Velzatinib Shows Activity Across Treatment Lines and KIT Mutation Profiles in Advanced GIST

Velzatinib (IDRX-42) demonstrated robust, durable clinical activity across all treatment lines irrespective of KIT mutation status in patients with advanced or metastatic gastrointestinal stromal tumors (GIST), with circulating tumor DNA (ctDNA) analyses showing particularly strong activity in patients harboring detectable KIT exon 9 mutations at baseline, according to data from the phase 1/1b StrateGIST-1 trial (NCT05489237) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Across all subgroups, at a median follow-up of 16.5 months, patients who received velzatinib in the third line (n = 26) experienced an objective response rate (ORR) of 27% (95% CI, 11.6%-47.8%) and a median progression-free survival (PFS) of 9.2 months (95% CI, 3.7-12.9). Among all patients treated in the fourth line or later (n = 140), with a median follow-up of 16.6 months, the ORR was 24% (95% CI, 16.8%-31.5%), and the median PFS was 5.6 months (95% CI, 5.3-7.4). The data cutoff was December 2025.

“Velzatinib demonstrates robust, durable clinical activity across all treatment lines, irrespective of KIT mutation status. [It was] particularly effective in patients with detectable KIT exon 9 mutations by ctDNA [circulating tumor DNA].” - Michael C. Heinrich, MD, presenting author.“

Heinrich is a professor of medicine at Oregon Health and Science University in Portland.

How was the StrateGIST-1 trial designed?

Velzatinib is a next-generation KIT inhibitor designed to cover a broad spectrum of primary and secondary KIT mutations, including resistance mutations arising in KIT exons 13, 14, 17, and 18 that drive acquired resistance to standard tyrosine kinase inhibitors (TKIs). The current analysis focused on circulating tumor DNA (ctDNA) response, assessing velzatinib's ability to clear individual KIT variants from plasma and exploring baseline ctDNA as a potentially prognostic marker.

StrateGIST-1 is an open-label, phase 1/1b study evaluating the safety and efficacy of velzatinib for advanced GIST. The phase 1 component used standard 3 plus 3 dose escalation, testing a capsule formulation at once-daily doses of 120 mg, 240 mg, 400 mg, 600 mg, 800 mg (400 mg twice daily), and 1200 mg (600 mg twice daily), as well as a reformulated tablet at doses of 200 mg, 300 mg, 500 mg, and 600 mg once daily.

Following dose escalation, 300 mg and 500 mg once daily were selected as recommended phase 1b doses (RP1bDs) for further investigation in 4 phase 1b expansion cohorts defined by line of prior therapy. These included a first-line cohort, a second-line cohort, a third-line or later cohort of patients with prior approved TKI exposure, and a third-line or later cohort of patients previously exposed to investigational TKIs.

The data presented in this analysis focused on outcomes in the third and fourth lines and beyond, as of the December 2025 cutoff.¹ Efficacy results from patients treated in the first line and second line at the RP1bD based on an April 2026 data cutoff were shared in a concurrent presentation at the meeting.²

Were efficacy outcomes consistent in the third vs fourth line and beyond?

In patients who had not received prior bezuclastinib (n = 22), the ORR was 32% (95% CI, 13.9%-54.9%), the median PFS was 11.1 months (95% CI, 3.7-16.6), the median time to response (TTR) was 3.5 months (range, 1-4), and the median duration of response (DOR) was 8.3 months (95% CI, 4.8-not estimable [NE]).¹ In the fourth line, patients with no prior exposure to ripretinib (Qinlock), bezuclastinib, NB003, or THE-630 (n = 39) achieved an ORR of 44% (95% CI, 27.8%-60.4%), a median PFS of 11.0 months (95% CI, 5.6-18.3), a median TTR of 3.6 months (range, 1-11), and a median DOR of 18.5 months (95% CI, 7.5-NE).

Were outcomes consistent across KIT mutation subgroups?

ORR by baseline KIT mutation status assessed via ctDNA across all cohorts and dose levels showed the highest response rate in patients with any KIT exon 9 mutation (44%; n = 43), followed by exon 17 (23%; n = 87), exon 11 (19%; n = 119), exon 14 (20%; n = 10), and exon 13 (17%; n = 66). Individual patients with mutations in more than 1 exon were represented in multiple groups.

PFS by baseline molecular subgroup further illustrated the breadth of velzatinib's activity. For patients with only a KIT exon 9 mutation at baseline across all lines, the median PFS had not yet been reached with the 300-mg dose at the September 2025 cutoff. The median PFS for patients with KIT exon 11 mutations only was 7.33 months; for those with exon 11 plus exon 13 mutations only, it was 5.45 months; and for those with exon 11 plus exon 17 mutations only, it was 7.36 months. Similar clinical benefit was observed among patients harboring mutations in exons 11, 13, and 17.

What did the ctDNA analysis reveal about prognostic markers and molecular clearance?

Baseline ctDNA detectability emerged as an independent prognostic factor. Approximately 20% of patients did not have detectable KIT/PDGFRA mutations in baseline ctDNA. Among patients without detectable KIT/PDGFRA ctDNA mutations at baseline (n = 45), the median PFS was 16.59 months compared with 7.26 months in those with detectable mutations (n = 180), representing a 61% lower risk of progression for ctDNA-undetectable patients (HR, 0.39; P < .001).

ctDNA analysis was performed at baseline and at weeks 2, 4, 8, and 32. ctDNA clearance was defined as a greater than 99% reduction in the mutant KIT variant allele frequency from baseline. More than 75% of patients achieved ctDNA clearance across individual KIT exon mutations, with the following clearance rates:

• KIT exon 9: 80.4% (n = 37)
• KIT exon 11: 66.7% (n = 78)
• KIT exon 13: 79.7% (n = 51)
• KIT exon 14: 80.0% (n = 8)
• KIT exon 17: 81.6% (n = 71)

Patients with mutations in more than 1 exon were counted in each applicable group.

“Patients with baseline low ctDNA levels below the detection limit had a lower risk of progression,” Heinreich noted. “Velzantinib also substantially reduced ctDNA levels across a broad spectrum of KIT mutation profiles.

Heinrich concluded his presentation by stating that baseline exon-level KIT mutation status and ctDNA detectability may serve as prognostic markers, and that future studies will investigate the relationship between clinical benefit and molecular response.

What additional first- and second-line data from StrateGIST-1 were shared in a related presentation at ASCO?

Among patients receiving velzatinib in the first-line setting (n = 23), the unconfirmed ORR (uORR) was 65% (95% CI, 42.7%-83.6%), including 1 complete response (CR; 4%) and 14 partial responses (PRs; 61%).² Stable disease (SD) was observed in 30% of patients (n = 7), and no patients experienced progressive disease (PD); 1 patient (4%) was not evaluable. Investigators also reported that all patients experienced some degree of tumor volume reduction. The median follow-up was 7.4 months (95% CI, 5.6-12.9).

In the second-line cohort (n = 48), velzatinib achieved a uORR of 40% (95% CI, 25.8%-54.7%), including 2 CRs (4%) and 17 PRs (35%). An additional 24 patients (50%) experienced SD, and 5 patients (10%) had PD. At a median follow-up of 18.4 months (95% CI, 16.6-22.1), the median PFS was 13.7 months (95% CI, 8.6-18.4).

Activity was observed across clinically relevant subgroups of KIT resistance mutations, and the agent had a well-tolerated safety profile. Investigators similarly concluded that velzatinib demonstrated promising antitumor activity and a tolerable safety profile in both settings across a range of KIT mutation profiles in patients with advanced GIST.

Disclosures: Heinrich reported stock ownership in von Pfeffel Pharmaceuticals; a consulting or advisory role for Cogent Pharmaceuticals, Deciphera, Natera, NewBay, Novartis, and von Pfeffel Pharmaceuticals; and travel expenses covered by Deciphera.

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(16 suppl):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(16 suppl):11501. doi:10.1200/JCO.2026.44.16_suppl.11501.