Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

Abstract

Purpose Nivolumab is a fully human immunoglobulin G4 programmed death–1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. Results A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Conclusion Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.

The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

“…Meanwhile, PD-L1 expression in tumor cells and inflammatory cells was associated with aggressive pathologic features and poor prognosis in patients with CCRCC [11]. Recently, PD-1/PD-L1 pathway blockade showed therapeutic benefit in patients with renal cell carcinoma (RCC) [12,13], thus being raised as a novel therapeutic strategy. In advanced non-small cell cancer, anti-PD-1 inhibitor (pembrolizumab) had an acceptable side effect profile and showed antitumor activity and PD-L1 expression in tumor cells correlated with improved efficacy of pembrolizumab [14].…”

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

“…Although beneficial in preventing excessive or harmful inflammation under normal conditions, in the context of cancer, tumor and stromal PD-L1 expression presents a barrier to immune function by contributing to the exhaustion of the antitumor lymphocytes that might otherwise clear the malignancy (6). Consequently, the PD-1:PD-L1 pathway has emerged as a critical target for cancer immunotherapy, and monoclonal antibodies that block either side of this inhibitory interaction have demonstrated impressive activity across a broad set of cancer subtypes, even at advanced and metastatic stages of disease (7)(8)(9)(10)(11).…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Studies have demonstrated that after initial apparent disease progression, some patients derive clinical benefit from continued administration of immunotherapy [22,38,57,111,[118][119][120][121]. In a phase 3 study (CheckMate 025), 69% of patients with metastatic RCC treated with nivolumab beyond first progression subsequently demonstrated tumor reduction in target lesions, and almost half (48%) had a 30% reduction in tumor burden from baseline [111].…”