On November 2, 2023 IDRx, Inc., a clinical-stage biopharmaceutical company dedicated to transforming cancer treatment with purpose-built precision therapies, reported preliminary clinical data from the dose escalation portion of the company’s ongoing Phase 1 StrateGIST study of IDRX-42 in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) who have previously received one or more prior lines of tyrosine kinase inhibitor (TKI) therapy (Press release, IDRx, NOV 2, 2023, View Source [SID1234636845]). IDRX-42 is a highly potent, multi-mutation-selective inhibitor of KIT targeting all major classes of primary drivers and resistance mutations in patients with KIT-mutant GIST (including mutations in exons 9, 11, 13 and 17).
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These early data, which demonstrate promising antitumor activity and a favorable safety profile of IDRX-42 in a heavily pre-treated group of patients with advanced GIST after failure of imatinib and other lines of TKI therapies, will be presented by Professor Patrick Schöffski, MD, MPH, head of the Department of General Medical Oncology at the University Hospitals Leuven, in a poster at the Connective Tissue Oncology Society (CTOS) 2023 Annual Meeting, being held November 1‑4, in Dublin, Ireland.
"Advanced GIST generally carries a poor prognosis after failure of imatinib and new therapies such as IDRX-42, that target key primary activating drivers as well as secondary resistance mutations in KIT, are urgently needed," said Prof. Schöffski. "These preliminary data demonstrate exciting and clinically meaningful antitumor activity in a highly refractory and difficult to treat GIST patient population and warrant the investigation of IDRX-42 in earlier lines of therapy."
"We are highly encouraged by these initial data of IDRX-42, supporting a potentially best-in-class profile to improve the outcomes of patients with GIST in all lines of therapy, which we believe remains one of targeted oncology’s great unmet medical needs," said Ben Auspitz, co-founder and chief executive officer of IDRx. "Importantly, these preliminary data will help guide our discussions with physicians regarding development strategies for IDRX-42 in patients with GIST in early lines of therapy to prevent the emergence of genomically-driven resistance mutations. Early suppression of such resistance mutations in KIT is likely to benefit patients with GIST, versus trying to treat clinically heterogeneous disease in any individual with multiple resistant clones."
Presentation Highlights:
Initial data (October 5, 2023 cut-off date) from the dose escalation portion of the ongoing Phase 1 StrateGIST study include 33 patients (all with KIT-mutant GIST) who received IDRX-42 across doses ranging from 120 mg once daily (QD) to 400 mg twice daily (BID). Patients were heavily pretreated, with a median of 4 prior lines of therapy. 28 patients are evaluable for objective response. Median duration on treatment was 16 weeks and continuing, with 70% (23/33) of patients remaining on treatment at time of data cutoff. Maximum tolerated dose (MTD) has not yet been reached.
Confirmed partial responses (PRs) by modified RECIST have been demonstrated to date in four patients (at 120 mg QD, 400 mg QD, and 600 mg QD [n=2]).
Although an MTD has not yet been reached, a 68% (19/28 patients) clinical benefit rate (confirmed complete response/PR or stable disease ≥16 weeks) was observed across the initial doses studied to date. 4/28 patients are on study for <16 weeks and continuing on study drug.
Tumor shrinkage and confirmed partial responses were observed across all major classes of KIT mutational variants, including both primary driver mutations in exons 9 and 11, and secondary resistance mutations in exons 13 and 17. Additionally, notable reductions in mutant allele fraction were observed in circulating tumor DNA across these classes of KIT variants.
Preliminary pharmacokinetic analyses demonstrate dose-dependent increases in exposure, with a long half-life (approximately 125 hours), and a 5 to 8-fold accumulation between single-dose and steady-state at Cycle 2 (Day 28).
IDRX-42 exhibited a favorable safety and tolerability profile with most adverse events being mild (Grade 1) in severity. Treatment related adverse events included diarrhea (70%), nausea (52%), and vomiting (27%). No safety-related treatment discontinuations have been observed to date. Two events coded as dose-limiting toxicities were reported (Grade 3 syncope at 600 mg QD, and Grade 3 vomiting at 400 mg BID); both patients chose to continue on study with dose reduction and are continuing on treatment for 5 months and 2 months, respectively.
Four dose levels (120, 240, 400 and 600 mg QD) have been cleared to date, and dose escalation continues with accrual to the 800 mg (400 mg BID) cohort ongoing.
Presentation Details:
Title: Phase 1 Study of IDRX-42 in Patients with Advanced Gastrointestinal Stromal Tumors Resistant to Prior Systemic Therapy: Early Results
Presenter: Patrick Schöffski, MD, MPH
Abstract Number: P 26
Presentation Type: Poster
Session: CTOS Poster Reception 5:30-6:30 p.m. GMT, Thursday, November 2nd
Location: The Convention Center, Dublin, Ireland
About GIST
Gastrointestinal stromal tumors (GIST) are the most common subtype of soft tissue sarcoma. Approximately 80% of cases arise from gain of function mutations in the KIT receptor tyrosine kinase, driving the malignancy through constitutive activation of aberrant signaling. Resistance mutations in KIT emerge in ~90% of patients treated with imatinib, the current standard of care for GIST. In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type.
About the StrateGIST Study
StrateGIST1 is an ongoing, open-label, first-in-human Phase 1/1b study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of IDRX-42 in patients with metastatic and/or surgically unresectable GIST after failure of imatinib and other approved drugs. The study is currently enrolling patients with documented pathogenic mutation in KIT or any platelet-derived growth factor receptor alpha (PDGFRA) mutation (other than PDGFRA exon 18) at sites in the U.S., Belgium, Germany, and Spain. The Phase 1b portion will include expanded exploratory cohorts based on defined lines of prior TKI therapy.
About IDRX-42
IDRX-42 is a potent, oral, highly selective KIT inhibitor targeting all major categories of activating and resistance mutations in patients with KIT-mutant GIST (including variants in exons 9, 11, 13 and 17). In preclinical studies, IDRX-42 demonstrated superior antitumor activity compared to imatinib, the current first-line of therapy, in GIST human xenograft models expressing mutations in KIT exons 9 and 11. In xenograft models expressing secondary resistance mutations in KIT exon 13 or 17, IDRX-42 treatment resulted in potent and dose-dependent antitumor activity superior to the second-line standard of care agent, sunitinib. IDRX-42 is current being evaluated in a first-in-human Phase 1/1b study.