Drug Targeting ENPP3 Is Active in Heavily Pretreated, Advanced Metastatic RCC

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An antibody-drug conjugate targeting ectonucleotide pyrophosphatase/phosphodiesterase 3 conjugated to monomethyl auristatin F had some antitumor activity in patients with advanced, metastatic renal ce
An antibody-drug conjugate targeting ectonucleotide pyrophosphatase/phosphodiesterase 3 conjugated to monomethyl auristatin F had some antitumor activity in patients with advanced, metastatic renal ce

An antibody-drug conjugate (ADC) targeting ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) had some antitumor activity in patients with advanced, metastatic renal cell carcinoma (RCC), according to a first-in-human study published in Clinical Cancer Research.1

ENPP3 is a novel target that is specific to RCC. This target was chosen for the study because it has minimal expression in normal tissue.

The phase 1 studies (ClinicalTrials.gov Identifiers: NCT01672775 and NCT01114230) looked at two anti-ENPP3 antibody-drug conjugates (ADCs): Chinese hamster ovary (CHO)-derived AGS-16C3F and hybridoma-derived AGS-16M8F.

In the phase 1 study of AGS-16M8F, 26 patients were administered the drug intravenously every 3 weeks at doses ranging from 0.6 mg/kg to 4.8 mg/kg. The study was terminated before reaching a maximum tolerated dose. The median duration of treatment was 12 weeks. One patient achieved durable partial response and one patient had prolonged stable disease.

In the phase 1 study of AGS-16C3F, 34 patients were started with the bridging dose that was used in the AGS-16M8F trial (4.8 mg/kg given every 3 weeks) — but the researchers noted that this dose of AGS-16C3F was not tolerated as well as the other investigational ADC, leading investigators to reduce the dose multiple times until they reached their recommended dose of 1.8 mg/kg. The 1.8 mg/kg dose was found to be safe and was associated with antitumor activity.

The protocol-defined maximum tolerated dose was reported to be 3.6 mg/kg, though this, too, was not well tolerated when multiple doses were administered. The study authors wrote they amended the dosing protocol to add planned dose levels of 2.7, 1.8, 1.2, and 0.6 mg/kg.

Reversible keratopathy, specifically, was a dose-limiting adverse event that required multiple dose de-escalations. Approximately half of the subjects reported eye-related adverse symptoms. Three patients treated at the 1.8 mg/kg dose had durable partial responses ranging from 100 weeks to 143 weeks.

“Despite historical failures of cytotoxic agents in RCC, AGS-16C3F had encouraging clinical activity, with 3 partial responses and tolerable toxicity,” the researchers wrote. “These findings warrant further clinical investigation of AGS-16C3F for the treatment of RCC.”

Reference

  1. Thompson JA, Motzer RJ, Molina AM, et al. Phase 1 trials of anti-ENPP3 antibody-drug conjugates in advanced refractory renal cell carcinomas. Clin Cancer Res. 2018;24(18):4399-4406.

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