Immunotherapy In Metastatic Renal Cell Carcinoma Research Articles

Real-World Outcomes of Latinx Versus Non-Latinx Patients Treated With First-Line Immunotherapy for Metastatic Renal-Cell Carcinoma.

There are limited data regarding the impact of ethnicity among patients receiving immune checkpoint inhibitors. We evaluated real-world outcomes between Latinx and non-Latinx patients with metastatic renal-cell carcinoma (mRCC) treated with first-line nivolumab/ipilimumab within 2 different healthcare settings. We performed a retrospective analysis of patients with mRCC who received nivolumab/ipilimumab within the Los Angeles County Department of Health Services (LAC-DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between January 1, 2015 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. Of 94 patients, 40 patients (43%) were Latinx while the remainder were non-Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (53%) and 44 (47%) patients received their care at COH and LAC-DHS, respectively. Most Latinx patients (95%) were treated at LAC-DHS, and most non-Latinx patients (89%) were treated at COH. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs. 25.2 months, hazard ratios [HR] 3.61, 95% CI 1.96-6.66, P ≤ .01). Multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; P = .01). At a median follow-up of 11.0 months, the median OS was not reached in either arm at the time of data cutoff. Latinx patients with mRCC had a shorter PFS treated with frontline nivolumab/ipilimumab compared to their non-Latinx counterparts. No difference was observed in OS although these data were immature. Larger studies are needed to further interrogate the social and economic determinants of ethnicity on clinical outcomes in mRCC.

Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma

ABSTRACTIntroduction: Nivolumab is a recombinant, humanized monoclonal antibody that binds PD-1. The binding of PD-1 with PD-L1, expressed on antigen-presenting cells and tumor cells, suppresses the ability of T-lymphocytes to recognize and destroy tumor cells. Nivolumab reverts this inhibitory signal and has led to a significant prolongation of overall survival in patients with metastatic renal cell carcinoma (RCC).Areas covered: The rationale for immunotherapy in metastatic RCC, key immune checkpoint pathways, nivolumab pharmacodynamics, results from the main clinical trials, and predictors of response are discussed.Expert opinion: Nivolumab demonstrated a statistically significant advantage over everolimus in overall survival in metastatic RCC patients after first-line antiangiogenic therapy. Nevertheless, a number of issues remain to be resolved regarding the use of this drug in RCC. It is now imperative to identify which patients can benefit most from immunotherapy and studies are ongoing to define its role in other settings and/or in combinations with antiCTLA4 or antiangiogenic drugs.

Retracted: Immunotherapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) evokes an immune response, which occasionally has resulted in spontaneous and dramatic remissions. In an attempt to reproduce or accentuate this response, various immunotherapeutic strategies have been studied. The most consistent antitumor activity has been reported with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). In recent years, randomized trials have suggested that high-dose, intravenous bolus IL-2 is superior in terms of response rate and possibly in terms of response quality to regimens that involve either low-dose IL-2 and IFN-alpha, intermediate- or low-dose IL-2 alone, or low-dose IFN-alpha alone. More significantly, investigations associated with those trials suggested that the potential exists for identifying predictors of response (or resistance) and limiting IL-2 therapy to those patients who hare most likely to benefit. Although the role of low-dose, single-agent cytokines is limited, combinations of cytokines with targeted therapy may have merit. Several studies, including 2 completed, large, phase 3 trials of interferon plus bevacizumab versus interferon alone, have demonstrated superior efficacy with the combination regimen compared with cytokine monotherapy and suggested the potential of an additive effect that requires further exploration. For patients who are unlikely to benefit from IL-2 or who are unable to receive it, the emergence "targeted immunotherapy" offers hope for improved clinical outcome. Improvements in patient selection, novel agents, and combination therapy will be required to optimize the benefits of immunotherapy in metastatic RCC as the list of effective therapies grows.

Peripheral Blood Neutrophils as Independent Immunologic Predictor of Response and Long-Term Survival upon Immunotherapy in Metastatic Renal-Cell Carcinoma

The aim of this study was to evaluate the prognostic impact of pretreatment neutrophils, previously rendered statistically independent, on the response and on long-term survival of metastatic renal carcinoma patients treated with outpatient subcutaneous (s.c.) interleukin-2 (IL-2) and s.c. interferon (IFN)-alpha. We assessed a total of 495 patients receiving s.c. IL-2/s.c. IFN-alpha-based therapy. While 417 patients with neutrophil counts <6500 cells/microL at baseline achieved 30% objective responses and a median survival of 22 months, 78 patients with pretreatment neutrophil counts >or= 6500 cells/microL had 18% objective responses and a median survival of 9 months (p=0.0000). In conclusion, pretreatment peripheral blood neutrophils <6500/microL constitute an immunologic predictor of tumor response and long-term survival in metastatic renal-cell carcinoma patients treated with s.c. IL-2 and s.c. IFN-alpha-based regimens.

Patients with Metastatic Renal Cell Carcinoma with Long-Term Disease-Free Survival After Treatment with Sunitinib and Resection of Residual Metastases

A complete response (CR) to therapy in patients with metastatic renal cell carcinoma (RCC) is rare but has been achieved in a minority of patients using high-dose interleukin-2. Surgical CR after partial response to immunotherapy in metastatic RCC has been anecdotally reported, although the low overall response rate to cytokines precludes this procedure in the majority of patients. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Clinical efficacy has been demonstrated, with high objective response rates observed in a variety of solid tumor types, including RCC. Herein, we report 2 cases of patients with cytokine-refractory metastatic RCC who received sunitinib and achieved sufficient decrease in tumor burden to permit subsequent surgical resection, resulting in long-term CR.

Sarcomatoid differentiation as a prognostic factor for immunotherapy in metastatic renal cell carcinoma

The objective of the current study was to determine the significance of sarcomatoid differentiation as a prognostic factor for immunotherapy in metastatic renal cell carcinoma (RCC). Patients with metastatic RCC were included in this study and were categorized according to sarcomatoid differentiation. Patients with sarcomatoid differentiation had more aggressive tumor characteristics than those without sarcomatoid differentiation. After immunotherapy, the median progression-free survival was 9.0 months (95% confidence interval [CI] 1.4-52.7) for patient without sarcomatoid differentiation and 3.2 months (95% CI 0.4-42.9) for patients with sarcomatoid differentiation, respectively (P=0.0001). The median overall survival was 22.2 months (95% CI 3.2-75.4) and 10.0 months (95% CI 0.7-60.1) in both groups. When comparing patients with sarcomatoid differentiation, there was no significant difference of overall survival in the immunotherapy group and the no immunotherapy group. Multivariate Cox proportional hazards model analysis showed that T stage (Hazard ratio [HR] 1.71; 95% CI 1.07-2.74; P=0.024), sarcomatoid differentiation (HR 2.18; 95% CI 1.30-3.66; P = 0.003), and the number of metastasis sites (HR 1.81; 95% CI 1.14-2.88; P=0.012) were independent predictors of progression-free survival. Sarcomatoid differentiation and the number of metastasis sites were independent prognostic predictors of overall survival. The estimated relative risks of sarcomatoid differentiation and the number of metastasis sites were 2.83 (95% CI 1.49-5.40; P=0.002) and 2.31 (95% CI 1.29-4.16; P=0.005), respectively. Our findings suggest that sarcomatoid differentiation is an important prognostic factor for immunotherapy in metastatic RCC.

Immunochemotherapy for Metastatic Renal Cell Carcinoma Using a Regimen of Interleukin-2, Interferon-alpha and 5-fluorouracil

Promising results of recent clinical trials with a triple drug bio-chemotherapy regimen encouraged its use in patients with renal cell carcinoma. In a phase II study of patients with metastatic renal cell carcinoma the efficacy and toxicity of a treatment regimen were evaluated using interleukin-2 and interferon-alpha 2 subcutaneously in combination with intravenous 5-fluorouracil. The treatment protocol consisted of an 8-week cycle given on an outpatient basis, with 6 to 9 MU/m2. interferon-alpha given 1 to 3 times a week during the 8 weeks, and sequentially combined with 5 to 20 MU/m2. interleukin-2, 3 times a week for 4 weeks and 750 mg./m.2 5-fluorouracil once a week for 4 weeks. Among 25 consecutive men and 9 women treated 3 (9%) had a complete and 10 (29%) had a partial remission (overall objective response rate 38%). Median response duration (complete plus partial) was 12.5 months (range 3 to 20+). Stable disease lasting 3 to 24+ months was noted in 12 patients (35%). There were only minor side effects, for a maximum toxicity grade of I in 3 patients, II in 25 and III in 6 according to the World Health Organization classification. There were no dose limiting toxicities and no treatment related deaths. Triple drug immunochemotherapy resulted in a significant clinical effect comparable to an aggressive intravenous interleukin-2 treatment regimen but without significant toxicity.

Immunotherapy for metastatic renal-cell carcinoma

The treatment of metastatic renal-cell carcinoma remains a major challenge. Immunotherapy is a new approach to the treatment of advanced cancer and might offer a window of hope to patients with renal-cell carcinoma. The enthusiasm for this form of cancer therapy is mainly due to the recent advances achieved in immunology and molecular biology. This report reviews our experience with immunotherapy for renal-cell carcinoma. Although it is yet experimental, adoptive immunotherapy and combined cytokine administration appears to be a promising therapeutic modality for a selected group of patients with advanced renal-cell carcinoma.