Lisa Astor 

Safety and tolerability results from a phase 1 study of neoadjuvant nivolumab (Opdivo) in patients with nonmetastatic high-risk clear cell renal cell carcinoma (ccRCC) support further research with the anti–PD-1 immune checkpoint inhibitor in this setting.

On a phase 1 study poster shared during the 2020 Society of Urologic Oncology Annual Meeting, first author Hiten D. Patel, MD, MPH, of the Department of Urology at Loyola University Medical Center, and coauthors wrote, “[this] early phase trial demonstrates the safety of neoadjuvant PD-1 blockade with preserved [quality of life] when administered to patients with nonmetastatic high risk ccRCC.”

Immune checkpoint inhibitors have demonstrated significant efficacy in treating patients with treatment-naïve metastatic RCC compared with the prior standard-of-care sunitinib (Sutent), as with the FDA-approved combination of nivolumab and ipilimumab (Yervoy).

 The investigators sought to discover if the benefit of PD-1/PD-L1 inhibitors could be extended to the neoadjuvant setting, as an earlier study of neoadjuvant treatment with the multikinase inhibitor axitinib (Inlyta) had demonstrated significant shrinking of RCC tumors prior to surgery.

The study was a prospective, open-label, single arm phase 1 trial (NCT02575222) that explored the safety and tolerability of nivolumab prior to surgery in patients with resectable nonmetastatic high-risk RCC. Patients with T2a-T4 with or without positive lymph nodes were eligible for the study if they were scheduled to undergo a partial or radical nephrectomy, had an ECOG performance status of 0 or 1, and adequate organ and bone marrow function.

Safety was the primary end point by CTCAE version 4.0 and secondary end points included objective tumor response rate by both RECIST and immune-related RECIST criteria, quality of life, metastasis-free survival, and overall survival.

Nivolumab was administered at 3 mg/kg on day 1 of each of a total of 3 consecutive 14-day cycles. Treatment was followed by surgery within 7 days of completion of the third cycle.

A total of 17 patients were included in the early-phase trial consisting of 16 with ccRCC and 1 with papillary disease. Fifteen had stage cT3a disease, 2 had cT3b, and all were negative for lymph node involvement.

Grade 3 adverse events (AEs) were reported in 11.8% of patients, and no grade 4 or 5 events were reported. AEs of any grade were reported in 82.4% of patients and were considered potentially due to nivolumab in 58.8%. The most common AEs reported were fatigue (41.2%), pruritis (29.4%), and rash (29.4%), all grade 1 in severity.

No delays were reported in surgery, and no postoperative complications of Clavien grade 3 or higher were observed.

At 24.7 months of median follow-up, the 2-year metastasis-free survival rate was 85.1%, and the overall survival rate was 100%.

The 15 patients with ccRCC were restaged prior to surgery, but an overall minimal difference was observed in both the long and short axes from baseline to after treatment with nivolumab. However, 1 patient had an immune-related pathologic response and the rest had stable disease by radiographic criteria.

The 1 patient who achieved a pathologic response demonstrated a regression bed with features of wound healing as well as immune infiltration.

“Data suggest a proportion of patients may experience an immunologic response to treatment despite small impact on tumor volume with a short course of therapy,” Hiten et al wrote.

Patients also reported in the Functional Assessment of Cancer Therapy-Kidney Symptom Index questionnaire an improvement in quality-of-life measurements, especially at 12 months after surgery.

Neoadjuvant nivolumab is also currently being studied in the phase 3 PROSPER RCC study in comparison with observation for patients with RCC undergoing nephrectomy (NCT03055013).

1. Patel HD, Gorin MA, Rowe SP, et al. Neoadjuvant nivolumab in patients with high-risk non-metastatic renal cell carcinoma. Presented at: 2020 SUO Annual Meeting; December 2-5, 2020; Virtual. Abstract 92.

2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. 

. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126

3. Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. 

2014;66(5):874-880. doi:10.1016/j.eururo.2014.01.035

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Phase 1 data suggest the anti–PD-1 immune checkpoint inhibitor is safe and tolerable in the neoadjuvant setting for patients with nonmetastatic high-risk clear cell renal cell carcinoma.

Lisa Astor

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