Regorafenib

For GSK, ASCO was the perfect setting to share its plans to revolutionize treatment for a rare gut cancer that hasn\'t seen new innovation in decades.\n 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 17 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.”

Cogent Biosciences (Nasdaq: COGT), based in Waltham, Massachusetts, has submitted a New Drug Application (NDA) to the US FDA for bezuclastinib in combination with sunitinib (Sutent) in patients with gastrointestinal stromal tumors (GIST) who have received prior treatment with imatinib. The FDA has accepted the application and granted Priority Review, with a PDUFA target action date of November 30, 2026. The NDA seeks approval for bezuclastinib used in combination with sunitinib in the second-line GIST setting, specifically in patients with imatinib-resistant or intolerant disease. The FDA has indicated it does not plan to convene an advisory committee and has not identified any potential review issues at this stage, the company said. The filing builds on prior regulatory designations, including Breakthrough Therapy Designation and eligibility for Real-Time Oncology Review, both granted following Phase III PEAK trial data. The combination of Priority Review and these earlier designations reflects the FDA’s assessment of the unmet need in this patient population, where sunitinib monotherapy has remained the standard of care since its approval in 2006. The NDA is supported by data from the Phase III PEAK trial (NCT05208047), a global, randomized, open-label study evaluating bezuclastinib in combination with sunitinib versus sunitinib monotherapy in patients with imatinib-resistant or intolerant advanced GIST. As of the data cutoff of September 30, 2025, the combination arm met the primary endpoint of progression-free survival (PFS) with a hazard ratio of 0.50 (95% CI: 0.39–0.65; p \< 0.0001), corresponding to a 50% reduction in the risk of disease progression or death compared with sunitinib alone. Median PFS, assessed by blinded independent central review, was 16.5 months for the combination versus 9.2 months for sunitinib monotherapy. In imatinib-resistant patients, the objective response rate (ORR) was 46% in the combination arm compared with 26% in the sunitinib arm. Overall survival data remain immature. On safety, Grade 3 or higher treatment-emergent adverse events occurring in either arm included hypertension (29.4% combination vs 27.4% sunitinib), neutropenia (15.2% vs 15.4%), elevated ALT/AST (10.8% vs 1.4%), anemia (9.3% vs 4.8%), and diarrhea (7.8% vs 7.2%). Treatment discontinuation due to treatment-related adverse events occurred in 7.4% of patients in the combination arm versus 3.8% in the sunitinib arm. Hepatic laboratory abnormalities were predominantly low grade, transient, and reversible; all Grade 3 ALT/AST elevations resolved and no Grade 4 elevations were reported. Bezuclastinib dose reductions due to ALT/AST elevations occurred in 12.7% of patients, with 1.5% discontinuing bezuclastinib for this reason. Bezuclastinib is a selective KIT tyrosine kinase inhibitor designed to inhibit KIT exon 17 activation-loop mutations alongside primary KIT mutations — a resistance mechanism that limits the efficacy of earlier-generation TKIs including sunitinib. In the GIST setting, acquired resistance to imatinib is driven predominantly by secondary KIT kinase domain mutations, many of which fall in the activation loop and are poorly covered by sunitinib. The filing adds to a second-line GIST landscape that has seen no new approved therapy since sunitinib’s approval nearly two decades ago. Approved agents across lines of therapy include regorafenib (Stivarga) in the third-line setting, avapritinib (Ayvakit) for PDGFRA exon 18-mutant disease, and ripretinib (Qinlock) for patients who have received three or more prior kinase inhibitors. None of these approvals addressed the second-line population with a combination approach or demonstrated superiority over an active comparator in a randomized Phase III trial in this setting, according to the available clinical record. The PEAK data, if reflected in an eventual approval, would position bezuclastinib plus sunitinib as the first regimen to demonstrate a statistically significant PFS advantage over sunitinib monotherapy in a randomized trial in post-imatinib GIST. Full results from PEAK are scheduled for oral presentation at the American Society of Clinical Oncology annual meeting on May 30, 2026. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.