Gotistobart in combination with pembrolizumab in patients with advanced melanoma who have progressed on PD-1 inhibitors with or without CTLA-4 inhibitors.

9551 Background: Patients with advanced melanoma who progress on PD-1 and CTLA-4 inhibitors (IO-R/R) have poor prognosis. Gotistobart is a pH-sensitive anti-CTLA-4 mAb and we hypothesized that gotistobart in combination with pembrolizumab (pembro) could improve outcomes for ipilimumab plus nivolumab (ipi/nivo) treatment failure. PRESERVE-001 (NCT04140526) is a phase 1/2 study that evaluates safety and efficacy of gotistobart with pembro in patients with IO-R/R advanced melanoma. Methods: Patients with IO-R/R advanced melanoma were treated with 3 mg/kg or 6 mg/kg gotistobart plus 200 mg of pembro, Q3W. Treatment beyond progression was allowed at the physician’s discretion. Primary endpoints were ORR (RECIST 1.1) and safety. Exploratory endpoints included OS and an ad-hoc analysis of next-treatment free survival (NTFS; next treatment was identified as initiation of a new antineoplastic agent). Results: As of December 19, 2024, 33 and 34 patients received 3 mg/kg and 6 mg/kg gotistobart plus pembro, with median follow up associated with OS of 14.7 and 10.7 months, respectively. Of these, 67% (22/33) and 68% (23/34) had progressed on ipi/nivo. 30% (20/67) had tumors ≥10cm at study entry. Unconfirmed ORR (uORR) was 25.0% (8/32) and 26.5% (9/34), respectively, with 2 patients achieving CR in the 6 mg/kg group. Of patients who had prior ipi/nivo, uORR was 23.8% (5/21) and 21.7% (5/23), respectively. Efficacy was noted regardless of BRAF mutation status. NTFS rates at 12 months were 45.3% (95% CI 26.0–62.7) and 38.5% (95% CI 20.3–56.4), respectively. OS rates at 18 months were 61.7% (95% CI 40.1–77.5) and 51.9% (29.3–70.4), respectively. Grade ≥ 3 TRAEs were observed in 51.5% and 61.8% of patients in the 3 mg/kg and 6 mg/kg groups, respectively, with colitis/diarrhea or AST/ALT increase being most common. 30.3% and 32.4% of patients, respectively, were able to continue treatment after dose reduction. Conclusions: Gotistobart 3 mg/kg or 6 mg/kg plus pembro 200 mg, Q3W, provided durable response and clinically meaningful OS benefit, regardless of prior ipi treatment, with nearly half of patients being next-treatment free at one year follow up. To our knowledge,this is one of the largest cohorts ever studied in patients with advanced melanoma R/R to ipi/nivo. Clinical trial information: NCT04140526 . Additional parameters Gotistobart 3 mg/kg (N = 33) Gotistobart 6 mg/kg (N=34) Median age (range) 62 (29–83) 66 (24–81) Female n (%)/Male n (%)) 12 (36%)/21 (64%) 12 (35%)/22 (65%) ECOG score = 1 (of 0 or 1) 18 (55%) 16 (47%) Prior treated with ipi/nivo 22 (67%) 23 (68%) Gotistobart treatment duration in weeks, median (range) 19.0 (3–96) 8.9 (3–130) uORR % (n) 25.0% (8/32) 26.5% (9/34) uORR in patients prior treated with ipi/nivo % (n) 23.8% (5/21) 21.7 (5/23) DCR % (95% CI) 50 (31.9, 68.1) 50 (32.4, 67, 6) NTFS rates at 12 months % (95% CI) 45.3 (26.0, 62.7) 38.5 (20.3, 56.4) OS rate at 18 months % (95% CI) 61.7 (40.1–77.5) 51.9 (29.3–70.4)