High LAG-3 RNA Levels Predict Response, Not Survival, in Metastatic RCC

High RNA expression of lymphocyte activation gene-3 (LAG3) is associated with significantly improved objective response rates (ORR) to first-line immunotherapy combinations in patients with metastatic renal cell carcinoma (RCC), according to a new retrospective analysis. However, this initial response does not translate into a statistically significant overall survival (OS) benefit, suggesting a phenotype of adaptive immune resistance where T-cell exhaustion eventually limits long-term outcomes.¹

The study, which utilized the Tempus multimodal database, analyzed genomic and transcriptomic data from 566 patients with metastatic RCC. All patients received standard-of-care first-line immuno-oncology (IO) combinations, including nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), nivolumab plus cabozantinib (Cabometyx), or pembrolizumab plus lenvatinib (Lenvima). These regimens were established as frontline standards by pivotal trials such as CheckMate 214 (NCT02231749),² KEYNOTE-426 (NCT02853331),³ CheckMate 9ER (NCT03141177),⁴ and the CLEAR study (NCT02811861).⁵

A Paradox of Response and Survival

Researchers stratified patients into four quartiles (Q1–Q4) based on LAG3 RNA expression levels.¹ The analysis revealed a statistically significant association between higher LAG3 expression and improved tumor response. Patients in the highest quartile of expression (Q4) achieved an ORR of 51%, compared to 37% in the lowest quartile (Q1) (P =.034).

Despite these higher response rates, the study found no significant correlation between LAG3 levels and OS. While median OS showed a nonsignificant trend favoring higher quartiles (35.0 months in Q4 vs 25.7 months in Q1), the difference was not statistically meaningful (P =.2 for Q4 vs Q1).

The "Inflamed yet Exhausted" Microenvironment

The discordance between response and survival may be explained by the specific immunological profile associated with LAG3. High expression of the gene was linked to a "complex immunological phenotype" characterized as both inflamed and exhausted, explained Rana McKay, MD, University of California San Diego, during a presentation of the study.

Tumors with high LAG3 levels exhibited robust infiltration of pro-immune effector cells, including CD8-positive T cells, natural killer (NK) cells, and M1 macrophages. However, these tumors also contained high levels of immunosuppressive elements, such as regulatory T cells (Tregs) and M2 macrophages, and showed strong co-expression of other immune checkpoint genes, including PDCD1 (PD-1), CTLA4, and TIGIT.

The authors concluded that while LAG3 marks an inflamed tumor phenotype primed to respond to initial immunotherapy, the concurrent exhaustion markers suggest a state of adaptive resistance that may curtail durable survival benefits.

Genomic Associations and Metastatic Sites

The study also identified distinct clinical and genomic characteristics associated with LAG3 expression. Higher expression levels were correlated with a significantly lower prevalence of liver metastases, dropping from 18% in the lowest quartile to 7% in the highest (P =.019).

Genomically, high LAG3 expression was associated with somatic alterations in BAP1. Loss-of-function mutations in BAP1 are known to enhance tumor immunogenicity by upregulating MHC class I expression and promoting T-cell infiltration, which aligns with the "inflamed" phenotype observed in the high-LAG3 cohort.

Clinical Implications

Currently, no biomarkers are routinely used in clinical practice to guide frontline immunotherapy selection for RCC. While this study highlights LAG3 RNA expression as a potential predictor of initial response, the authors noted that further validation is required. Specifically, future research must correlate RNA findings with LAG-3 protein expression to establish its utility as a clinical biomarker.

REFERENCES:

1. McKay RR, Dugan AJ, Jariwala U, et al. Lymphocyte activation gene-3 (LAG3) expression patterns and immunotherapy (IO) response in metastatic renall cell carcinoma (mRCC). Presented at: 2025 ESMO Congress; October 17–21, 2025; Berlin, Germany. Abstract 2593MO.

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.

3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16.

4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982.

5. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. doi: 10.1056/NEJMoa2035716. Epub 2021 Feb 13.