Articles

A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer

Lin J, Song AJ, Hoffman-Censits J, et al.
Am J Clin Oncol. 2020 Feb;43(2):82-86.
DOI: 10.1097/COC.0000000000000636.

Abstract

Objectives

There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors.

Materials and methods

mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry.

Results

Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92).

Conclusion

Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

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Impact of Patients’ Gender on Efficacy of Immunotherapy in Patients With Metastatic Kidney Cancer: A Systematic Review and Meta-analysis.

Hassler MR1, Abufaraj M2, Kimura S, et al.
Clin Genitourin Cancer. 2019 Sep 27.
DOI: 10.1016/j.clgc.2019.09.004.

Abstract

Recent meta-analyses on checkpoint inhibitors in cancer report conflicting data regarding the association of patient gender with inhibitor efficacy. In advanced kidney cancer, checkpoint inhibitors have shown improved outcomes in first- and second-line settings compared with standard of care, but the role of patient gender on treatment outcome is unclear. We aimed to assess the efficacy of immunotherapyaccording to patient gender in advanced kidney cancer. We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed using PubMed, Scopus, Web of Science, and The Cochrane Library to identify eligible studies published through February 16, 2019. Studies were included if they reported on the differential outcomes of male and female patients with metastatic kidney cancer receiving immunotherapy. Our outcomes of interest were overall survival (OS) or progression-free survival (PFS). Four randomized controlled trials comprising a total of 3664 patients (2715 males and 949 females) met our inclusion criteria. Both men and women with metastatickidney cancer had an OS and PFS advantage with immunotherapy compared with standard-of-care, but no statistically significant difference between the genders was observed (OS hazard ratio [HR] for men, 0.69; 95% confidence interval [CI], 0.59-0.8; P = .40; HR for women, 0.62; 95% CI, 0.48-0.81; P = .13; PFS HR for men, 0.7; 95% CI, 0.59-0.82; P = .24; HR for women, 0.68; 95% CI, 0.52-0.90; P = .105). In patients with advanced kidney cancer receiving checkpoint inhibitors, there seems to be no association of patient genderwith treatment outcome.

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Prognostic and predictive molecular biomarkers in metastatic renal cell carcinoma patients treatedwith immune checkpoint inhibitors: a systematic review

Rebuzzi SE, Perrone F, Bersanelli M, et al.
Expert Rev Mol Diagn. 2019 Oct 24:1-17.
DOI: 10.1080/14737159.2019.1680286.

Abstract

Introduction

In recent years, the treatment landscape of metastatic renal cell carcinoma (mRCC) has been improved using immune-checkpoint inhibitors (ICI). Nevertheless, the number of patients experiencing clinical benefit from immunotherapy is still limited, while others obtain more benefit from tyrosine kinase inhibitors (TKI). The identification of prognostic and predictive factors would be crucial to better select patients most likely to benefit from immunotherapy among the other potentially available therapeutic options.

Areas covered

This systematic review summarizes the current knowledge (2010–2019) on molecular prognostic and predictive biomarkers, assessed in peripheral blood and/or from tumor tissue, in mRCC patients treated with ICI.

Expert opinion

Among all the biomarkers analyzed, PD-L1 expression on tumor tissue is the most studied. It has an unfavorable prognostic role for patients treated with TKI, which seems to be overcome by ICI-based combinations. Nevertheless, no clear predictive role of immunotherapy efficacy has been observed for PD-L1 in mRCC. Emerging evidence regarding pro-angiogenic or pro-immunogenic genomic and transcriptomic signatures suggests a potential predictive role in patients treated with ICI-based combinations. The rationale for TKI-ICI combinations is based on tumor microenvironment and genomic background, which represent the target of these two main therapeutic options for mRCC.

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First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options

Loo V, Salgia M, Bergerot P, et al.
Target Oncol. 2019 Dec;14(6):639-645.
DOI: 10.1007/s11523-019-00676-y.

Abstract

Until recently, a dichotomy existed in the front-line approach of metastatic clear-cell renal cell carcinoma (mRCC). Specifically, patients received either targeted therapy or immunotherapy. Targeted therapy entailed use of agents blocking signaling through the vascular endothelial growth factor (VEGF) receptor, such as cabozantinib, sunitinib, or pazopanib. Immunotherapy entailed dual therapy with nivolumab and ipilimumab, both checkpoint inhibitors for intermediate/poor International Metastatic RCC Database Consortium (IMDC)-risk disease patients. Within the past year, two datasets have emerged that led to recent approvals of combined therapy with VEGF and checkpoint inhibitors. These regimens (axitinib with either avelumab or pembolizumab) are among several that have been or will be evaluated for patients with newly diagnosed mRCC. We aim to facilitate treatment decisions through this comprehensive and contextualized overview of recent datasets in this therapeutic space.

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The impact of corticosteroid use during anti-PD1 treatment

Pan EY, Merl MY, Lin K.
J Oncol Pharm Pract. 2019 Sep 7.
DOI: 10.1177/1078155219872786.

Abstract

Background

The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy.

Methods

This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed.

Results

The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile.

Conclusion

High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.

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Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study

Procopio G, Apollonio G, Cognetti F, et al.
Eur Urol Oncol. 2019 Nov;2(6):699-707
DOI: 10.1016/j.euo.2019.08.011

Abstract

Background

In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy.

Objective

To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radicalmetastasectomy in mRCC patients.

Design, setting, and participants

The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile.

Outcome measurements and statistical analysis

RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves.

Results and limitations

At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm.

Conclusions

This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy.

Patient summary

This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

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Prognostic value of perirenal and/or sinus fat infiltration in patients with pT3a renal cell carcinoma: A multicentre cohort study. LARCG Group

García Marchiñena P, Tobia I, Abreu D, et al.
Actas Urológicas Españolas, Volume 43, Issue 9, November 2019, Pages 495-502
DOI: 10.1016/j.acuro.2019.01.005

Abstract

Introduction and objectives

The objective of this study is to evaluate overall survival (OS), cancer-specific survival (CSS), relapse-free survival, local and distant (LRFS and DRFS, respectively) rates in patients with pT3a renal cell carcinoma (RCC) considering the perirenal and/or sinus fat infiltration (FI) as prognostic factors.

Materials and methods

Retrospective cohort of patients with pT3a RCC who underwent radical or partial nephrectomy. The data were extracted from the LARCG (Latin American Renal Cancer Group) database. The demographic, clinical, pathological and surgical variables were evaluated. FI was divided into 4 groups (vein, perirenal, sinus and both fats infiltration). The Kaplan Meier and Cox regression curves were performed.

Results

293 patients were included in the study. The mean age was 61.4 years. The median follow-up was 21 months (r: 1-194). CSS, RFS, LRFS and DRFS estimated at 3 years in the group of both fats’ infiltration were 53.1, 45.1, 58.7 and 51.6 months, respectively, and always statistically lower than the rest (P˂0.005). In the multivariate analysis, the infiltration of both fats significantly increased specific mortality, overall and local relapse with respect to vein infiltration (HR: 4.5, 2.42 and 8.08, respectively). The Fuhrman grade and renal pelvis infiltration were independent predictors of CSS and RFS.

Conclusions

Infiltration of both fats increases the risk of overall and local relapse in pT3a RCC. In the same way, it is associated with a lower cancer-specific survival and should be considered as a factor of poor prognosis.

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Validation of the GRade, Age, Nodes and Tumor (GRANT) score within the Surveillance Epidemiology and End Results (SEER) database: A new tool to predict survival in surgically treated renal cell carcinoma patients

Buti S, Karakiewicz P, Bersanelli M, et al.
Scientific Reports volume 9, Article number: 13218 (2019)
DOI: 10.1038/s41598-019-49250-6

Abstract

The purpose of the present study was to validate the new GRade, Age, Nodes and Tumor (GRANT) score for renal cell carcinoma (RCC) prognostication within a large population of patients. Within the Surveillance, Epidemiology, and End Results database, we identified patients with either clear-cell or papillary RCC, who underwent nephrectomy between 2001 and 2015. Harrell’s C-Index, calibration plot and decision curve analysis were used to validate the GRANT model using a five-risk group stratification (0 vs. 1 vs. 2 vs. 3 vs. 4 risk factors). The primary endpoint was overall survival (OS) at 60 months. The analyses were repeated according to the histologic subgroup. The overall population included 73217 cases; 60900 with clear-cell RCC and 12317 with papillary histology, respectively. According to a five-risk group stratification, 23985 patients (32.8%) had no risk factor (0), 35019 (47.8%) had only one risk factor (1), 13275 (18.1%) had risk score 2854 (1.2%) had 3 risk factors and 84 (0.1%) of cases had a GRANT score of 4, respectively. At 60 months, OS rates as determined by the GRANT score were respectively 94% (score 0) vs. 86% (score 1) vs. 76% (score 2) vs. 46% (score 3) vs. 16% (score 4). In both histologic subtypes, the GRANT score yielded good calibration and high net benefit. OS C-Index values were 0.677 and 0.650 for clear-cell and papillary RCC at 60 months after surgery, respectively. In conclusion, the GRANT score was validated with a five-risk group stratification in a huge population from the SEER database, offering a further demonstration of its reliability for prognostication in RCC.

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Complete Surgical Metastasectomy for Renal Cell Carcinoma in the Post-cytokine Era

Lyon TD, Thompson RH, Shah PH, et al.
Journal of Urology, August 2019
DOI: https://doi.org/10.1097/JU.0000000000000488

Abstract

Purpose

Data supporting complete metastasectomy (CM) for metastatic renal cell carcinoma (RCC) is derived primarily from the era of cytokine therapy, and whether CM remains beneficial among patients receiving more recently approved systemic therapies has not been well studied. The objective of this study was to examine survival outcomes among patients treated with CM in the era of targeted therapy and checkpoint blockade availability.

Methods

We queried our institutional nephrectomy registry to identify 586 patients who underwent partial or radical nephrectomy for unilateral, sporadic RCC with a first occurrence of metastases between 2006 and 2017, including 158 treated with CM. Associations of CM with cancer-specific and overall survival were assessed using Cox proportional hazards models.

Results

Median follow-up after diagnosis of metastases was 3.9 years, during which time 403 patients died, including 345 from RCC. Of the CM patients, 147 (93%) did not receive any systemic treatment for their index metastatic lesion(s). Two-year CSS was significantly greater for patients with CM than for those without (84% vs. 54%, p<0.001). After adjusting for age, sex, and the timing, number, and location of metastases, CM was associated with a significantly reduced likelihood of death from RCC (HR 0.47, 95% CI 0.34-0.65, p<0.001).

Conclusions

Complete surgical resection of metastases from RCC is associated with improved CSS in the post-cytokine era and may be considered for appropriate patients following a process of shared decision-making.

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Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma

Singla N, Elias R, Ghandour RA, et al.
Urologic Oncology, September 2019
DOI: https://doi.org/10.1016/j.urolonc.2019.08.012

Abstract

Objective

To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC).

Methods

Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes.

Results

Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients.

Conclusions

Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision.

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