Velzatinib Shows Activity Across KIT Mutation Spectrum in Advanced GIST

Velzatinib (IDRX-42) produces clinical activity across primary and secondary KIT mutations in patients with advanced or metastatic gastrointestinal stromal tumors (GIST), according to findings presented at the 2026 ASCO Annual Meeting.¹

In the StrateGIST 1 trial (NCT05489237), the broad-spectrum KIT tyrosine kinase inhibitor (TKI) led to greater than 99% reductions in circulating tumor DNA (ctDNA) variant allele frequency (VAF) in the majority of treated patients across all major mutation subsets, and baseline ctDNA detectability was shown to function as an independent prognostic marker of progression risk. In the exon 9 mutation subgroup in particular, overall response rates (ORRs) and survival outcomes were substantially superior to those observed with exon 11 primary mutations.

“Velzatinib is effective against primary activating mutations in KIT exons 9 and 11, as well as secondary resistance mutations in KIT exons 13 and 17,” Michael C. Heinrich, MD, of Oregon Health & Science University, said in his presentation.

The Unmet Need in Later-Line GIST

Approximately 75% to 80% of GIST cases are driven by KIT mutations, with resistance to standard TKI therapy arising primarily through acquisition of secondary mutations in KIT exons 13, 14, 17, and 18. Currently approved sequential TKIs carry progressively diminishing response rates: first-line imatinib (Gleevec) yields ORRs of 51% to 54%, second-line sunitinib (Sutent) 17.6%, third-line regorafenib (Stivarga) 5.5%, and fourth-line ripretinib (Qinlock) 9%. Velzatinib was designed to address this therapeutic attrition by inhibiting both common primary KIT mutations (exons 9 and 11) and key secondary resistance drivers (exons 13, 14, 17, and 18) with a single agent.

Trial Design and Methods

StrateGIST 1 is an open-label phase 1/1b study evaluating the safety and efficacy of velzatinib in patients with advanced or metastatic GIST. The phase 1 dose-escalation portion used a 3+3 design testing velzatinib doses ranging from 120 mg once daily up to 600 mg twice daily in capsule form, with subsequent tablet formulations also evaluated. Phase 1b expansion cohorts were enrolled at the recommended phase 1b dose(s) across 4 treatment-line cohorts: first line, second line, third line or beyond with approved TKIs, and third line or beyond with investigational TKIs.

As of the September 2025 data cutoff, 256 patients had received velzatinib across all lines of therapy. Clinical activity was assessed by modified RECIST (mRECIST) v1.1. Blood samples for ctDNA analysis using the Guardant360 assay were collected at baseline and serially at weeks 2, 4, 8, and 32. Hazard ratios were calculated using Cox proportional hazards regression.

Efficacy by Line of Therapy and KIT Mutation

Early-line data were presented separately: at an April 2026 data cutoff, the unconfirmed ORR was 65% in the first-line cohort and 40% in the second-line cohort treated at the recommended phase 1b dose; all first-line patients had a reduction in tumor volume and 83% and 45% in the respective cohorts remained on treatment. First-line progression-free survival (PFS) was immature with 7.4 months follow-up, whereas in the second line it reached a median of 13.7 months (95% CI, 8.6-18.4) with 18.4 months’ follow-up.²

Efficacy data from the December 2025 data cutoff demonstrated clinical activity across all treatment lines.¹ In the third-line cohort (n = 26; median follow-up, 16.5 months), ORR was 27% (95% CI, 11.6%-47.8%) and median PFS was 9.2 months (95% CI, 3.7-12.9), and median duration of response (DOR) was 8.3 months (95% CI, 4.8-not reached). Among the subset without prior bezuclastinib (n = 22), ORR increased to 32% (95% CI, 13.9-54.9) with median PFS of 11.1 months (95% CI, 3.7-16.6).

In the fourth-line-and-beyond cohort (n = 140; median follow-up 16.6 months), ORR was 24% (95% CI, 16.8%-31.5%), median PFS was 5.6 months (95% CI, 5.3-7.4), and median DOR was 11.1 months (95% CI, 7.5-18.5). In the clinically important subset without prior ripretinib, bezuclastinib, NB003, or THE-630 (n = 39), ORR rose to 44% (95% CI, 27.8%–60.4%), median PFS was 11.0 months (95% CI, 5.6-18.3), and median DOR was 18.5 months (95% CI, 7.5-not reached).

ORR by KIT mutation subtype detected via baseline ctDNA across all cohorts revealed a pronounced advantage for exon 9 mutations (44%; n = 43) compared with exon 11 (19%; n = 119), exon 13 (17%; n = 66), exon 14 (20%; n = 10), and exon 17 (23%; n = 87). PFS curves by mutation subgroup showed that patients with exon 9 mutations had not yet reached median PFS, while median PFS for exon 11 only, exon 11 plus exon 13, and exon 11 plus exon 17 subgroups were 7.33, 5.45, and 7.36 months, respectively. Similar clinical benefit was observed among those with exon 11, 13, and 17 mutations, supporting velzatinib’s activity against both primary and secondary resistance drivers.

ctDNA as a Prognostic and Pharmacodynamic Marker

Among the 180 patients with ctDNA data from the September 2025 cutoff, velzatinib produced greater than 99% reductions in KIT VAF, defined as ctDNA clearance, across all major mutation subsets: exon 9 (80.4%; n = 37), exon 11 (66.7%; n = 78), exon 13 (79.7%; n = 51), exon 14 (80.0%; n = 8), and exon 17 (81.6%; n = 71), indicating high pharmacodynamic activity irrespective of mutation type.

Baseline ctDNA detectability emerged as an independent prognostic factor. Approximately 20% of patients (n = 45) did not have detectable baseline KIT/PDGFRA mutations by ctDNA. These patients demonstrated substantially lower progression risk compared with the 180 patients with detectable mutations, with a median PFS of 16.59 months vs 7.26 months (HR, 0.39; P < 0.001).

Safety and Tolerability

Results from the 73 first- and second-line patients showed a 63% rate of grade 3 or higher treatment-emergent adverse events (TEAEs), with a 33% rate of velzatinib-related TEAEs of grade 3 or higher. Only 5% had velzatinib-related serious TEAEs. TEAEs led to velzatinib discontinuation in 5%, drug interruption in 55%, and dose reduction in 21%. The most common TEAEs included diarrhea, nausea, dysgeusia, neutropenia, and fatigue.

Conclusions and Clinical Significance

“We conclude that baseline exon-level KIT mutation status and ctDNA detectability provide potentially useful prognostic markers,” said Heinrich. “Future studies will investigate the relationship between clinical benefit and molecular response.”

Based on the second-line findings, the open-label multicenter phase 3 StrateGIST 3 trial (NCT07218926) began recruiting patients in December of 2025; it plans to enroll 450 patients with GIST who have received prior imatinib to be randomly assigned either velzatinib or sunitinib.³ Patients may not be enrolled if they have GIST that is wild type for both KIT and PDGFRA or if they have an activating PDGFRA exon 18 mutation. The trial will be stratified by KIT exon 11 vs exon 9 vs other mutations. The primary end point is PFS, and the study’s estimated duration is 5 years.

REFERENCES

1. Heinrich MC, Serrano C, George S, et al. Efficacy of velzatinib (IDRX-42) in patients with advanced/metastatic GIST by line of therapy and circulating tumor DNA response in the phase 1/1b StrateGIST 1 trial.J Clin Oncol. 2026;44(suppl 16):11520. doi:10.1200/JCO.2026.44.16_suppl.11520

2. Jones RL, Somaiah N, Bauer S, et al. Velzatinib (IDRX-42) as 1L or 2L therapy for advanced gastrointestinal stromal tumors (GISTs) by KIT mutation status: A subset analysis of the phase 1/1b StrateGIST 1 study. J Clin Oncol. 2026;44(suppl 16):11501. doi:10.1200/JCO.2026.44.16_suppl.11501

3. George S, Bauer S, Doi T, et al. StrateGIST 3: A randomized, phase 3 study of velzatinib (IDRX-42) versus sunitinib in patients with advanced gastrointestinal stromal tumors after imatinib therapy. J Clin Oncol. 2026;44(suppl 16):TPS11588. doi:10.1200/JCO.2026.44.16_suppl.TPS11588