Articles

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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Cytoreductive nephrectomy: questions remain after CARMENA

Sumeet Bhanvadia, Sumanta K. Pal
Nature Reviews Urology Volume 15, pages 530–532 (2018)
DOI: 10.1038/s41585-018-0064-3

Cytoreductive nephrectomy, a standard approach for de novo metastatic renal cell carcinoma in the era of cytokine therapy, has been upheld during the age of targeted therapy on the basis of retrospective data. Now, the first level I prospective data from the CARMENA and SURTIME trials challenge this standard.

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Cytoreductive Nephrectomy — Patient Selection Is Key

Motzer RJ, Russo P.
N Engl J Med 2018; 379:481-482
DOI: 10.1056/NEJMe1806331

Metastatic renal-cell carcinoma has diverse clinical presentations ranging from incidental detection to a highly symptomatic systemic illness. Patients with metastatic renal-cell carcinoma are assigned a risk category — favorable, intermediate, or poor — on the basis of two published models containing five or six pretreatment selection factors, including presence of anemia, elevated serum calcium concentration, and degree of disability from cancer-related symptoms (performance status). This stratification provides important prognostic insight about whether patients should be treated with cytoreductive radical nephrectomy, systemic therapies, or both. Nephrectomy for stage IV disease removes the primary kidney tumor and its potential for bleeding and…

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Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial

Bex A, Mulders P, Jewett M, et al.
JAMA Oncol. 2018 Dec 13
DOI: 10.1001/jamaoncol.2018.5543.

Abstract

IMPORTANCE:

In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.

OBJECTIVE:

To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.

DESIGN, SETTING, AND PARTICIPANTS:

This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.

INTERVENTIONS:

Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.

MAIN OUTCOMES AND MEASURES:

Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.

RESULTS:

The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).

CONCLUSIONS AND RELEVANCE:

Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.

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