Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).

9507 Background: IMC-F106C is a novel ImmTAC bispecific protein (PRAME × CD3). Dose escalation results showed robust T cell activation, T cell infiltration into tumor, and clinical activity in various solid tumors (NCT04262466; Hamid 2022). We present updated CM data from monotherapy (mono) and anti-PD1 combination (combo) cohorts. Methods: HLA-A*02:01+ unresectable/metastatic (m) CM patients (pts) previously treated with immune checkpoint inhibitors (ICI) were eligible. Primary objectives were safety and selection of recommended dose; additional objectives were efficacy and ctDNA response (Natera, Guardant). Stable disease (SD) with any tumor reduction confirmed with ≥ 1 subsequent scan was analyzed based on association with overall survival (OS) for tebentafusp. Molecular response was defined ≥ 0.5 log 68% ctDNA reduction by week 9. PRAME was tested by immunohistochemistry (IHC; PRAME+ defined as H-score ≥1). Efficacy is presented by PRAME− and PRAME+ (documented + and unknown) groups. IMC-F106C dosed IV with 2 step-up doses and weekly target dose (20-320 mcg mono, 160 mcg combo). Pembrolizumab (pembro) dosed at IV 400 mg Q6W. Data cutoff: Dec 2023. Median follow-up of mono was 11 months. Results: 46 mCM pts (40 mono, 6 combo) received IMC-F106C ≥ 20 mcg. All mono pts received prior ICI (100% anti-PD1, 88% anti-CTLA4); 25% had prior BRAF/MEK inhibitors. 35/40 mono pts were grouped by IHC as positive (25 PRAME+, 10 unknown) vs. 5 PRAME−. Adverse events (AEs) were consistent with prior experience. Most common AE was Grade 1/2 CRS (50%); mostly in first 3 weeks. No drug related AEs led to treatment discontinuation or death. Safety for pembro combo to date was consistent with the individual agents. 31/40 mono pts had a RECIST evaluable tumor assessment. The clinical benefit rate (CBR) of PR + SD was 61% (19/31). 35% (11/31) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 4 PR (ORR 13%) and 7 SD (26 of 31 pts were PRAME+; the CBR in these was 65% and included all 11 (42%) with confirmed tumor reduction. In 5 PRAME−, there was no tumor reduction. Both median progression free survival (PFS) and 6-month OS rates were higher in PRAME + vs –: 4.5 vs 2.1 months and 94% vs 40%, respectively. 12/40 mono pts received therapy for > 6 months and 14/40 mono pts remain on therapy. 41% of ctDNA-evaluable, PRAME+ mono pts had a molecular response (9/22); this was associated with longer PFS and OS. Correlative biomarkers will be shared. Conclusions: IMC-F106C was well tolerated with promising clinical activity in ICI-pretreated, mCM patients without clinical options. Clinical activity, measured by any confirmed tumor reduction and ctDNA molecular response, is enriched in PRAME+ patients at ~40% and associated with longer PFS and OS. IMC-F106C can be combined with anti-PD1. A Ph 3 trial of IMC-F106C with nivolumab in 1 st line mCM has been initiated (PRISM-MEL301; NCT06112314). Clinical trial information: NCT04262466 .