Redefining Immune Strategies: LAG-3 With PD-1 in Kidney Cancer

Katy Beckermann, MD, PhD, of Vanderbilt-Ingram Cancer Center, and Michael Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, discuss the rationale behind targeting LAG-3 as a novel checkpoint inhibitor, highlighting its potential in combination therapy with anti-PD-1 in kidney cancer.

Together, they address questions regarding the durability of responses compared to CTLA-4 inhibitors and discusses ongoing research and considerations for future treatment strategies.

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Dr. Beckermann: There has been exciting data and a new checkpoint inhibitor approved for melanoma. Could you discuss the rationale for targeting LAG-3 as a novel checkpoint inhibitor?

Dr. Atkins: As is widely known, PD-1 is a checkpoint expressed on T cells. When it binds to its ligand, PD-L1, it shuts off T cell activity. Anti-PD-1 antibodies reactivate T cell immunity against tumors.

However, other checkpoints on T cells, like LAG-3, become expressed, causing T cell exhaustion, potentially interfering with blocking PD-1 to fully reactivate the immune system. Combining anti-PD-1 with anti-LAG-3 has shown improved activity against melanoma, with about a 10% increase in overall survival and response rate, and less toxicity than nivo/ipi. This combination has become an alternative for metastatic melanoma patients.

In kidney cancer, and likely other cancers, patients with expression of PD-1 and LAG-3 on their T cells may have reduced activity from anti-PD-1 alone. This provides a rationale for combining LAG-3 inhibition with anti-PD-1 in kidney cancer.

Dr. Beckermann: Considering the early stage of the LAG-3 and PD-1 concept, do you anticipate a similar durability between CTLA-4 and LAG-3 inhibition?

In melanoma, CTLA-4 inhibition has shown impressive durability with 5-year overall survival data reaching almost 60%. Do you think the LAG-3 signal will have similar durability, or are there concerns that its targeting, with a slightly different profile, may not achieve the same longevity?

Dr. Atkins: While we lack data, responses to anti-PD-1 alone in melanoma appear as durable as PD-1 and CTLA-4 combination therapy. Thus, I anticipate responses to PD-1 LAG-3 inhibition will also be durable.

One unique aspect of anti-PD1 and anti-CTLA-4 therapy is the ongoing responses seen after treatment cessation, with patients discontinuing due to toxicity responding as well or better than those continuing therapy. However, this aspect has not been studied with anti-PD-1 anti-LAG-3 combinations.

In melanoma, the treatment protocol involves 4 doses of ipi/nivo induction followed by maintenance nivo, whereas LAG-3 combinations continue indefinitely without looking at discontinuation. Additionally, the ability of LAG-3 to enhance anti-PD-1 activity against brain metastasis has not been fully explored in melanoma, though it may be less critical in kidney cancer.

While some aspects remain unresolved, the durability of responses is expected. Eventually, like with nivo/ipi or anti-PD-1 alone, treatment cessation may become feasible in melanoma.

View their continued comments on The Potential Synergistic Power of LAG-3 and PD-1 in Kidney Cancer and Beyond LAG-3: Promising Immuno-Oncology Targets in Kidney Cancer.