Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.

BACKGROUND: Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo. METHODS: The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4-12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512. FINDINGS: Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3-43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71-1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3-5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo. INTERPRETATION: Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Updated systematic review and network meta-analysis of first-line treatments for metastatic renal cell carcinoma with extended follow-up data.

Immune checkpoint inhibitor (ICI)-based combination therapies are the recommended first-line treatment for metastatic renal cell carcinoma (mRCC). However, no head-to-head phase-3 randomized controlled trials (RCTs) have compared the efficacy of different ICI-based combination therapies. Here, we compared the efficacy of various first-line ICI-based combination therapies in patients with mRCC using updated survival data from phase-3 RCTs. Three databases were searched in June 2023 for RCTs that analyzed oncologic outcomes in mRCC patients treated with ICI-based combination therapies as first-line treatment. A network meta-analysis compared outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. Subgroup analyses were based on the International mRCC Database Consortium risk classification. The treatment ranking analysis of the entire cohort showed that nivolumab + cabozantinib (81%) had the highest likelihood of improving OS, followed by nivolumab + ipilimumab (75%); pembrolizumab + lenvatinib had the highest likelihood of improving PFS (99%), ORR (97%), and CR (86%). These results remained valid even when the analysis was limited to patients with intermediate/poor risk, except that nivolumab + ipilimumab had the highest likelihood of achieving CR (100%). Further, OS benefits of ICI doublets were not inferior to those of ICI + tyrosine kinase inhibitor combinations. Recommendation of combination therapies with ICIs and/or tyrosine kinase inhibitors based on survival benefits and patient pretreatment risk classification will help advance personalized medicine for mRCC.

Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study.

BACKGROUND: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up. METHODS: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861. FINDINGS: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93]). INTERPRETATION: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.

Patients' Perceptions Regarding the Relevance of Items Contained in the Functional Assessment of Cancer Therapy Kidney Symptom Index-19.

BACKGROUND: There is a lack of consensus regarding the optimal method of assessing health-related quality of life (HR-QOL) among patients with metastatic renal cell carcinoma (mRCC). This study explored the perceived relevance of items that make up the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), as judged by patients with mRCC. METHODS: This was a multinational cross-sectional survey. Eligible patients responded to a questionnaire composed of 18 items that assessed the perceived relevance of each item in the FKSI-19 questionnaire. Open-ended questions assessed additional issues deemed relevant by patients. Responses were grouped as relevant (scores 2-5) or nonrelevant (score 1). Descriptive statistics were collated, and open-ended questions were analyzed and categorized into descriptive categories. Spearman correlation statistics were used to test the association between relevance and clinical characteristics. RESULTS: A total of 151 patients were included (gender: 78.1 M, 21.9F; median age: 64; treatment: 38.4 immunotherapy, 29.8 targeted therapy, 13.9 immuno-TKI combination therapy) in the study. The most relevant questions evaluated fatigue (77.5), lack of energy (72.2), and worry that their condition will get worse (71.5). Most patients rated blood in urine (15.2), fevers (16.6), and lack of appetite (23.2) as least relevant. Qualitative analysis of open-ended questions revealed several themes, including emotional and physical symptoms, ability to live independently, effectiveness of treatment, family, spirituality, and financial toxicity. CONCLUSION: There is a need to refine widely used HR-QOL measures that are employed among patients diagnosed with mRCC treated with contemporary therapies. Guidance was provided for the inclusion of more relevant items to patients' cancer journey.

Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis.

INTRODUCTION: Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies. OBJECTIVE: We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy. METHODS: We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy. RESULTS: We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26-2.23, I2 = 79%, p < 0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00-2.62, I2 = 84%, p = 0.05) and PFS (HR = 1.71; CI:1.00-2.94, I2 = 82%, p = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer. CONCLUSIONS: We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.

Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC - What Difference Does it Make?

Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.

Immune-Checkpoint-Inhibitor Therapy-Principles and Relevance of Biomarkers for Pathologists and Oncologists.

Immune-checkpoint-inhibitor (ICI) therapy has been one of the major advances in the treatment of a variety of advanced or metastatic tumors in recent years. Therefore, ICI-therapy is already approved in first-line therapy for multiple tumors, either as monotherapy or as combination therapy. However, there are relevant differences in approval among different tumor entities, especially with respect to PD-L1 testing. Different response to ICI-therapy has been observed in the pivotal trials, so PD-L1 diagnostic testing is used for patient selection. In addition to PD-L1 testing of tumor tissue, liquid biopsy provides a noninvasive way to monitor disease in cancer patients and identify those who would benefit most from ICI-therapy. This overview focuses on the use of ICI-therapy and how it relates to common and potential future biomarkers for patient-directed treatment planning.

Profile of the multicenter cohort of the German Cancer Consortium's Clinical Communication Platform.

Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium's (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0-20 years, 8.3% 21-40 years, 30.9% 41-60 years, 50.1% 61-80 years, 8.8% 81+ years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort's data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions.

Ten recommendations for sarcoma surgery: consensus of the surgical societies based on the German S3 guideline "Adult Soft Tissue Sarcomas".

PURPOSE: The evidence-based (S3) guideline "Adult Soft Tissue Sarcomas" (AWMF Registry No. 032/044OL) published by the German Guideline Program in Oncology (GGPO) covers all aspects of sarcoma treatment with 229 recommendations. Representatives of all medical specialties involved in sarcoma treatment contributed to the guideline. This paper compiles the most important recommendations for surgeons selected by delegates from the surgical societies. METHODS: A Delphi process was used. Delegates from the surgical societies involved in guideline process selected the 15 recommendations that were most important to them. Votes for similar recommendations were tallied. From the resulting ranked list, the 10 most frequently voted recommendations were selected and confirmed by consensus in the next step. RESULTS: The statement "Resection of primary soft tissue sarcomas of the extremities should be performed as a wide resection. The goal is an R0 resection" was selected as the most important term. The next highest ranked recommendations were the need for a preoperative biopsy, performing preoperative MRI imaging with contrast, and discussing all cases before surgery in a multidisciplinary sarcoma committee. CONCLUSION: The evidence-based guideline "Adult Soft Tissue Sarcomas" is a milestone to improve the care of sarcoma patients in Germany. The selection of the top ten recommendations by surgeons for surgeons has the potential to improve the dissemination and acceptance of the guideline and thus improve the overall outcome of sarcoma patients.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

Improving survival in metastatic renal cell carcinoma (mRCC) patients: do elderly patients benefit from expanded targeted therapeutic options?

INTRODUCTION: Treatment advances in metastatic renal cell carcinoma (mRCC) have improved overall survival (OS) in mRCC patients over the last two decades. This single center retrospective analysis assesses if the purported survival benefits are also applicable in elderly mRCC patients. METHODS: 401 patients with mRCC treated at Hannover Medical School from 01/2003-05/2016 were identified and evaluated by chart review. Treatment periods were defined as 01.01.2003-31.12.2009 (P1) and 01.01.2010-31.05.2016 (P2). Age groups were defined according to WHO classes (≤ 60 years: younger, > 60-75 years: elderly and > 75 years: old). Descriptive statistics, Kaplan-Meier analysis and logistic regression were performed. RESULTS: Median OS improved from 35.1 months in P1 to 59.1 months in P2. Sub-division into the respective age groups revealed median survival of 38.1 (95%-CI: 28.6-47.6) months in younger patients, 42.9 (95%-CI: 29.5-56.3) months among elderly patients and 27.3 (95%-CI: 12.8-41.8) months among old patients. Risk reduction for death between periods was most evident among old patients (young: HR 0.71 (95%-CI: 0.45-1.13, p = 0.2); elderly: HR 0.62 (95%-CI: 0.40-0.97, p = 0.04); old: HR 0.43 (95%-CI: 0.18-1.05, p = 0.06)). Age ≥ 75 years was an independent risk factor for death in P1 but not in P2. CONCLUSION: Improved OS in the targeted treatment period was confirmed. Surprisingly elderly and old patients seem to profit the most form expansion of therapeutic armamentarium, within the TKI-dominated observation period.

CaboPoint: a phase II study of cabozantinib as second-line treatment in patients with metastatic renal cell carcinoma.

Cabozantinib is an inhibitor of multiple tyrosine kinases, including AXL, MET and VEGF receptors. Here, we describe the rationale and design for the phase II CaboPoint trial (ClinicalTrials.gov identifier: NCT03945773), which will evaluate the efficacy and safety of cabozantinib as a second-line treatment in patients with unresectable, locally advanced or metastatic renal cell carcinoma whose disease has progressed despite checkpoint inhibitor therapy. Patients will be recruited into two cohorts: prior ipilimumab plus nivolumab (cohort A) or prior checkpoint inhibitor-VEGF-targeted therapy (cohort B). All patients will receive once-daily oral cabozantinib 60 mg for up to 18 months. The primary end point is objective response rate. Secondary end points include overall survival, progression-free survival and safety.

Most patients diagnosed with kidney cancer have a type of tumor called renal cell carcinoma (RCC). Most cases of RCC are described as 'clear cell' because the tumor cells appear clear when viewed under a microscope. Cabozantinib is an oral treatment approved for use in some patients with advanced RCC, including those with clear cell disease. Cabozantinib slows RCC progression by targeting pathways that help tumors grow, including inhibition of VEGF. The ongoing CaboPoint study will assess the efficacy and safety of cabozantinib in patients with clear cell RCC that has progressed despite previous anticancer treatment involving an immune checkpoint inhibitor (CPI). CPI therapy helps the body to detect tumors and to launch its own anticancer response. Patients included in CaboPoint must be adults with clear cell RCC that is not suitable for surgery and has either spread within the kidney or to other organs, despite previous CPI-based therapy. In total, 250 patients will be recruited: 125 who received previous combination CPI treatment (ipilimumab plus nivolumab; group A) and 125 who received previous CPI treatment plus anti-VEGF therapy (group B). Patients will start cabozantinib at a dose of 60 mg/day and continue treatment for up to 18 months. The main outcome to be studied will be the number of patients with a reduction in tumor size (objective response rate). The length of time patients live with their disease, the effect of treatment on symptoms and patient safety will also be evaluated. Clinical trial registration: NCT03945773 (ClinicalTrials.gov).

First-line pazopanib in intermediate- and poor-risk patients with metastatic renal cell carcinoma: Final results of the FLIPPER trial.

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma: Final results of the MARC-2 trial.

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs <65 years and 51.4% (95% CI, 34.7-65.7) vs 18.2% (95% CI, 5.7-36.3) for patients with body mass index (BMI) >25 vs ≤25 kg/m2 . A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most.

Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP.

BACKGROUND: Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP. METHODS: This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS). RESULTS: One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9-4.8 and 6.8-9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm. CONCLUSIONS: Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity. CLINICAL TRIAL REGISTRATION: The study was registered at clinicaltrials.gov as NCT00894569.

Comprehensive analysis of serum chromogranin A and neuron-specific enolase levels in localized and castration-resistant prostate cancer.

OBJECTIVES: To assess chromogranin A (CGA) and neuron-specific enolase (NSE) levels and changes in these at different stages of prostatic adenocarcinoma (PCA). METHODS: Overall, 1095 serum samples from 395 patients, divided into three treatment groups, were analysed; the radical prostatectomy (RP) cohort (n = 157) included patients with clinically localized PCA, while the docetaxel (DOC) and the abiraterone (ABI)/enzalutamide (ENZA) cohorts included 95 and 143 patients, respectively, with metastatic castration-resistant prostate cancer. CGA, NSE and total PSA levels were measured using the KRYPTOR method. RESULTS: Baseline CGA and NSE levels were higher in castration-resistant (DOC and ABI/ENZA cohorts) than in hormone-naïve, clinically localized PCA (P < 0.001). High baseline CGA levels were independently associated with poor overall survival in both the DOC and the ABI/ENZA cohorts, with a stronger association in the ABI/ENZA cohort. In the ABI/ENZA cohort, a > 50% CGA increase at 3 months was associated with poor survival, especially in patients with high baseline CGA levels. CONCLUSIONS: The two- to threefold higher neuroendocrine marker levels in castration-resistant compared to hormone-naïve PCA support the presence of neuroendocrine transdifferentiation under androgen deprivation therapy. Our results showed patients with high baseline CGA levels who experienced a further CGA increase during ABI and ENZA treatment had the poorest prognosis. Serum CGA levels could help in tailoring and monitoring therapy in advanced PCA.

What is next in second- and later-line treatment of metastatic renal cell carcinoma? review of the recent literature.

PURPOSE OF REVIEW: The current treatment landscape of metastatic renal cell carcinoma has changed dramatically from the dominance of single-agent tyrosine kinase inhibitor (TKI) therapy to immune-checkpoint inhibitor (ICI)-based combinations in recent years. However, the optimal subsequent therapy remains ill-defined owing to the novelty of this approach. RECENT FINDINGS: Treatment with TKIs after failure of single or dual ICI therapies may result in robust clinical efficacy. Nonetheless, there is a trend toward lower efficacy of TKIs after previous ICI-TKI combination therapy. Currently, tivozanib is the only drug whose third- and later-line use after failure of TKI and ICI is supported by evidence, with significantly longer progression-free survival and higher objective response rates than sorafenib. Data from retrospective studies highlight the safety and clinical activity of ICI rechallenge. SUMMARY: Overall, the level of evidence remains low. Treatment after failure of dual ICI therapy is not well defined and may consist of any available TKI. Although first-line use of TKI is less common, strong evidence suggests cabozantinib or nivolumab as standard options in that setting. The recommendations after first-line TKI-ICI therapy failure mirror this recommendation, although the data are less robust.

Impact of sarcopenia in advanced and metastatic soft tissue sarcoma.

INTRODUCTION: Advanced or metastatic soft tissue sarcoma (a/mSTS) is associated with a dismal prognosis. Patient counseling on treatment aggressiveness is pivotal to avoid over- or undertreatment. Recently, evaluation of body composition markers like the skeletal muscle index (SMI) became focus of interest in a variety of cancers. This study focuses on the prognostic impact of SMI in a/mSTS, retrospectively. METHODS: 181 a/mSTS patients were identified, 89 were eligible due to prespecified criteria for SMI assessment. Baseline CT-Scans were analyzed using an institutional software solution. Sarcopenia defining cut-off values for the SMI were established by optimal fitting method. Primary end point was overall survival (OS) and secondary endpoints were progression free survival (PFS), disease control rate (DCR), overall response rate (ORR). Descriptive statistics as well as Kaplan Meier- and Cox regression analyses were administered. RESULTS: 28/89 a/mSTS patients showed sarcopenia. Sarcopenic patients were significantly older, generally tended to receive less multimodal therapies (62 vs. 57 years, P = 0.025; respectively median 2.5 vs. 4, P = 0.132) and showed a significantly lower median OS (4 months [95%CI 1.9-6.0] vs. 16 months [95%CI 8.8-23.2], Log-rank P = 0.002). Sarcopenia was identified as independent prognostic parameter of impaired OS (HR 2.40 [95%-CI 1.4-4.0], P < 0.001). Moreover, DCR of first palliative medical treatment was superior in non-sarcopenic patients (49.2% vs. 25%, P = 0.032). CONCLUSION: This study identifies sarcopenia as a prognostic parameter in a/mSTS. Further on, the data suggest that sarcopenia shows a trend of being associated with first line therapy response. SMI is a promising prognostic parameter, which needs further validation.

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events.

With the recent approval of the combinations of axitinib with the immune checkpoint inhibitor (ICI) pembrolizumab or avelumab for first-line treatment of advanced renal cell carcinoma, guidance on how to distinguish between immune-related adverse events (AEs) caused by ICI versus axitinib-related AEs is necessary to optimise therapy with axitinib-ICI combinations. The recommendations here are based on (1) systematic review of published evidence, (2) discussion among experts in the field and (3) a survey to obtain expert consensus on specific measures for therapy management with the combinations axitinib/avelumab and axitinib/pembrolizumab. The experts identified areas of AEs requiring unique management during treatment with axitinib-ICI combinations that were not covered by current recommendations. Diarrhoea, hepatic toxicity, fatigue and cardiovascular AEs were found to be applicable to such specialised management. Triage between immune-suppressive and supportive measures is a key component in therapy management. Clinical monitoring and experience with both classes of agents are necessary to manage this novel therapeutic approach. We focused on AEs with an overlap between axitinib and ICI therapy. Our recommendations address AE management of axitinib-ICI combinations with the aim to improve the safety of these therapies.