ADAM trial: A multicenter, randomized, double-blinded, placebo-controlled, phase 3 trial of adjuvant avelumab (anti-PD-L1 antibody) in patients with Merkel cell carcinoma and lymph node metastases.

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LBA9504 Background: Merkel cell carcinoma (MCC) with lymph node (LN) metastases (mets) is historically associated with high risk of relapse and mortality despite surgery and/or radiation therapy (RT). Previously reported adjuvant trials (ADMEC-O and STAMP) have not shown a clear benefit with adjuvant PD-(L)1 blockade. Methods: ADAM trial (NCT03271372) is an investigator-initiated, phase III, multi-center, double-blinded, placebo-controlled study. We enrolled 100 patients (pts) with MCC and LN mets (stage III) treated definitively with surgery and/or RT, and without radiologic evidence of residual MCC. Pts were randomized (1:1), stratified by primary tumor/LN status and RT status, to receive IV avelumab (A; 800 mg/dose) or placebo (P), for up to 2 years (yrs) on a de-escalating schedule. The primary endpoint was relapse-free survival (RFS). 100 patients provide 86% power to observe a statistically significant (2-sided 5%) difference in RFS assuming true hazard ratio (HR) for RFS failure of 0.4. Secondary endpoints included distant metastasis-free survival (DMFS), disease-specific survival (DSS), overall survival (OS), and safety. Point estimates were obtained using Kaplan-Meier or cumulative-incidence methods, and Cox regression (stratified, with pre-specified adjustment of confounding variables as needed) was used to estimate HRs of failure. Results: 100 eligible pts (pathologic stage IIIB - 52; IIIA - 48) were randomized to A (N=48) vs P (N=52) between 12/2017 and 01/2024. At the data cutoff date (01/15/2026), median follow-up among relapse-free survivors was 4.2 yrs [range 1.9-7.1]. Median age was 70 yrs overall (A-72 [50-86], P- 67 [35-83]) and 93% of pts had received adjuvant RT. The HRs for RFS, relapse, DMFS, DSS and OS are listed in the Table below. The point estimates for MCC relapse for A vs P arms, respectively, were 12.8% vs 40.4% at 1 year, 21.3% vs 42.3% at 2 years and 28.3% vs 44.5% at 3-, 4- and 5-year timepoints. Grade 3/4 treatment-related adverse events (TRAE) rate was 15% (n=7) in A and 0% in P arms; no grade 5 TRAEs occurred. Conclusion: In this study, adjuvant avelumab was associated with reduced risk of MCC relapse in pts with LN mets. High MCC-specific survival in both arms points to effectiveness of PD-(L)1 blockade in adjuvant and metastatic settings. These data will inform future discussions regarding adjuvant therapy in clinical practice. Clinical trial information: NCT03271372 . Efficacy endpoints. Endpoint HR for Failure, Avelumab vs Placebo (95% CI, p-value)Stratified /Adjusted stratified Number of eventsAvelumab/Placebo RFS 0.61 (0.32-1.16, p=0.132) /0.54 (0.28-1.05, p=0.069) 16/24 Relapse* 0.51 (0.26-1.00) /0.47 (0.23-0.94) 13/23 DMFS 0.93 (0.44-1.97) /0.89 (0.41-1.94) 13/15 DSS 1.81 (0.43-7.55) /** 5/3 OS 2.37 (0.73-7.73) /** 9/5 *Not a pre-specified analysis; **Not enough events to accommodate adjustment.

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