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Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3–not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7–18·9] vs 11·1 months [9·1–12·5]; 0·71 [0·60–0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57–0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. F Hoffmann–La Roche Ltd and Genentech Inc.

Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).

In a double-blind, randomized trial involving nearly 1000 patients followed for a median of 2 years, pembrolizumab injections for 1 year after surgery led to improved disease-free survival at 24 months as compared with placebo (77% vs. 68%). Almost one third of patients in the pembrolizumab group had a grade 3 adverse event, but no deaths were due to pembrolizumab.

Improved survival in renal-cell cancer after 1 year of adjuvant therapy was seen with pembrolizumab. At 4 years, 91% of pembrolizumab-treated patients were alive, as compared with 86% of those who received placebo after surgery.

In a randomized trial involving patients with previously untreated advanced renal-cell carcinoma, nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free and overall survival and the likelihood of response. A total of 19.7% of the patients in the combination group discontinued one or both of the trial drugs prematurely.

Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5–24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22–0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48–0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31–0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40–1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

Among patients with advanced renal-cell carcinoma, overall survival and progression-free survival were longer among patients who received pembrolizumab and axitinib than among those who received sunitinib, and more patients in the pembrolizumab–axitinib group than in the sunitinib group had a response.

In a randomized trial involving previously untreated patients with metastatic intermediate- or poor-risk renal-cell cancer, nivolumab plus ipilimumab was associated with higher response rates, longer overall survival, and greater improvement in quality of life than sunitinib.