PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

INTRODUCTION: Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. METHODS: A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. RESULTS: In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. CONCLUSION: Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. METHODS: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. FINDINGS: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. INTERPRETATION: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. FUNDING: F Hoffmann-La Roche and Exelixis.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

PURPOSE: The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. MATERIALS AND METHODS: In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. RESULTS: Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). CONCLUSIONS: Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma.

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. METHODS: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. RESULTS: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001). CONCLUSIONS: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma.

BACKGROUND: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. METHODS: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0). RESULTS: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). CONCLUSIONS: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT01136733.

Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. PATIENTS AND METHODS: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. RESULTS: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0-17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%-62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively). CONCLUSIONS: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

PURPOSE: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center. METHODS: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS). RESULTS: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001). CONCLUSION: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.

Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

BACKGROUND: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. METHODS: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. RESULTS: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. CONCLUSION: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

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.

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

BACKGROUND: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. METHODS: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). RESULTS: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. CONCLUSIONS: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058707.

Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations.

BACKGROUND: Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. METHODS: A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. RESULTS: A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2-24.5). Median OS was 24.5 months (95% CI, 12-NE) and 12 months OS rate was 63.3% (95% CI, 48.6-74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). CONCLUSIONS: Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma.

BACKGROUND: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study.

BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) risk model is an established prognostic tool for metastatic renal-cell carcinoma that integrates clinical and laboratory data, but is agnostic to tumour genomics. Several mutations, including BAP1 and PBRM1, have prognostic value in renal-cell carcinoma. Using two independent clinical trial datasets of patients with metastatic renal-cell carcinoma, we aimed to study whether the addition of the mutation status for several candidate prognostic genes to the MSKCC model could improve the model's prognostic performance. METHODS: In this retrospective cohort study, we used available formalin-fixed paraffin-embedded tumour tissue and clinical outcome data from patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors in the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258). Eligible patients in both trials were treatment-naive; had histologically confirmed, advanced, or metastatic renal-cell carcinoma; and a Karnofsky performance status score of at least 70. For each cohort, data from patients in all treatment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation cohort) were pooled for this analysis. In the training cohort, tumour tissue was used to evaluate somatic mutations by next-generation sequencing, and the association between cancer-specific outcomes (overall survival, progression-free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2) was tested. Only those genes with prognostic value in this setting were added to the MSKCC risk model to create a genomically annotated version. The validation cohort was used to independently test the prognostic value of the annotated model compared with the original MSKCC risk model. FINDINGS: 357 (32%) of 1110 patients assigned to protocol treatment in the COMPARZ study between August, 2008, and September, 2011, were evaluable for mutation status and clinical outcomes in the training cohort. The independent validation cohort included 258 (55%) of 471 evaluable patients, enrolled between October, 2009, and June, 2011, on the RECORD-3 study. In the training cohort, the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 were prognostic in terms of overall survival (TP53wt/BAP1mut, TP53mut/BAP1wt o TP53mut/BAP1mut vs TP53wt/BAP1wt hazard ratio [HR] 1·57, 95% CI 1·21-2·04; p=0·0008; PBRM1wt vs PBRMmut, HR 1·58, 1·16-2·14; p=0·0035). The mutation status for these three prognostic genes were added to the original MSKCC risk model to create a genomically annotated version. Distribution of participants in the training cohort into the three risk groups of the original MSKCC model changed from 87 (24%) of 357 patients deemed at favourable risk, 217 (61%) at intermediate risk, and 53 (15%) at poor risk, to distribution across four risk groups in the genomically annotated risk model, with 36 (10%) of 357 deemed at favourable risk, 77 (22%) at good risk, 108 (30%) at intermediate risk, and 136 (38%) at poor risk. Addition of genomic information improved model performance for predicting overall survival (C-index: original model, 0·595 [95% CI 0·557-0·634] vs new model, 0·637 [0·595-0·679]) and progression-free survival (0·567 [95% CI 0·529-0·604] vs 0·602 [0·560-0·643]) with adequate discrimination of the proportion of patients who achieved an objective response (Cochran-Armitage one-sided p=0·0014). Analyses in the validation cohort confirmed the superiority of the genomically annotated risk model over the original version. INTERPRETATION: The mutation status of BAP1, PBRM1, and TP53 has independent prognostic value in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Improved stratification of patients across risk groups by use of a genomically annotated model including the mutational status of these three genes warrants further investigation in prospective trials and could be of use as a model to stratify patients with metastatic renal-cell carcinoma in clinical trials. FUNDING: Novartis Pharmaceuticals Corporation, MSKCC Support Grant/Core Grant, and the J Randall & Kathleen L MacDonald Research Fund.

Molecular Subtypes Improve Prognostic Value of International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Model.

INTRODUCTION: Gene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77-84], and an 8-gene signature model [Eur Urol 2015;67:17-20], in the setting of systemic therapy for metastatic disease. MATERIALS AND METHODS: Metastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy. RESULTS: Overall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk-ccA (n = 17)-and the high-risk-ccB (n = 37)-subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51-0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47-0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49-0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor. CONCLUSION: The ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:286-292 IMPLICATIONS FOR PRACTICE: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.

A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.

Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.