Single dose of neoadjuvant ipilimumab and nivolumab in resectable melanoma with CD8+ cell imaging: Interim results of the C-IT Neo trial.

9513 Background: Neoadjuvant (neoadj) immune checkpoint blockade (ICB) is standard of care for patients (pts) with resectable stage III/IV melanoma. A single ICB dose induces substantial peripheral immune activation and 1 dose of neoadj pembrolizumab has promising activity. The efficacy of 1 dose of combination ICB is unknown and clinically important to describe given the toxicity of sequential combination ICB. Methods: In this phase II single-arm trial, pts with resectable stage IIIB-IV melanoma received 1 dose of neoadj nivolumab (nivo) 1mg/kg and ipilimumab (ipi) 3mg/kg 4 weeks prior to resection. The primary endpoint is major pathologic response (MPR), defined as pathologic complete response (pCR) or near CR (≤10% viable tumor). Using a Simon minimax two-stage design, MPR < 30% is deemed not promising and > 50% promising; positive if >12 MPR in 28 pts. Secondary endpoints were response rate (RECIST 1.1), recurrence free survival (RFS), and safety. CD8-PET imaging was done pre-ICB and pre-surgery, using 89 Zr-radiolabeled crefmirlimab to evaluate association with MPR. Autoradiography and CD8 cell infiltrate by IHC were used to verify the on-target binding of crefmirlimab in surgical specimens. Results: Stage I successfully met the interim efficacy threshold with 5 of 12 pts demonstrating an MPR, thus advancing to stage II. Here we report interim results of the 19 pts enrolled by data cut-off 01/02/2025. Baseline stages were IIIB (53%, n = 10), IIIC (42%, n = 8) and IV (5%, n = 1); 80% cutaneous, 10% acral and 10% unknown primary melanoma. An MPR was observed in 53% (95% CI: 29,76) of pts (n = 10, 7 pCR, 3 near pCR), partial pathologic response (PR) in 21% (n = 4), and non-response in 26% (n = 5). Of the 18 evaluable, RECIST response was 28% (n = 5, all PR), 61% (n = 11) had stable disease, and 11% (n = 2) progressive disease (PD). The rate of grade >3 treatment-related adverse events (TRAE), in neoadj and adjuvant setting, was 11% (n = 2); 1 pt was hospitalized with adrenal insufficiency, no grade 5 events occurred on study. All pts proceeded to surgery with median time to surgery of 29 days (IQR 26,31). 14 pts (74%) received adjuvant therapy; 13 anti-PD-1 and 1 BRAF targeted therapy. Median follow-up was 16 months (IQR 8;23) and 12-month RFS from surgery was 91% (95% CI: 75, 100). Of the 3 pts with recurrent or progressive disease; 0 had an MPR and 2 died from progressive melanoma. CD8-PET was completed in 19 pts pre-ICB and 17 pts pre-surgery. SUVmax pre-ICB, pre-surgery and the percent change over-time was not significantly associated with MPR. CD8-PET tracer evaluation by autoradiography correlated with CD8+ cell infiltrate on IHC by pathologist assessment. Conclusions: C-IT-Neo is the first study evaluating a single dose of combination ICB in the neoadjuvant setting. Interim results show one dose has low grade 3+ TRAE and high efficacy with MPR of 53%. The trial is actively enrolling, with ongoing analysis of CD8-PET imaging and immune biomarkers. Clinical trial information: NCT05289193 .