Neoadjuvant Nivolumab May Boost Survival Outcomes in Patients With Renal Cell Carcinoma

Neoadjuvant nivolumab (Opdivo; Bristol Myers Squibb), an immune checkpoint inhibitor (ICI), prior to nephrectomy may improve survival outcomes in patients with high-risk and non-metastatic clear cell renal cell carcinoma (ccRCC), according to authors who published findings from a phase 1 trial in Scientific Reports. Nivolumab caused the primary tumor to become inflamed, and this baseline inflammation may be linked with better response to nivolumab treatment.

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Nivolumab is a PD-1 inhibitor which, along with PD-L1 inhibitors, are ICIs with therapeutic capabilities against tumors. However, research looking at the biological reasons for tumors to respond or resist anti-PD-1 monotherapy is limited, which could inhibit further understanding about the efficacy of nivolumab in a combination regimen.

“We are now witnessing unprecedented improvements in survival outcomes for patients with inherently inflamed tumors, [but] updated prognostic models applicable to the ICI are needed,” study authors wrote.

Investigators of this study aimed to evaluate the effects of PD-1 inhibition on immune cell populations in the tumor. They also aimed to correlate PD-1 inhibition with a changed immune landscape.

The prospective, phase 1 study included 15 patients with non-metastatic ccRCC who received neoadjuvant nivolumab prior to nephrectomy (kidney removal). Since nearly 1 in 3 patients with locally advanced RCC who get nephrectomy have recurrent disease, it’s important to understand other possible treatment options, such as perioperative nivolumab.

Investigators collected tissue samples (while the tumor remained in situ) of tumors treated with nivolumab and compared their immune environments with those of treatment-naïve patients. The team also evaluated peripheral blood mononuclear cells and circulating cytokines.

The tumor samples showed that PD-1 inhibition impacts the circulating immune cell populations in the tumor microenvironment. In the tumors treated with nivolumab, there was an observable increase in the effector T cell phenotype and a reduction in immunosuppressive regulator T cell subsets.

These changes in T cell subsets suggest that anti-PD-1 therapy induced inflammation within the primary tumor in situ, and these baseline inflammatory markers are also suggested to correlate with response to nivolumab treatment, study authors wrote. They also observed that circulating cytokine levels increased after nephrectomy, which may be associated with clinical response.

Further, “targeting these upregulated cytokines post-nephrectomy following neoadjuvant administration of nivolumab may improve systemic response and theoretically reduce recurrence in these high-risk populations,” the authors wrote.

According to the study authors, a previous study showed ICI prior to nephrectomy demonstrated an unprecedented complete pathologic response. The authors noted that in this study, there was no pathological complete response observed, although “nivolumab does appear to ‘prime’ the immune microenvironment for rational synergistic combination approaches to enhance response.”

There are limitations to the study, including small sample size and a possible under-sampling of tumor biopsies. New research could look at a combined treatment regimen of cytoreductive nephrectomy and ICI, or the efficacy of neoadjuvant treatment with a PD-1 inhibitor, followed by adjuvant ICI, according to the study authors.

“Our study provides important hypothesis-generating insights into the biology underlying response and resistance to anti-PD-1 monotherapy, which is crucial to better understand the synergistic effects of combination drug therapies in treating ccRCC,” study authors wrote.

Reference

Singla N, Nirschl TR, Obradovic AZ, et al. Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma. Sci Rep. 2024;14:1458. doi:10.1038/s41598-024-51889-9