A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer

106 Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999

Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study

431 Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was < 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999