Overcoming Immunotherapy Resistance Mechanisms in Kidney Cancer

In a collaboration between CancerNetwork® and KidneyCAN, Michael B. Atkins, MD, discussed his key research strategies focused on the improvement of adjuvant and neoadjuvant therapy options for patients with renal cell carcinoma (RCC) and other types of kidney cancer.

Atkins, a medical oncologist and the deputy director of the Georgetown Lombardi Comprehensive Cancer Center, noted that his aim is to understand mechanisms of resistance to frontline immunotherapy in kidney cancer. Various efforts include the phase 2 ARCITECT study (NCT05928806) assessing anti–CTLA-4 therapy in combination with PD-1 inhibition among patients with advanced RCC.1 Additionally, Atkins and his colleagues look to evaluate how anti–PD-1, anti–LAG-3, and anti–CTLA-4 combination regimens may improve outcomes with immunotherapy among those with kidney cancer.

KidneyCAN is a nonprofit organization with a mission to accelerate cures for kidney cancer through education, advocacy, and research funding. Learn more about KidneyCAN’s mission and work here.

Transcript:

My main research effort is trying to understand mechanisms of resistance to immunotherapy in frontline kidney cancer. What we have identified [when] working with colleagues at the Dana-Farber Cancer [Institute] through the kidney cancer spore is that patients who have high PD-1 on their [regulatory T cells] tend to have worse outcomes. Patients who have multiple checkpoints expressed on their CD8 T cells also do worse. Moving forward from that information, we’ve tried to test a Creg-depleting CTLA-4 [agent] together with an anti–PD-1 [agent] in kidney cancer vs [nivolumab (Opdivo)/ipilimumab (Yervoy)] in what we call the ARCITECT trial to see whether or not that improves the tail of the [progression-free survival (PFS)] and [overall survival] curves. We are moving forward in combination with Brian Rini, MD, and Katy Beckermann, MD, PhD, to look at anti–PD-1, anti–LAG-3, and anti–CTLA-4 triple combination [therapies] in kidney cancer, as another way of potentially improving the immune therapy.

I believe strongly that the way to improve the long-term outcomes and cure rate for patients with metastatic kidney cancer is to improve the first-line immunotherapy regimens based on a pure immunotherapy backbone. That’s the principal thing I’m working on. I’m also trying to identify the best treatment options for patients who progress after PD-1–based combinations, and I’m looking at moving HIF2α-targeting agents into the second line, where they’re not currently FDA-approved. [This is] based on data that we saw in the LITESPARK-013 trial [NCT04489771], where that population who had not seen a [tyrosine kinase inhibitor] tended to have the best response rates and PFS.2

References

1. Serzan MT, Jegede O, Bilen MA, et al. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). J Clin Oncol. 2024;42(suppl 4):TPS492. doi:10.1200/JCO.2024.42.4_suppl.TPS492
2. Agarwal N, Brugarolas J, Ghatalia P, et al. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann Oncol. 2024;35(12):1148-1156. doi:10.1016/j.annonc.2024.08.2338