Publications by authors named "Naomi B Haas"

66 Publications

From Basic Science to Clinical Translation in Kidney Cancer: A Report from the Second Kidney Cancer Research Summit.

Clin Cancer Res 2021 Dec 29. Epub 2021 Dec 29.

Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.

The second Kidney Cancer Research Summit was held virtually in October 2020. The meeting gathered worldwide experts in the field of kidney cancer, including basic, translational, and clinical scientists as well as patient advocates. Novel studies were presented, addressing areas of unmet need related to different topics. These include novel metabolic targets, promising immunotherapeutic regimens, predictive genomic and transcriptomic biomarkers, and variant histologies of renal cell carcinoma (RCC). With the development of pioneering technologies, and an unprecedented commitment to kidney cancer research, the field has tremendously evolved. This perspective aims to summarize the different sessions of the conference, outline major advances in the understanding of RCC and discuss current challenges faced by the field.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3238DOI Listing
December 2021

Novel Redirected T-Cell Immunotherapies for Advanced Prostate Cancer.

Clin Cancer Res 2021 Oct 21. Epub 2021 Oct 21.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California.

Immunotherapy has failed to achieve durable remissions in advanced prostate cancer patients. More potent T-cell-redirecting strategies may be needed to overcome the immunologically exclusive and suppressive tumor microenvironment. Clinical trials are underway, seeking to define the optimal target for T-cell redirection, such as PSMA, PSCA, or STEAP-1, as well as the optimal strategy, with CAR or bispecific antibodies. As results continue to emerge from these trials, understanding differential toxicity and efficacy of these therapies based on their targets and functional modifications will be key to advancing these promising therapies toward clinical practice. This review provides a unique depth and breadth of perspective regarding the diverse immunotherapy strategies currently under clinical investigation for men with advanced prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1483DOI Listing
October 2021

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.

BJU Int 2021 Sep 4. Epub 2021 Sep 4.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

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.
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http://dx.doi.org/10.1111/bju.15587DOI Listing
September 2021

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

N Engl J Med 2021 08;385(8):683-694

From Dana-Farber Cancer Institute, Boston (T.K.C.); Poznan University of Medical Sciences, Poznan (P.T.), and Wojewódzki Szpital Zespolony im. L. Rydygiera w Toruniu, Torun (P.S.) - both in Poland; Sungkyunkwan University, Samsung Medical Center (S.H.P.), and Asan Medical Center, University of Ulsan College of Medicine (J.L.L.) - both in Seoul, South Korea; Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow (B.V.), Edinburgh Cancer Centre and University of Edinburgh, Edinburgh (S.N.S.), and Imperial College Healthcare NHS Trust (N.S.) and the Royal Free Hospital NHS Trust, University College London (T.P.), London - all in the United Kingdom; Fiona Stanley Hospital, Perth, WA (T.F.), and Macquarie University, Sydney (H.G.) - both in Australia; Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.C.); Fakultni Nemocnice Ostrava, Ostrava (J.H.), and Palacký University and University Hospital Olomouc, Olomouc (B.M.) - both in the Czech Republic; University Hospital Jean Minjoz, Besançon (A.T.-V.), University Hospital Bordeaux-Hôpital Saint-André, Bordeaux (M.G.-G.), Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse (C.C.), Centre Hospitalier Universitaire de Montpellier, Montpellier (D.T.), and Hôpital Européen Georges Pompidou, University of Paris, Paris (S.O.) - all in France; Fundación Arturo López Pérez, Santiago, Chile (M.M.); Abramson Cancer Center, Philadelphia (N.H.); Omsk Clinical Oncology Dispensary, Omsk, Russia (E.K.); the University of Michigan, Ann Arbor (A.A.); Rocky Mountain Cancer Centers and U.S. Oncology Research, Denver (J.M.B.); Texas Oncology, U.S. Oncology Research, Woodlands (G.D.), and the University of Texas Southwestern, Dallas (H.H.); the University of Toyama, Toyama, Japan (H.K.); Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); Merck, Kenilworth, NJ (R.F.P., P.Z., K.I., J.W.-R.); and USC Norris Comprehensive Cancer Center, Los Angeles (D.I.Q.).

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.).
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http://dx.doi.org/10.1056/NEJMoa2106391DOI Listing
August 2021

Adherence to oral therapies among patients with renal cell carcinoma: Post hoc analysis of the ECOG-ACRIN E2805 trial.

Cancer Med 2021 09 18;10(17):5917-5924. Epub 2021 Aug 18.

Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non-adherence.

Methods: ECOG-ACRIN E2805 was a double-blind, placebo-controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient-completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log-binomial regression was used to identify correlates of non-adherence (<80% of prescribed pills reported as taken).

Results: Mean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non-adherence was associated with race/ethnicity (non-Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80).

Conclusion: Among patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase.

Clinical Trial Registration Number: This trial is registered with ClinicalTrials.gov, number NCT00326898.
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http://dx.doi.org/10.1002/cam4.4140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419781PMC
September 2021

Use of Bone Resorption Inhibitors in Metastatic Castration-Resistant Prostate Cancer-20 Years Later, and the Answer Is Still Yes.

JAMA Netw Open 2021 07 1;4(7):e2117159. Epub 2021 Jul 1.

Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.17159DOI Listing
July 2021

Adoptive Cellular Therapy for Solid Tumors.

Am Soc Clin Oncol Educ Book 2021 Mar;41:57-65

Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient's own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as "living drugs" as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.
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http://dx.doi.org/10.1200/EDBK_321115DOI Listing
March 2021

Plasma KIM-1 Is Associated with Recurrence Risk after Nephrectomy for Localized Renal Cell Carcinoma: A Trial of the ECOG-ACRIN Research Group (E2805).

Clin Cancer Res 2021 06 8;27(12):3397-3403. Epub 2021 Apr 8.

Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Purpose: No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy.

Experimental Design: The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4-12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS).

Results: Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42-0.73; < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement ( = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56-0.91; < 0.001).

Conclusions: Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287837PMC
June 2021

Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma.

Eur Urol 2021 07 9;80(1):20-31. Epub 2021 Mar 9.

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts.

Objective: To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial.

Design, Setting, And Participants: The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial.

Outcome Measurements And Statistical Analysis: The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests.

Results And Limitations: A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model's discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]).

Conclusions: We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic.

Patient Summary: Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.
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http://dx.doi.org/10.1016/j.eururo.2021.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627688PMC
July 2021

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

Prostate Cancer Prostatic Dis 2021 06 2;24(2):448-456. Epub 2020 Oct 2.

Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide.

Methods: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide.

Results: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003).

Conclusions: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.
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http://dx.doi.org/10.1038/s41391-020-00295-zDOI Listing
June 2021

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors.

JNCI Cancer Spectr 2020 Apr 6;4(2):pkz093. Epub 2019 Nov 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Background: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors.

Methods: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker.

Results: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t: 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months.

Conclusions: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.
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http://dx.doi.org/10.1093/jncics/pkz093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165800PMC
April 2020

Eligibility and Radiologic Assessment for Adjuvant Clinical Trials in Kidney Cancer.

JAMA Oncol 2020 Jan;6(1):133-141

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: To harmonize the eligibility criteria and radiologic disease assessment definitions in clinical trials of adjuvant therapy for renal cell carcinoma (RCC).

Method: On November 28, 2017, US-based experts in RCC clinical trials, including medical oncologists, urologic oncologists, regulators, biostatisticians, radiologists, and patient advocates, convened at a public workshop to discuss eligibility for trial entry and radiologic criteria for assessing disease recurrence in adjuvant trials in RCC. Multiple virtual meetings were conducted to address the issues identified at the workshop.

Results: The key workshop conclusions for adjuvant RCC therapy clinical trials were as follows. First, patients with non-clear cell RCC could be routinely included, preferably in an independent cohort. Second, patients with T3-4, N+M0, and microscopic R1 RCC tumors may gain the greatest advantages from adjuvant therapy. Third, trials of agents not excreted by the kidney should not exclude patients with severe renal insufficiency. Fourth, therapy can begin 4 to 16 weeks after the surgical procedure. Fifth, patients undergoing radical or partial nephrectomy should be equally eligible. Sixth, patients with microscopically positive soft tissue or vascular margins without gross residual or radiologic disease may be included in trials. Seventh, all suspicious regional lymph nodes should be fully resected. Eighth, computed tomography should be performed within 4 weeks before trial enrollment; for patients with renal insufficiency who cannot undergo computed tomography with contrast, noncontrast chest computed tomography and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be performed. Ninth, when feasible, biopsy should be undertaken to identify any malignant disease. Tenth, when biopsy is not feasible, a uniform approach should be used to evaluate indeterminate radiologic findings to identify what constitutes no evidence of disease at trial entry and what constitutes radiologic evidence of disease. Eleventh, a uniform approach for establishing the date of recurrence should be included in any trial design. Twelfth, patient perspectives on the use of placebo, conditions for unblinding, and research biopsies should be considered carefully during the conduct of an adjuvant trial.

Conclusions And Relevance: The discussions suggested that a uniform approach to eligibility criteria and radiologic disease assessment will lead to more consistently interpretable trial results in the adjuvant RCC therapy setting.
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http://dx.doi.org/10.1001/jamaoncol.2019.4117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127869PMC
January 2020

Local Recurrence Following Resection of Intermediate-High Risk Nonmetastatic Renal Cell Carcinoma: An Anatomical Classification and Analysis of the ASSURE (ECOG-ACRIN E2805) Adjuvant Trial.

J Urol 2020 04 9;203(4):684-689. Epub 2019 Oct 9.

Fox Chase Cancer Center-Temple Health System, Philadelphia, Pennsylvania.

Purpose: We describe what is to our knowledge a novel classification system for local recurrence after surgery of renal cell carcinoma. We assessed its prognostic implications using prospective, randomized controlled data.

Materials And Methods: We queried the ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery) (ECOG-ACRIN [Eastern Cooperative Oncology Group-American College of Radiology Imaging Network] E2805) trial data for patients with fully resected, intermediate-high risk, nonmetastatic renal cell carcinoma with local recurrence. We used certain definitions, including type I-single recurrence in a remnant kidney or ipsilateral renal fossa, type II-single recurrence in the ipsilateral vasculature, the ipsilateral adrenal gland or a lymph node, type III-single recurrence in other intra-abdominal soft tissues or organs and type IV-any combination of types I-III or multiple recurrences of a single type. Multivariable logistic regression and the log rank test were performed to identify clinicopathological predictors and compare survival, respectively.

Results: Of the 1,943 patients 300 (15.4%) had local recurrence, which was type I, II, III and IV in 66 (22.0%), 97 (32.3%), 87 (29.0%) and 50 (16.7%), respectively. Surgical modality (minimally invasive vs open) and type of surgery (partial vs radical) did not predict any local recurrence. Five-year cancer specific survival and overall survival were worse in patients with type IV recurrence (each p <0.001). There was no difference in survival among patients with types I to III recurrence.

Conclusions: In patients with intermediate-high risk nonmetastatic renal cell carcinoma local recurrence appears to be a function of biology more than of surgical modality or surgery type. The prognosis for solitary intra-abdominal local recurrences appear similar regardless of location (types I-III). Local recurrences involving multiple sites and/or subdivisions are associated with worse survival (type IV).
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http://dx.doi.org/10.1097/JU.0000000000000588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337326PMC
April 2020

Angiogenic Factor and Cytokine Analysis among Patients Treated with Adjuvant VEGFR TKIs in Resected Renal Cell Carcinoma.

Clin Cancer Res 2019 10 30;25(20):6098-6106. Epub 2019 Aug 30.

Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Purpose: The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial.

Experimental Design: Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels.

Results: VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib ( < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib ( < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib ( < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status.

Conclusions: Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057142PMC
October 2019

Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models With Prospective Trial-Based Validation.

J Clin Oncol 2019 08 19;37(23):2062-2071. Epub 2019 Jun 19.

1Fox Chase Cancer Center, Philadelphia, PA.

Purpose: To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial.

Patients And Methods: Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities.

Results: Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.

Conclusion: In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.
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http://dx.doi.org/10.1200/JCO.19.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085167PMC
August 2019

The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER?

Future Oncol 2019 May 10;15(15):1683-1695. Epub 2019 Apr 10.

Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.
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http://dx.doi.org/10.2217/fon-2018-0951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595543PMC
May 2019

Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma.

Clin Cancer Res 2019 04 11;25(7):2080-2087. Epub 2019 Jan 11.

Abramson Cancer Center and the Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Purpose: Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC).

Patients And Methods: Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing.

Results: No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease + partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS ≥ 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control.

Conclusions: Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2204DOI Listing
April 2019

Association between age and sex and mortality after adjuvant therapy for renal cancer.

Cancer 2019 05 8;125(10):1637-1644. Epub 2019 Jan 8.

Cancer Research Foundation Inc, Chappaqua, New York.

Background: In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial.

Methods: The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study.

Results: Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P = .01), but not sorafenib (P = .10).

Conclusions: Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.
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http://dx.doi.org/10.1002/cncr.31955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486432PMC
May 2019

Perioperative Therapy in Renal Cell Carcinoma: What Do We Know, What Have We Learned, What's Next?

J Clin Oncol 2018 Oct 29:JCO2018789131. Epub 2018 Oct 29.

Naomi B. Haas, Abramson Cancer Center; and Robert G. Uzzo, Fox Chase Cancer Center, Philadelphia, PA.

Recent adjuvant vascular endothelial growth factor tyrosine kinase inhibitor trials in resected high-risk renal cell carcinoma that compared sunitinib, sorafenib, pazopanib, and axitinib with placebo controls have demonstrated mixed impact on disease-free survival, no improvement in overall survival, and, thus, controversy. Here, we discuss the results and conduct of these trials to provide new insight into the goals and strategies of treating resected renal cell cancer that is at high risk for recurrence. The potential for leveraging what we have learned from these trials to conduct successful contemporary adjuvant and perioperative immune checkpoint inhibition trials and future adjuvant trial design is discussed.
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http://dx.doi.org/10.1200/JCO.2018.78.9131DOI Listing
October 2018

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.

Br J Cancer 2018 11 15;119(10):1200-1207. Epub 2018 Oct 15.

Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers.

Methods: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response.

Results: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells.

Conclusions: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy.

Clinical Trial Registration: NCT02303990 ( www.clinicaltrials.gov ).
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http://dx.doi.org/10.1038/s41416-018-0281-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251028PMC
November 2018

Patterns of Relapse and Implications for Post-Nephrectomy Surveillance in Patients with High Risk Nonclear Cell Renal Cell Carcinoma: Subgroup Analysis of the Phase 3 ECOG-ACRIN E2805 Trial.

J Urol 2019 01;201(1):62-68

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: The natural history of nonclear cell renal cell carcinoma following surgery with curative intent remains poorly defined with postoperative surveillance informed by guidelines largely intended for clear cell renal cell carcinoma. We evaluated relapse patterns and potential implications for post-nephrectomy surveillance in patients with nonclear cell renal cell carcinoma enrolled in the E2805 trial, the largest randomized trial of adjuvant antiangiogenic therapy of high risk renal cell carcinoma.

Materials And Methods: We retrospectively analyzed the records of patients with completely resected nonclear cell renal cell carcinoma. Participants received up to 54 weeks of postoperative therapy with sunitinib, sorafenib or placebo and underwent surveillance imaging at standardized intervals for 10 years. For recurrence rates by site the cumulative incidence was estimated, accounting for competing risks. The adequacy of strict adherence to post-nephrectomy surveillance guidelines was evaluated.

Results: A total of 403 patients with nonclear cell renal cell carcinoma were enrolled in the study. During a median followup of 6.2 years 36% of nonclear cell renal cell carcinomas recurred. Five-year recurrence rates were comparable for nonclear and clear cell renal cell carcinoma in the 1,541 patients, including 34.6% (95% CI 29.8-39.4) and 39.5% (95% CI 36.9-42.1), respectively. However, patients with nonclear cell renal cell carcinoma were significantly more likely to have abdominal sites of relapse (5-year recurrence rate 26.4% vs 18.2%, p = 0.0008) and significantly less likely to experience relapse in the chest (5-year recurrence rate 13.7% vs 20.9%, p = 0.0005). Current surveillance guidelines would potentially capture approximately 90% of relapses at any site.

Conclusions: Nonclear cell renal cell carcinoma may show a distinct pattern of relapse compared to clear cell renal cell carcinoma. Our findings emphasize the importance of cross-sectional, long-term imaging in patients with high risk, resected, nonclear cell renal cell carcinoma.
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http://dx.doi.org/10.1016/j.juro.2018.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614871PMC
January 2019

Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis.

Eur Urol 2018 11 18;74(5):611-620. Epub 2018 May 18.

Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

Context: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC).

Objective: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC.

Evidence Acquisition: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated.

Evidence Synthesis: The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HR: 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (OR: 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR: 0.83, 95% CI: 0.73-0.95, p=0.005).

Conclusions: This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs.

Patient Summary: Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects.
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http://dx.doi.org/10.1016/j.eururo.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515772PMC
November 2018

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

Circ Heart Fail 2018 03;11(3):e004408

From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.).

Background: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood.

Methods And Results: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; =0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; <0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all <0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time.

Conclusions: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360089PMC
March 2018

Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.

J Clin Oncol 2018 05 6;36(15):1498-1504. Epub 2018 Apr 6.

Maha Hussain, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; Catherine M. Tangen, Fred Hutchinson Cancer Research Center; Daniel W. Lin, University of Washington, Seattle, WA; Ian M. Thompson Jr, University of Texas Health Science Center, San Antonio; Gregory P. Swanson, Baylor Scott and White Health, Temple, TX; David P. Wood, Beaumont Physician Partners and Clinical Faculty, Royal Oak; Wael Sakr, Wayne State University School of Medicine, Detroit, MI; Nancy A. Dawson, Lombardi Comprehensive Cancer Center, Washington, DC; Naomi B. Haas, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Thomas W. Flaig, E. David Crawford, and L. Michael Glode, University of Colorado Cancer Center, Denver, CO; Tanya B. Dorff and David I. Quinn, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; and Nicholas J. Vogelzang, Comprehensive Cancer Centers of Nevada, Las Vegas, NV.

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA ≤ 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided α = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.
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http://dx.doi.org/10.1200/JCO.2017.76.4126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959197PMC
May 2018

Longitudinal and dynamic measurement invariance of the FACIT-Fatigue scale: an application of the measurement model of derivatives to ECOG-ACRIN study E2805.

Qual Life Res 2018 06 5;27(6):1589-1597. Epub 2018 Mar 5.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: While quality of life measures may be used to assess meaningful change and group differences, their scaling and validation often rely on a single occasion of measurement. Using the 13-item FACIT-Fatigue questionnaire at three timepoints, this study tests whether individual items change together in ways consistent with a general fatigue factor.

Methods: The measurement model of derivatives (MMOD) is a novel method for measurement evaluation that directly assesses whether a given factor structure accurately describes how individual test items change over time. MMOD transforms item-level longitudinal data into a set of orthogonal change scores, each one representing either a within-person longitudinal mean or a different type of longitudinal change. These change scores are then factor analyzed and tested for invariance. This approach is applied to the FACIT-Fatigue scale in a sample of patients with renal cell carcinoma treated on 'ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) study 2805.

Results: Analyses revealed strong evidence of unidimensionality, and apparent factorial invariance using traditional techniques. MMOD revealed a small but statistically significant difference in factor structure ([Formula: see text], [Formula: see text]), where factor loadings were weaker and more variable for measuring longitudinal change.

Conclusions: The differences in factor structure were not large enough to substantially affect scale usage in this application, but they do reveal some variability across items in the FACIT-Fatigue in their ability to detect change. Future applications should consider differential sensitivity of individual items in multi-item scales, and perhaps even capitalize upon these differences by selecting items that are more sensitive to change.
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http://dx.doi.org/10.1007/s11136-018-1817-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004788PMC
June 2018

Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma.

Clin Cancer Res 2018 07 12;24(13):3005-3013. Epub 2018 Jan 12.

Memorial Sloan Kettering Cancer Center, New York, New York.

PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (C) and efficacy and safety was evaluated. Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C) and 250 patients at week 16 or 20 (late C). Pazopanib pharmacokinetic (PK) data were analyzed via a population model approach. Relationship between C or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AE) and AE-related treatment discontinuation proportions were summarized by C quartiles. Most (>90%) patients with early or late C data started on 600 mg. Mean early and late C overlapped across dose levels. Patients with higher early C quartiles achieved longer DFS (adjusted HR, 0.58; 95% confidence interval, 0.42-0.82; = 0.002). Patients achieving early or late C >20.5 μg/mL had significantly longer DFS: not estimable (NE) versus 29.5 months, = 0.006, and NE versus 29.9 months, = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model-based simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C In the adjuvant setting, higher pazopanib C was associated with improved DFS and did not increase treatment discontinuations or grade 3/4 AEs, with the exception of hypertension. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748622PMC
July 2018

Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805.

Clin Cancer Res 2018 01 24;24(1):217-223. Epub 2017 Oct 24.

Division of Medical Oncology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.

Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables. High MVD (above the median) was associated with prolonged OS for the entire cohort ( = 0.021) and for patients treated with placebo ( = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib ( = 0.060). MVD was not associated with DFS ( = 1.00). On multivariable analysis, MVD remained independently associated with improved OS ( = 0.013). High MVD correlated with Fuhrman grade 1-2 ( < 0.001), clear cell histology ( < 0.001), and absence of necrosis ( < 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904512PMC
January 2018

A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866 and Vemurafenib in Patients with Advanced BRAF V600-Mutant Solid Tumors.

Clin Cancer Res 2018 01 19;24(1):22-32. Epub 2017 Oct 19.

Abramson Cancer Center and the Division of Hematology & Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600-mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8 T-cell infiltration following treatment with PX-866. PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 T-cell infiltration in some patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754240PMC
January 2018

Recent advances in localized RCC: A focus on VEGF and immuno-oncology therapies.

Urol Oncol 2018 01 16;36(1):23-30. Epub 2017 Oct 16.

Abramson Cancer Center, Philadelphia, PA. Electronic address:

Recent advances in advanced renal cell cancer (RCC) research have produced new drugs and therapies for patients with metastatic disease leading to higher response rates, improvements in progression-free survival, and longer overall survival. These advances have yet to be realized in patients with early-stage kidney cancer, and to date, no drug has been approved for the adjuvant treatment of localized kidney cancer. The current standard of care for localized high-risk kidney cancers is resection of the primary tumor. Here, we review the results of recently completed adjuvant vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) trials in RCC that have been reported, or are awaiting results. Further, we discuss the new immune checkpoint inhibitor adjuvant trials planned. There is hope that these trials may lead to new options and longer survival for patients with localized high-risk kidney cancer.
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http://dx.doi.org/10.1016/j.urolonc.2017.09.008DOI Listing
January 2018

Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma.

J Clin Oncol 2017 Dec 13;35(35):3916-3923. Epub 2017 Sep 13.

Robert J. Motzer and Paul Russo, Memorial Sloan Kettering Cancer Center, New York, NY; Naomi B. Haas, University of Pennsylvania, Philadelphia, PA; Frede Donskov, Aarhus University Hospital, Aarhus, Denmark; Marine Gross-Goupil, Bordeaux University Hospital, Bordeaux, France; Sergei Varlamov, Altai Regional Cancer Center, Barnaul; Evgeny Kopyltsov, State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia; Jae Lyun Lee, University of Ulsan College of Medicine; Ho Yeong Lim, Sungkyunkwan University, Seoul, Republic of Korea; Bohuslav Melichar, Palacky University Medical School and Teaching Hospital, Olomouc; Milada Zemanova, Charles University and General University Hospital, Prague, Czech Republic; Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Toni K. Choueiri, Dana-Farber Cancer Institute, Boston, MA; Lori A. Wood, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia; M. Neil Reaume, Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Arnulf Stenzl, University Hospital Tübingen, Tübingen; Christian Doehn, University of Lübeck Medical School and Urologikum Lübeck, Lübeck, Germany; Simon Chowdhury, Guy's and St Thomas' National Health Service Foundation/St Thomas' Hospital, London; Ray McDermott, Tallaght University Hospital and Cancer Trials Ireland, Dublin; Agnieszka Michael, University of Surrey, Guildford, United Kingdom; Weichao Bao, Marlene J. Carrasco-Alfonso, and Maurizio Voi, Novartis Oncology, East Hanover, NJ; Paola Aimone, Novartis Pharma AG, Basel, Switzerland; and Cora N. Sternberg, San Camillo Forlanini Hospital, Rome, Italy.

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT) and safety. Results The primary analysis results of DFS ITT favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.
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http://dx.doi.org/10.1200/JCO.2017.73.5324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018511PMC
December 2017
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