Articles

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohortstudy

Martínez Chanzá N, Xie W, Asim Bilen M, et al.
Lancet Oncol. 2019 Feb 28
DOI: 10.1016/S1470-2045(18)30907-0

Abstract

BACKGROUND:

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

METHODS:

We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinomatreated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.

FINDINGS:

Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.

INTERPRETATION:

While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.

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State of the Future: Translational Approaches in Renal Cell Carcinoma in the Immunotherapy Era

Bakouny Z, Flippot R, Braun DA, et al.
Eur Urol Focus. 2019 Feb 28.
DOI: 10.1016/j.euf.2019.02.014

Abstract

The emergence of immune checkpoint inhibitors as treatment options for metastatic renal cell carcinoma (RCC) has significantly improved outcomes for patients, but also posed new challenges for researchers. Only a subset of patients respond to these therapies, and some who initially respond ultimately develop therapeutic resistance. In this brief report, we review and discuss the importance of novel technological advances for immunotherapy translational research in RCC. In particular, we highlight the potential of single-cellsequencing methods and novel PD-L1 tracer-based imaging modalities for biomarker discovery, as well as ex vivo tumor spheroids for the creation of tumor “immunograms”.

PATIENT SUMMARY:

Immunotherapy, which leverages a patient’s immune system to target tumors, is effective for a substantial number of patients with metastatic kidney cancer. We review novel technologies that may help in understanding why some patients do not respond to these treatments, with the goals of eventually being able to identify which patients will respond to therapy and developing strategies to overcome therapeutic resistance.

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Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Lalani A, Xie W, Martini D, et al.
J Immunother Cancer. 2018 Jan 22;6(1):5.
DOI: 10.1186/s40425-018-0315-0

Abstract

BACKGROUND:

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

METHODS:

We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR.

RESULTS:

Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes.

CONCLUSIONS:

Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

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Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Rini B, Plimack E, Stus V, et al.
N Engl J Med. 2019 Feb 16.
DOI: 10.1056/NEJMoa1816714

Abstract

BACKGROUND:

The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.

METHODS:

In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.

RESULTS:

After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.

CONCLUSIONS:

Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).

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Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Motzer R, Penkov K, Haanen J, et al.
N Engl J Med. 2019 Feb 16
DOI: 10.1056/NEJMoa1816047

Abstract

BACKGROUND:

In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plusaxitinib with the standard-of-care sunitinib.

METHODS:

We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.

RESULTS:

A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.

CONCLUSIONS:

Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).

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Combination Therapy as First-Line Treatment in Metastatic Renal-Cell Carcinoma

Escudier B.
N Engl J Med. 2019 Feb 16.
DOI: 10.1056/NEJMe1900887

This article has no abstract; the first 100 words appear below.

The treatment of metastatic renal-cell carcinoma has been revolutionized twice in the past 12 years by data showing that vascular endothelial growth factor (VEGF) inhibition can induce tumor shrinkage and increase progression-free survival and that immune checkpoint inhibitors can induce durable responses and increase overall survival among patients with this form of cancer. Guidelines for the treatment of metastatic renal-cell carcinoma have changed dramatically to recommend agents that target these two major pathways. In 2007, a trial showed that sunitinib, a tyrosine kinase inhibitor with potent VEGF inhibition, was superior to interferon alfa, and sunitinib became a new standard of…

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Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial

Cella D, Grünwald V, Escudier B, et al.
Lancet Oncol. 2018. January 15, 2019
DOI: 10.1016/S1470-2045(18)30778-2

Abstract

BACKGROUND:

In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.

METHODS:

In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.

FINDINGS:

Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0–27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus −3·14 (−6·03 to −0·25) for sunitinib (p<0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus −4·32 (−8·54 to −0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (−1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0·54; 95% CI 0·46–0·63), FACT-G total score (0·63, 0·52–0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63–0·89) and UK utility scores (0·67, 0·57–0·80).

INTERPRETATION:

Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.

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The creation, development and diffusion of the LARCG – Latin American Renal Cancer Group

Stênio de Cássio Zequi, Diego Abreu Clavijo and all other LARCG Members.
IBJU Vol. 43 (1): 3-6, January – February, 2017
DOI: 10.1590/S1677-5538.IBJU.2017.01.02

Introduction

As usually verified in many malignancies, the majority of the scientific information about renal cell carcinoma (RCC) is produced in developed countries mainly in North America and Europe. This knowledge is derived from great casuistries, joined in multi-institutional collaborative study groups or in International dise- ases consortiums.

Consistent epidemiologic and scientific data originated in the Latin America (LA) are lacking. LA is a large subcontinent, composed by more than 20 countries (much of them great economies), encompassing around 640 million habitants. Latin American population ethnicity is unique, due to an intense miscegenation, differing from northern hemispheric populations. The LA’s population was composed by several civilizations over the years: pre Colombians, (Amerindians), black slaves descendant’s (distinct groups of the African slaves that were sent to North America and Caribe). The predominance of Europeans in LA corresponded to Iberians, and Italians, few French and Germans. We have few Anglo-Saxon, Scandinavian and Northern and Eas- tern Europeans. Regarding Middle East and Africans, the more prevalent immigrants were Syrian, Lebaneses, Jewishs and few Armenians. Also, there are few Arabic, Persian and North African populations. From Asia, the predominance has been established by Japanese and in the last decades, by some Korean and Chinese. There is almost no people from South Asia, Oceania and Pacific Islands etc., differing from US, for example. The LA racial miscegenation resulted in particular genetic groups such as Mulattoes, Mestizos, Zambos, Cimarron’s, Cafuzzos, mamelucos etc.

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Functional and oncologic outcomes after nephron-sparing surgery in a solitary kidney: 10 years of experience

José Ignacio Costabel, Patricio García Marchiñena, Federico Tirapegui, Augusto Dantur, Alberto Jurado, Guillermo Gueglio.
Departamento de Urología del Hospital Italiano de Buenos Aires, Argentina.
Int Braz J urol. 2016; 42: 253-61

Abstract

Objectives:

To evaluate functional and oncologic outcomes of partial nephrectomy (PN) in patients with a solitary kidney.

MATERIALS AND METHODS:

A retrospective analysis of patients with a solitary kidney undergoing nephron-sparing surgery between March 2003 and March 2013 was performed. GFR was recorded before the procedure and 3 months after surgery, thus establishing a change (cGFR). Several variables that may influence cGFR were analyzed. Complications are herein described, namely bleeding, fistula, acute renal failure and end-stage renal disease (ESRD). Local recurrence and margin status are also described. Survival rates were calculated using the Kaplan Meier method (2 patients with metastasis at the time of surgery were excluded from the analysis).

RESULTS:

Forty-five patients were available for analysis. Median follow-up was 27.56 months (r 3-96). Mean cGFR was-7.12mL/min (SD 2.1). Variables significantly related with lower GFR after surgery were loss of renal mass (p=0.01)) and male gender (p=0.03). Four patients (8.8%) experienced hemorrhage. Nine patients (20%) developed a urinary fistula. Only one patient with bleeding required open surgery. Two patients (4.4%) needed transient dialysis. Three patients (6.6%) developed ESRD. Four patients (8.8%) had positive surgical margins (PSMs) and four patients (88%) had local recurrence (2 of these had PSMs). Five patients (11.1%) died during follow-up. Four patients (8.8%) died because of renal cancer. Estimated 2-year overall survival, disease-free survival and cancer specific survival rates were 88.4% (CI 95% 70.5-96); 87.7% (CI 95% 68.1-96) and 92.4% (CI 95% 75-98), respectively.

CONCLUSIONS:

Loss of renal mass and male gender were associated with lower postoperative GFR. Our outcomes were comparable with those in the World literature.

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