RCC Treatment May Require Multifaceted Approach With Novel Immune Therapies

Despite recent approvals, oncologists are still aiming to learn how to adopt the cancer-immunity cycle in renal cell carcinoma (RCC) to inform the development of novel immunotherapies, according to Vivek Narayan, MD, MSCE.

“I think with novel immune therapy development in kidney cancer, it appears that we're really building on the effective backbone of PD1/CTLA4 inhibition,” Narayan, assistant professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania, said during a presentation at 2023 International Kidney Cancer Symposium: North America.¹ “…It's really going to require multifaceted approaches informed by the RCC Cancer Immunity Cycle to ultimately improve clinical outcomes.”

During the presentation, he highlighted the unmet need in the therapeutic management for advanced RCC, despite recent approvals such as the combination use of nivolumab (Opdivo) plus cabozantinib (Cabometyx), pembrolizumab (Keytruda) plus lenvatinib (Lenvima), as well as tivozanib (Fotivda) monotherapy. “These are largely associated with only incremental benefit, and we still have a lack of options beyond standard VEGF receptor TKI- and immune checkpoint inhibitor-based approaches,” Narayan said, adding that the vast majority of patients experience a primary or acquired resistance after an initial therapeutic response.

Vivek Narayan, MD, MSCE

Despite resistance, kidney cancer can be an immune responsive tumor. For example, in a retrospective analysis of 259 patients with metastatic RCC treated with HD IL-2 alone, 23 experienced a complete response and 30 achieved a partial response, for an overall objective response rate of 20%.²

However, additional limitations persist, including: low or middling tumor mutational burden, compared with other cancer types; unclear cancer-specific antigens that may drive anti-tumor immune response; ineffective antigen presentation; high T-cell infiltration, although this may not always be associated with clinical response to checkpoint inhibition, according to Narayan; and considerable heterogeneity in advanced RCC, with immune infiltrated vs angiogenic subtypes, as well as variable immune cell phenotypes and immune cell metabolic functions.

RCC Cancer Immunity Cycle

Therefore, Narayan discussed the RCC Cancer Immunity Cycle, which outlines the key steps required for a successful anti-RCC immune response, describes the development of promising new immunotherapies, summarizes encouraging targets within the RCC microenvironment, and reviews the landscape of antigen-directed therapies in RCC.³

“When we think about the necessary steps for effective cancer immunity, moving from the release of cancer cell antigens and effective cancer antigen presentation, to priming an activation of immune cells, trafficking and infiltration into a tumor microenvironment, and, ultimately, in cancer cell cytotoxicity, we can think about unique aspects of kidney cancer that may either promote or inhibit effective cancer immunity,” he added.

For example, the relative paucity of tertiary lymphoid structures in the disease and how antigen presentation factors within the tumor immune microenvironment could limit the effective cancer infiltration of effector T cells in RCC. Further, genomic abnormalities could also be associated with more favorable responses to immune checkpoint inhibition, whereas neoadjuvant therapies could induce unfavorable responses.

“So we think about this adaptive cancer immunity cycle, we can think about now novel therapy development, and how it may seek to exploit various aspects of this cycle,” Narayan said. “And I think the first place to start is beginning with novel immune checkpoint strategies and targets.”

Novel Therapy Development

In the randomized, open label, multicenter, phase 2 Advanced Renal Cell Cancer Combination ImmunoThErapy Clinical Trial (ARCITECT; NCT05928806), Michael B. Atkins, MD, and colleagues are evaluating botensilimab– an Fc-enhanced next-generation anti–CTLA-4 antibody–plus a novel anti-PD1 antibody vs ipilimumab (Yervoy) and nivolumab in treatment-naïve patients with metastatic clear cell RCC.⁴

“…The idea [is] that this may allow for more selective or high affinity binding to FC gamma receptors. So, the clinical hypothesis here is that this may optimize engagement with APCs, thereby better promoting antigen-specific T-cell responses, and also preferentially depleting regulatory T cells in the tumor immune microenvironment, thereby enhancing the effector to regulatory T cell ratio,” Narayan explained.

Beyond PD1/CTLA4 checkpoints, he added that LAG-3, TIGIT, and more are being explored. For example, in the multicenter, open-label, phase 1b Stellar-002 trial (NCT05176483), investigators are evaluating XL092–a novel, oral inhibitor of multiple receptor tyrosine kinases including MET, VEGFR2, AXL, and MER–alone and in combination with nivolumab, with or without ipilimumab, in patients with advanced solid tumors.⁵

Lastly, Narayan highlighted immune metabolic targeting. For example, Eric Jonasch, MD, and Katy Beckermann, MD, PhD, are the primary investigators of the phase 1/2 study evaluating ipilimumab, nivolumab, and ciforadenant. The trial aims to investigate the combination’s safety, tolerability, and depth of response.

“Just looking back at the Cancer Immunity Cycle, it's clear that although we have novel immune checkpoints and immune metabolic targeting strategies under active clinical development, it's really a number of things targeting various aspects of this cycle, like therapeutic vaccines to enhance priming and activation.,” Narayan concluded.

^References:

^{1. Narayan V. Novel Immune Therapies in Early Phase Clinical Development for RCC. Presented at: 2023 International Kidney Cancer Symposium: North America; November 10-11, 2023; Nashville, TN.}

<sup>2. Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma. Cancer. 2008;113(2):293-301. doi:10.1002/cncr.23552.
3. Braun DA, Bakouny Z, Hirsch L, et al. Beyond Conventional Immune Checkpoint Inhibition: Renal Cell Carcinoma at the Forefront of Solid Tumor Immunology. Nat Rev Clin Oncol. 2021;18(4):199–214. doi:10.1038/s41571-020-00455-z.</sup>

^{4. ClinicalTrials.gov. Advanced Renal Cell Cancer Combination ImmunoThErapy Clinical Trial (ARCITECT). Accessed: November 11, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05928806.}

^{5. Mcgregor B, Choueiri T, Shah N, et al. A multicohort phase 1b study (STELLAR-002) of XL092 in combination with immunotherapy in patients with advanced solid tumors. J Immunother Cancer. 2022;10(2):A775. doi:10.1136/jitc-2022-SITC2022.0742.}