Selective glutaminase-1 inhibitor shows antitumor activity across cancer types
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IACS-6274, a selective glutaminase-1 inhibitor, appeared safe and demonstrated antitumor activity among patients with biomarker-selected advanced solid tumors, according to phase 1 study results presented at the virtual ASCO Annual Meeting.
Glutaminase (GLS1) plays a key role in the dysregulated cellular metabolism that occurs in many cancers. Researchers at The University of Texas MD Anderson Cancer Center discovered and developed IACS-6274, a GLS1 inhibitor, and found it had excellent pharmacokinetics and conferred antitumor activity in biomarker-defined preclinical models.
“By understanding the underlying biology of different cancers, we were able to identify molecular predictive biomarkers to target tumors with critical dependencies on GLS1 (ie, ‘Achilles heels’), so as to enrich our patient population with those who will respond to and benefit from IACS-6274, for example, in targeting patients who have cancers with KEAP1/NFE2L2 mutations, asparagine synthetase (ASNS)-low tumors and immune checkpoint inhibitor-resistant cancers,” Timothy A. Yap, MBBS, PhD, associate professor of investigational cancer therapeutics and medical director of the Institute for Applied Cancer Science at MD Anderson, told Healio. “Importantly, these are patient populations that respond poorly to current available targeted and immunotherapy agents, and so represent really important areas of clinical unmet need.”
Yap and colleagues jointly conducted a first-in-human trial with Ipsen of IACS-6274 (also called IPN60090) among 22 patients (median age, 63.5 years; 73% women) with advanced ovarian cancer (n = 8), non-small cell lung cancer (n = 7), melanoma (n = 2), and leiomyosarcoma, gastric cancer, anal cancer, endometrial cancer and head and neck squamous cell carcinoma (all n = 1). The cohort included patients with ASNS loss (n = 6) and STK11 (n = 5), KEAP1 (n = 5), NFE2L2 (n = 4) and NF1 (n = 1) mutations. Twelve patients had received two to four prior lines of therapy, and 10 had received five or more lines of therapy.
Researchers administered escalating twice-daily doses of IACS-6274 using a Bayesian optimal interval design, in which one patient each received 20 mg, 40 mg and 80 mg, four patients received 120 mg, 11 patients received 180 mg, and four patients received 240 mg.
Researchers conducted pharmacokinetic and pharmacodynamic studies in serial tumor and blood samples, and they assessed peripheral glutamine metabolism in peripheral blood mononuclear cells.
They found that IACS-6274 had a half-life of 7.56 hours, with plasma exposure showing a dose-dependent increased across the dosage cohorts. Researchers also observed a “robust” pharmacokinetic and pharmacodynamic relationship across doses and patients (P < .001).
Patients who received 180 mg — which researchers recommended as the phase 2 dose — displayed steady-state exposures at day 14 with a maximum concentration of 45.8 M (± 18.6 M) and an average area under the curve from 0 to 12 hours of 382.48 M per hour (± 159.27 M per hour).
At day 14, glutamate-to-glutamine ratios decreased 82.5% compared with baseline among patients who received 120 mg, 83.9% among patients who received 180 mg and 85.3% among patients who received 240 mg (all P < .0001), all crossing the 80% threshold of inhibition used to determine maximally efficacious dosage used in preclinical models, Yap said during his presentation.
Seventeen of 20 evaluable patients achieved stable disease as best response per RECIST version 1.1, with that response persisting for 6 months or longer, with or without tumor regression, among two patients with ASNS-loss advanced ovarian cancer, two patients with PD-1/PD-L1-exposed melanoma — one of whom is still on the trial at 15 months — one patient with NF1-mutated leiomyosarcoma and one patient with STK11-mutated advanced NSCLC.
The disease control rate at 12 weeks was 60%.
“This was a phase 1 clinical trial that included a heavily pretreated patient population with a diverse range of very advanced cancers that were refractory to available existing therapies known to provide clinical benefit for their condition,” Yap told Healio. “Most of our patients had progressed on multiple lines of prior therapies, including chemotherapy, immunotherapy and/or targeted agents. Therefore, to see a disease control rate at 12 weeks of 60% in this heavily pretreated and resistant population of [patients with advanced cancer] is certainly notable.”
Common adverse events related to treatment with IACS-6274 included grade 1 to grade 2 photopsia (n = 7), photophobia (n = 7), increased creatinine (n = 4) and increased aspartate aminotransferase (n = 4). Among patients who received the 180 mg and 240 mg doses, three experienced grade 3 reversible nausea and two experienced grade 2 vomiting and fatigue. One patient who received 240 mg experienced grade 3 acute renal failure and posterior reversible encephalopathy syndrome, which researchers noted fully resolved.
Researchers are planning future studies of IACS-6274 in combination with immunotherapy, other targeted therapies and chemotherapy among molecularly selected patients.
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Yap TA, et al. Abstract 3001. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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