two decades ago.
George, who contributed heavily to sunitinib’s development, is now on the steering committee for GKS’s phase 3 trials of velzatinib and presented the poster outlining the pharma’s StrateGIST 3 plans.
GSK is not the only company looking to modernize GIST care. Cogent Biosciences presented full data from the phase 3 trial of its KIT inhibitor bezuclastinib at ASCO, too, demonstrating an average progression-free survival of 16.5 months in Gleevec-resistant patients when paired with Sutent compared to 9.2 months for Sutent alone.
“Importantly, there was a clear benefit across all mutational patient subgroups,” Cogent president and CEO Andrew Robbins said in a May 30 release. Bezuclastinib is already sitting with the FDA for an approval decision, with a verdict expected by November 30.
“We plan to launch bezuclastinib later this year and are well prepared to ensure bezuclastinib combination access for GIST patients in need,” Robbins said.
Bezuclastinib targets a specific KIT mutation and thus needs to be used in combination with other KIT inhibitors to hit the full panoply. So, while it may become a new standard of care in second-line treatment, should it be approved, it has a less clear path to replacing Gleevec in newly diagnosed patients.
“The rationale behind the combination of sunitinib and bezuclastinib is that you're hitting all the mutations,” Dana-Farber’s George explained. “The hope with drugs like velzatinib is that with a single drug, you will hit that broad range of mutations.”
Deciphera Pharmaceuticals, a subsidiary of Ono Pharma, also previously tried to take its late-line GIST medicine Qinlock into second-line treatment, but the molecule failed to beat Sutent. A later analysis revealed some promising patient subgroups who may see stronger efficacy from Qinlock than Sutent, however, raising a potential opportunity that Deciphera is now pursuing.
As the next generation of KIT inhibitors rises, George is excited by the prospect of combining them with other up-and-coming GIST targets that have yet to be revealed.
“There is absolutely a lot of interest in thinking about combinations of KIT,” she told Fierce. “GIST is ripe for a really strong paradigm shift.”