Introduction:

Adjuvant therapies to date have demonstrated limited efficacy for high-risk non-metastatic clear cell renal cell carcinoma (ccRCC). Neoadjuvant treatment with immune checkpoint inhibitors represents a novel approach to impacting the disease process for these patients but has not yet been evaluated in clinical trials. We conducted an early phase evaluation of safety of nivolumab for patients with high-risk non-metastatic ccRCC with secondary objectives of assessing tumor response, quality of life (QOL), and survival.

Methods:

A prospective, single arm, open-label trial to assess the safety and feasibility of neoadjuvant nivolumab in patients with histologically confirmed high-risk ccRCC (T2a-T4NanyM0 or TanyN1M0) planned to undergo radical or partial nephrectomy was conducted between February 2016 and June 2020 (clinicaltrials.gov identifier NCT02575222).  Enrolled patients received nivolumab (3 mg/kg) on day 1 of each of 3 consecutive 14-day cycles of therapy for a total of 3 doses followed by surgery within 7 days of completion of cycle 3. Primary endpoint was safety and tolerability of nivolumab with toxicities/adverse events tabulated by CTCAE version 4.0 grading and Clavien grading for surgical complications. Secondary endpoints included objective tumor response rates via RECIST and irRECIST, QOL alterations during therapy, and metastasis-free and overall survival.

Results:

A total of 17 patients were enrolled with 14/17 (82.4%) reporting CTCAE adverse events and 2/17 (11.8%) experiencing grade 3 events. A total of 10/17 (58.8%) patients had an adverse event of any grade potentially attributable to nivolumab with 4/17 (23.5%) experiencing grade 2 events and no grade 3 events. No patients had Clavien ≥III complications after surgery with 5/17 (29%) experiencing Clavien I-II complications. All evaluable ccRCC patients (15/15) had stable disease per radiographic criteria with 2/15 (13.3%) suggesting possible clinical downstaging. Absolute tumor size decreased minimally (median -0.1cm, range +6.0%, -15.7%). One patient had a >15% decrease in tumor long-axis along with a robust immune-related pathologic response (irPR). No other patient, however, was observed to have an irPR. QOL remained stable during treatment with improvements relative to baseline noted at ≥6 months. With 24.7 months median follow-up, metastasis-free and overall survival were 85.1% and 100% at 2-years, respectively.

Conclusion:

Neoadjuvant nivolumab for high-risk non-metastatic ccRCC demonstrated acceptable rates of adverse events with preservation of QOL. All patients had stable disease after therapy with minimal decrease in absolute tumor size except for one patient who also had a robust irPR.

Funding: Bristol Myers Squibb