Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

OBJECTIVE: To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. PATIENTS AND METHODS: A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. RESULTS: The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). CONCLUSIONS: Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. METHODS: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. RESULTS: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%-8.3%) versus non-AYAs (2%; 95% CI, 1.2%-2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%-33.5%) compared with non-AYAs (46%; 95% CI, 41.9%-50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%-47.5%) versus 47% (95% CI, 42.3%-51.7%), and 54% (95% CI, 33.9%-72.5%) versus 63% (95% CI, 58.6%-67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31-0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59-0.92) were each associated with a lower risk of hypertension. CONCLUSIONS: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

Disease-free survival as a predictor of overall survival in localized renal cell carcinoma following initial nephrectomy: A retrospective analysis of Surveillance, Epidemiology and End Results-Medicare datac.

OBJECTIVES: This study aimed to assess whether disease-free survival (DFS) may serve as a predictor for long-term survival among patients with intermediate-high risk or high risk renal cell carcinoma (RCC) post-nephrectomy when overall survival (OS) is unavailable. METHODS: The Surveillance, Epidemiology and End Results-Medicare database (2007-2016) was used to identify patients with non-metastatic intermediate-high risk and high risk RCC post-nephrectomy. Landmark analysis and Kendall's τ were used to evaluate the correlation between DFS and OS. Multivariable regression models were used to quantify the incremental OS post-nephrectomy associated with increased time to recurrence among patients with recurrence, adjusting for baseline covariates. RESULTS: A total of 643 patients were analyzed; mean age of 75 years; >95% of patients had intermediate-high risk RCC at diagnosis; 269 patients had recurrence post-nephrectomy. For patients with versus without recurrence at the landmark points of 1, 3, and 5 years post-nephrectomy, the 5-year OS were 37.0% versus 70.1%, 42.3% versus 72.8%, and 53.2% versus 78.6%, respectively. The Kendall's τ between DFS and OS post-nephrectomy was 0.70 (95% CI: 0.65, 0.74; p < 0.001). After adjusting for baseline covariates, patients with one additional year of time to recurrence were associated with 0.73 years longer OS post-nephrectomy (95% CI: 0.40, 1.05; p < 0.001). CONCLUSION: The significant positive association of DFS and OS among patients with intermediate-high risk and high risk RCC post-nephrectomy from this study supports the use of DFS as a potential predictor of OS for these patients when OS data are immature.

Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. FINDINGS: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab. INTERPRETATION: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy. FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study.

BACKGROUND: ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity. RESULTS: Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4-not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment. CONCLUSIONS: Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination. CLINICAL TRIAL REGISTRATION: NCT02325557.

Adjuvant therapy in patients with sarcomatoid renal cell carcinoma: post hoc analysis from Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2805.

OBJECTIVES: To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805. PATIENTS AND METHODS: The original trial (E2805) was a randomised, double-blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805. RESULTS: A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3-4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very-high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5-year disease-free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.45-1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53-1.28 for sorafenib vs placebo). CONCLUSIONS: Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.