**03/25/2025**

### Association Between LAG3 Expression and Immune Checkpoint Inhibitor (ICI) Efficacy in Advanced Melanoma

**AACR 2025** PRESENTATION

**Authors** Inderjit Mehmi, Jacob Mercer, Adam Dugan, Binyam Yilma, Catherine Hegarty-Traverso, Calvin Chao, Stamatina Fragkogianni, Omid Hamid

**Background** – Predictive biomarkers for first-line (1L) ICI therapy in advanced melanoma are lacking. aLAG-3/PD1 is approved regardless of _LAG3_ expression despite evidence of poorer RR and PFS (Relativity-047). The relationship between _LAG3_ expression and clinical benefit to 1L non-aLAG-3 ICIs is unknown.

**Methods** – We evaluated _LAG3_ expression as a biomarker for benefit towards 1L non-aLAG-3 ICIs in a real-world (rw) advanced melanoma cohort. De-identified NGS data from patients (pts; N=367) with stage III-IV (advanced) cutaneous melanoma was analyzed in the Tempus Database. Pts were treated with 1L ICIs, aCTLA4/PD1 (n=222) or aPD1 (n=145). Pts treated with 1L aLAG-3/PD1 were limited and not included. Tissue was collected prior to 1L and sequenced with xT DNA (648-gene panel) and xR RNA assays.  _LAG3_ high ( _LAG3_-H) and low ( _LAG3_-L) expressors were defined by median _LAG3_ RNA transcripts per million. PD-L1 was determined by IHC. QuanTIseq was used to estimate immune cell proportions. Rw overall survival (rwOS) was calculated from treatment (tx) start to death from any cause. Rw objective response rate (rwORR) was defined as the proportion of pts with a documented complete or partial response within 90 days of tx start. Hazard ratio (HR) was calculated using a Cox proportional hazards (CoxPH) model and p-values using the Wald test.

**Results** _– LAG3_-H was associated with PD-L1+ status ( _LAG3_-H 52% vs _LAG3_-L 5.5%) and higher proportions of adaptive immune cells, including CD8+ (2.7% vs 0.1%), B (4.3% vs 3.1%), and inhibitory Treg cells (4.5% vs 2.9%; p<0.001 for all). In the aPD1 cohort, _LAG3_-H (n=77) had higher rwORR vs _LAG3_-L (n=68; 67% vs 15%, p=0.002). In the aCTLA4/PD1 cohort, _LAG3_-H (n=109) had similar rwORR vs _LAG3_-L (n=113; 46% vs 37%, p=0.42). CoxPH analysis found a significant interaction between _LAG3_ and 1L ICIs on rwOS (p=0.02), suggesting the ICI effect on rwOS differs between _LAG3_-L and _LAG3_-H (p=0.02). In the _LAG3_-L group, pts treated with aPD1 had reduced rwOS compared to the aCTLA4/PD1 cohort (HR, 1.88, p=0.03), while in the _LAG3_-H group pts treated with aPD1 had higher rwOS compared to the aCTLA4/PD1 cohort (HR, 0.67, p=0.2).  _LAG3_ was associated with immune microenvironment changes and modulated 1L aPD1 but not aCTLA4/PD1 efficacy in pts with advanced melanoma. Similar to the Relativity-047 trial that showed _LAG3_ alters aLAG-3/PD1 efficacy, pts with _LAG3_-H treated with aPD1 had improved outcomes vs pts with _LAG3_-L. However, pts with _LAG3_-H treated with aCTLA4/PD1 had similar outcomes vs pts with _LAG3_-L.

**Conclusions** – Differences in rwOS observed between aCTLA4/PD1 and aPD1-treated pts within the _LAG3_ expression subsets indicates potential predictive value of this biomarker. Future studies will prospectively validate these novel findings in pts with advanced melanoma to confirm the finding that aCTLA4/PD1 is optimal for pts with _LAG3_ -L and alternative 1L ICIs are best for pts with _LAG3_-H.