Success for a New Type of Checkpoint Inhibitor

Kate Hitchcock, MD, PhD


June 18, 2021

“In the immunotherapy era, smart use of tumor and immunologic biomarkers will help better match therapies to patients.”
 -  Dr Raymond J. Tesi, 2018

ASCO 2021 brings us news of RELATIVITY-047, which tested the combination of anti-PD-1 nivolumab with a drug called relatlimab that is an inhibitor of the lymphocyte activation gene-3 (LAG-3) pathway. LAG-3 behaves something like CD4 and CD8 in that it acts as a negative co-receptor when it associates with the T-cell receptor-CD3 complex. It plays a role in T-cell activation, proliferation, and homeostasis as well as in the function of Treg cells. LAG-3(-/-) mice have increased numbers of CD4+ and CD8+ cells in their memory T-cell pool. If you’d like to read more about the science behind the development of anti-LAG-3 agents, I recommend Dr Elena Burova’s excellent paper, which you can find here.

In the RELATIVITY-047 study, with a median follow-up of 13 months, median PFS was improved with the addition of relatlimab to nivolumab ((10.1 months [95% CI, 6.4–15.7]) versus nivolumab alone (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; p = 0.0055)). Serious adverse events were more common in the combined relatlimab plus nivolumab group (19% vs 10% for nivolumab alone) as was toxicity-related treatment discontinuation (15% vs 7%), but the study was not big enough to test a difference in treatment-related deaths (3 and 2, respectively).

This is not the first time that the anti-PD-1 anti-LAG-3 combination has been discussed at ASCO. For example, Dr Kyriakos Papadopoulos and company have talked about their study in a broad group of malignancies, but this was presented as an ongoing effort without interim results (ASCO 2019). You can see a nice poster-layout explanation of that study here.

Beyond the validation for this particular drug, ASCO’s chief medical officer, Dr Julie R. Gralow, pointed out to Medscape that the study further solidifies the technique of dual immune checkpoint blockade that acts on multiple pathways in order to short-circuit some of the mechanisms of resistance to these agents.

Beyond the therapeutic effects, I’m excited to see that folks at University Medical Center Groningen are working on a dose-finding study for immuno-PET imaging based on this receptor as well. You can see some nice images of that type in mice in this May 2021 study from Vrije Universiteit Brussel. As Dr Tessi describes in his commentary linked above, the best immunotherapy we have is useless if given to the wrong patient.

What does this mean for all of us down in the trenches? It’s conceivable that in a few years you could do pre-treatment imaging of your patient to determine whether their tumor will respond to therapy that incorporates these new agents, and if that’s a yes, it’s possible that dual-inhibitor therapy will result in improved PFS with an acceptable risk of increased toxicity. Immune checkpoint inhibitors as single agents have been very useful, but not a home run. It looks like there is clear benefit in exploring combinations of these drugs in order to fight cancer cells’ amazing ability to work around blockade of a single pathway, and it’s logical that LAG-3 is a place for us to be looking.

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About Dr Kate Hitchcock
Kate Hitchcock, MD, PhD, is a radiation oncologist, biomedical engineer, and retired aircraft carrier driver who grew up as a Wyoming cowgirl. When she is not at the hospital, you can find her with Carolyn, Mary, Tyler, Nick, Marlee, and Colby the barking dog, enjoying the natural splendor of the great state of Florida. She thinks you should visit sometime and try to solve the puzzle of why the natives have so carefully shunted all of the tourists toward the House of Mouse. Connect with her on Twitter: @hitchcock_kate


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