IACS-6274 is well tolerated and biologically active in selected advanced tumours

Results from a biomarker-driven phase 1 trial showed treatment with IACS-6274, a potent oral glutaminase-1 (GLS1) inhibitor, to be safe and well tolerated up to a dose of 180 mg twice daily. Preliminary anti-tumour activity was observed.

Deregulated cellular metabolism is a key hallmark of cancer, in particular for tumours harbouring KEAP1/NFE2L2 mutations or those expressing low Asparagine Synthetase (ASNS) levels, leaving these tumours subject to glutaminolysis for bioenergetics. GLS1 is a key enzyme in glutaminolysis, converting glutamine into glutamate.

IACS-6274 is a potent oral GLS1 inhibitor with excellent pharmacokinetics and anti-tumour activity in biomarker-defined preclinical models. Dr Timothy Yap (MD Anderson Cancer Center, TX, USA) presented the results of a phase 1 trial (NCT03894540) of IACS-6274 in patients with molecularly selected advanced solid tumours [1]. Primary endpoints were safety and tolerability, maximum tolerated dose, and recommended phase 2 dose. One secondary endpoint was preliminary anti-tumour activity.

The trial enrolled 22 patients with advanced ovarian cancer (n=8), non-small cell lung cancer (n=7), melanoma (n=2), gastric cancer, anal cancer, endometrial cancer, leiomyosarcoma, and head and neck squamous cell carcinoma (all n=1). Molecular alterations assessed included ASNS loss (n=6), STK11 (n=5), KEAP1 (n=5), NFE2L2 (n=4), and NF1 (n=1). A total of 12 patients had 2–4 prior lines of therapy, 10 patients had ≥5. Patients received IACS-6274 at escalating doses ranging from 20–240 mg twice daily.

The most common grade 1-2 treatment-related adverse events were very transient photophobia and photopsia, observed mainly at the highest doses of 180 mg and 240 mg. Grade 3-4 treatment-related toxicities were mainly seen at the dose of 240 mg (i.e. acute renal failure, nausea, hypokalaemia, hypertension, PRES syndrome, and seizures, all of which fully resolved). Glutamate to glutamine ratios decreased in plasma samples in patients at day 14. Compared with baseline, patients at doses of 120, 180, and 240 mg had inhibition of 82.5% (P<0.0001), 83.9% (P<0.0001), and 85.3% (P<0.0001), respectively. The recommended phase 2 dose was 180 mg twice daily. Best response was stable disease in 17 of 20 evaluable patients. Disease control rate at 12 weeks was 60%. Durable stable disease for more than 6 months was observed in 6 patients (2 patients with advanced ASNS-loss ovarian cancer, 2 patients with PD1 inhibitor-resistant melanoma, 1 patient with NF1-mutant leiomyosarcoma, and 1 patient with STK11-mutant non-small cell lung cancer).

1. Yap TA, et al. First-in-human biomarker-driven phase I trial of the potent and selective glutaminase-1 (GLS1) inhibitor IACS-6274 (IPN60090) in patients (pts) with molecularly selected advanced solid tumours. Abstract 3001, ASCO 2021 Virtual Meeting, 4–8 June.

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Posted on 12 August 202118 August 2021