Depleting the amino acid arginine using a drug called ADI-PEG 20 enhances the efficacy of two well-established chemotherapy medications — Platinol (cisplatin) and Alimta (pemetrexed) — in patients with ASS1-deficient malignant pleural mesothelioma (MPM).
The study, “Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers,” appeared in the Journal Clinical Oncology.
MPM’s progression requires arginine. While the argininosuccinate synthetase 1 (ASS1) enzyme is vital for the synthesis of arginine, MPM patients whose cells express low ASS1 levels were found to have a more aggressive clinical phenotype and worse clinical outcomes. This is because low ASS1 promotes different metabolic pathways that ultimately help tumors grow.
But since cancer cells in low-ASS1 MPM tumors cannot synthesize arginine, they become dependent upon an external supply of arginine to survive and grow. ADI-PEG 20 can deplete that external supply. So, when given ASS1-deficient MPM patients, ADI-PEG 20 kills cancer cells while leaving the patient’s normal cells unharmed.
In this study, researchers analyzed ADI-PEG 20’s effects when combined with two chemotherapy medications, Platinol and Alimta. Specifically, they determined the recommended dose, safety and tolerability of ADI-PEG 20 along with Platinol and Alimta in patients with ASS1-deficient MPM or non small-cell lung cancer (NSCLC).
Patients with MPM (n=5) and with NSCLC (n=4) who had never been treated with chemotherapy received weekly ADI-PEG 20 doses of 18 mg/m², 27 mg/m² or 36 mg/m², together with Alimta 500 mg/m² and Platinol 75 mg/m². These were administered to patients every three weeks, reaching a maximum of six cycles.
Patients who reached stable disease could continue ADI-PEG 20 alone (monotherapy) until disease progression or withdrawal. In total, the median number of weeks patients received treatment was 23.5 (range, 13 to 47 weeks) for patients with NSCLC and 31.0 (range, 30 to 47 weeks) for patients with MPM.
All patients experienced, at minimum, stable disease, while 78 percent achieved a partial response with all doses tested. MPM patients survived a median 56.4 weeks, with a median 30.7 weeks of progression-free survival. NSCLC patients survived a median 55.5 weeks, with a median 23.0 weeks of progression-free survival.
Combining ADI-PEG 20 with Platinol and Alimta was better at suppressing arginine when compared to ADI-PEG 20 monotherapy. Previous studies showed that when patients received ADI-PEG 20 alone after an initial suppression, the levels of arginine concentrations returned to pretreatment levels within nine weeks. But in the triple combo, arginine concentrations remained depleted compared with baseline levels until the end of treatment.
“With limited treatments available for these patients, this triplet combination warrants further study,” researchers wrote, adding that the recommended Phase 2 dose was weekly, intramuscular ADI-PEG 20 36 mg/m² plus three-weekly intravenous cisplatin 75 mg/m² and pemetrexed 500 mg/m². The new therapy will continue to be tested in ASS1-deficient patients with MPM in a new randomized Phase 2/3 clinical trial (NCT02709512) that is now recruiting participants.