Targeting New Pathways to Improve Outcomes in Renal Cell Carcinoma

NASHVILLE, Tenn. — Building on the existing immune checkpoint inhibitor (ICI) platform, new treatment strategies for renal cell carcinoma (RCC) seek to adapt the cancer’s immunity cycle to inform development of more effective therapies, according to a review presented here.

Limited options exist beyond anti-VEGF and ICI-based strategies for patients with advanced disease, particularly those who receive combination ICI therapy as the initial strategy.

“Although we have a number of recent approvals, these are largely associated with building incremental benefit,” said Vivek Narayan, MD, of the University of Pennsylvania’s Abramson Cancer Center in Philadelphia, at the International Kidney Cancer Symposium. “Primary or acquired resistance after an initial therapeutic response unfortunately is inevitable. Yet we know that kidney cancer is an immune-responsive tumor. We’ve known about the historical efficacy of high-dose IL [interleukin]-2 in this disease and more recently with durable clinical responses to combining immune checkpoint inhibition.”

A recently proposed adaptive kidney cancer immunity cycle provides a useful framework for considering new therapeutic strategies, Narayan continued. The cycle encompasses the necessary steps for effective cancer immunity, beginning with the release of cancer-cell antigens and effective antigen presentation, followed by deployment and activation of immune cells that traffic and infiltrate into the tumor microenvironment, and ultimately cancer cell cytotoxicity.

“We can think about many aspects of kidney cancer that may either promote or inhibit effective cancer immunity,” he said. “When we think about this adaptive cancer immunity cycle, we can think about novel therapy development and how it may seek to exploit various aspects of the cycle.”

A logical starting point would be novel immune checkpoint strategies and targets. An ongoing phase II trial is evaluating the next-generation anti-CTLA-4 antibody botensilimab in combination with the anti-PD-1 agent balstilimab. Botensilimab is an Fc-enhanced antibody with high-affinity binding, potentially optimizing engagement with antigen-presenting cells and promoting antigen-specific T-cell responses.

Encouraging early results emerged from a phase I study evaluating the bispecific antibody MEDI5752, targeting PD-1 and CTLA-4, in combination with lenvatinib (Lenvima) or axitinib (Inlyta). Use as first-line therapy resulted in an objective response rate of 58.3%. The treatment was also associated with high rates of toxicity-related discontinuation, particularly hepatotoxicity. Additional studies are evaluating the bispecific agent in various combinations, including anti-VEGF agents in the front-line setting, said Narayan.

Beyond anti-PD-1/CTLA-4 strategies, other novel drugs with different targets are in early stages of clinical development. The multitargeted tyrosine kinase inhibitor XL092 (VEGF receptors, MET, AXL and MER among others) is being evaluated in three different combination strategies as first-line treatment for clear cell RCC. Separate treatment arms are pairing XL092 with nivolumab (Opdivo), nivolumab plus ipilimumab (Yervoy), and nivolumab/relatlimab (Opdualag).

CD73 in the adenosine pathway in immune metabolism, as the effects of adenosine/A2AR binding (on dendritic cells, macrophages, T cells, and natural killer cells) can inhibit anti-tumor immunity. In a preliminary study, the A2AR inhibitor ciforadenant, alone or in combination with an anti-PD-L1 antibody, was active in advanced RCC. Ciforadenant is being evaluated in combination with nivolumab and ipilimumab in an ongoing trial of newly diagnosed or recurrent stage IV clear cell RCC.

Progress in advanced RCC will require investigation of potential interventions at multiple steps in the RCC immunity cycle, said Narayan. Vaccines, modified cytokine therapies, CAR T cells, novel immune checkpoints, immune metabolism-targeting therapies, and immune costimulatory agents all have a potential role in the evolving clinical research landscape.

“It appears that we’re really building on the effective backbone of PD-1/CTLA-4 inhibition,” he said in conclusion. “It is really going to require multifaceted approaches informed by the RCC cancer immunity cycle to ultimately improve clinical outcomes.”