Early Efficacy/Safety Shown With THE-630 in Advanced GIST

Treatment with THE-630 in patients with advanced gastrointestinal stromal tumors (GIST) has demonstrated circulating tumor (ct)DNA reduction, prolonged stable disease (SD), and consistent safety in a phase 1/2 clinical trial (NCT05160168).¹

"The emerging potential activity in both classes of resistance mutations in the activation loop and ATP binding pocket is promising, as it is critically important to be active against both to provide a meaningful clinical benefit for patients," said Suzanne George, MD, associate division chief, Sarcoma Center, Dana-Farber Cancer Institute, and a principal investigator on the phase 1/2 trial, in a press release.

Results come from 25 patients with advanced GIST treated during the dose-escalation phase of the study in cohorts 1-6 at the 3-, 4-, 6-, 9-, 12-, 18-mg dose levels of THE-630, respectively. In terms of efficacy, 8 out of 9 evaluable patients treated in cohorts 4-6 had SD as their best response. The disease control rate observed so far in the dose-escalation phase was 89%.

Notably, patients treated with 5 prior lines of therapy who had KIT exon 11 and 17 mutations in ctDNA at baseline had ctDNA reductions following 36 weeks of treatment with THE-630. In 1 patient who had KIT exon 11 and 13 mutations at baseline, SD was shown through the 24-week mark. Overall, ctDNA reductions were shown at the higher dose levels.

The safety profile observed with THE-630 during the dose-escalation phase was consistent with that observed in the preclinical study. Patients in cohort 7 surpassed the dose-limiting toxicity (DLT) period without a DLT. Treatment-related adverse events (TRAEs) occurred in 65% of patients. Of the TRAEs observed, 94% were grades 1 and 2, and 6% were grade ≥ 3. The most common TRAEs were fatigue, increased aspartate aminotransferase, diarrhea, nausea, dry mouth, and dyspnea.

THE-630 is pan-variant tyrosine kinase inhibitor of KIT. The agent showed potent activity in cellular assays and tumor models with KIT exon 9 and 11 mutations as well as resistance mutation in exon 13/14, and 17/18, according to preclinical findings.²

The launch of the phase 1/2 study of THE-630 in patients with advanced GIST was based on the unmet need for new therapies in the fifth-line setting. All prior treatment lines have effective options. These options include imatinib (Gleevec) for first-line GIST, which offers an objective response rate (ORR) of 51.4% and a median progression-free survival (mPFS)of 18.9 months.In the second-line setting, sunitinib (Sutent) offers an ORR of 6.8% and a mPFS of 5.6 months. For patients in their third line of treatment, regorafenib (Stivarga) can produce an ORR of 4.8% and an mPFS of 4.5 months. Finally, in the fourth-line setting, ripretinib is available and offers a 9% ORR and a mPFS of 6.2 months.²

The phase 1/2 study is ongoing with a goal to investigate the safety, pharmacokinetics, and antitumor activity of THE-630 in patients with advanced GIST.³

"THE-630 has shown strong clinical proof of mechanism through cohort 6 with a safety and pharmacokinetic profile supportive of continued dose escalation," said Tim Clackson, PhD, president, and chief executive officer of Theseus, in the press release. "Importantly, with dose-dependent activity observed against both major classes of KIT resistance mutations, coupled with the increased frequency of stable disease at the higher doses tested thus far, we believe THE-630 could have a best-in-class profile and provide a much-needed alternative to combat the complex resistance that drives rapid progression of GIST. We are also encouraged by the further validation of our PRA, with reductions in ctDNA observed for specific mutations consistent with our preclinical predictions. These data support our ability to reach target exposures in cohort 8, and we look forward to reporting data through cohort 8 later this year."

_REFERENCES:

_{1. Theseus Pharmaceuticals reports initial dose escalation data from ongoing Phase 1/2 trial of THE-630 in patients with advanced GIST. News release. May 25, 2023. Accessed May 26, 2023. https://rb.gy/3ixjg}

_{2. Rivera VM, Huang W, Lu M, et al. Preclinical characterization of THE-630, a next-generation inhibitor for KIT-mutant gastrointestinal stromal tumors (GIST). Cancer Res. 2021; 81 (suppl 13): 1292. doi:10.1158/1538-7445.AM2021-1292}

_{3. A study of THE-630 in patients with advanced gastrointestinal stromal tumors (GIST). Clinicaltrials.gov. Updated January 25, 2023. Accessed May 26, 2023. https://clinicaltrials.gov/ct2/show/NCT05160168?term=THE-630&draw=2&rank=1}