Phase I studies of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC).

2503 Background: ENPP3 is expressed in greater than 90% of clear cell (CC) and 70% of papillary (PAP) RCC and represents an interesting target in this disease. Hybridoma-derived AGS-16M8F and CHO-derived AGS-16C3F are fully human IgG2k monoclonal antibodies (mAbs), conjugated to microtubule disrupting agent MMAF via a plasma-stable linker, which bind to ENPP3. The 2 ADCs have similar pharmacokinetic and toxicologic profiles. Methods: Two phase I studies were conducted sequentially to test safety, PK, and antitumor activity (RECIST v1.1) of AGS-16M8F and AGS-16C3F in CC and PAP RRCC (median prior systemic therapies = 3). ADCs were given q3w until PD or unacceptable toxicity. Results: AGS-16M8F and AGS-16C3F studies treated 26 and 34 subjects in dose range 0.6 - 4.8 and 1.8 - 4.8 mg/kg, respectively. Fatigue was the most common adverse event (AE) in both studies. In the AGS-16M8F study, maximum tolerated dose (MTD) was not reached, but 3/8 subjects at 4.8 mg/kg discontinued for ocular toxicity (OT). OTs were most commonly reversible keratopathy. In the AGS-16C3F study, the initial dose of 4.8 mg/kg exceeded MTD; 2/2 subjects had dose-limiting toxicities (DLTs); 1 was grade 4 OT. OTs were also observed at lower doses, usually after 2 doses. This led to a successive de-escalation to 3.6, 2.7, and 1.8 mg/kg. Thrombocytopenia (TCP) was frequently reported but a DLT in only 1 subject at 3.6 mg/kg (AGS-16C3F). PK of both ADCs was comparable. Serum concentrations decreased multi-exponentially; exposure was dose proportional. In both studies, the mean terminal half-life was approx. 7-8 days for the intact drug and approx. 4 days for MMAF. Conclusions: Both ADCs tested had associated OT but it was more prominent with AGS-16C3F. However AGS-16C3F was well tolerated at 1.8 mg/kg and showed antitumor activity as evidenced by median disease control of 23+ weeks and durable PR in 2/10 of CC and 1/3 PAP RRCC. A phase II study is planned with AGS-16C3F at 1.8 mg/kg. Clinical trial information: NCT01672775. AGS-16M8F AGS-16C3F AGS-16C3F All All 1.8 mg/kg N 26 34 13 Median prior systemic therapies 3 (0-8) 3 (0-9) 3 (2-7) Relevant AEs (All / ≥ grade 3) OT 8 / 1 29 / 10 12 / 2 TCP 8 / 3 11 / 6 2 / 1 Fatigue/asthenia 12 / 1 26 / 6 12 / 3 Median wks on therapy 12 (1-80) 9 (1-66) 18 (9-48+) ORR 1 PR, 9 SD 3 PR, 17 SD 3 PR, 9 SD Median Disease Control (PR+SD, wks) 21 (12-80) 18 (6 - 66) 23+ (9- 48+)