Publications by authors named "Robert A Figlin"

196 Publications

Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.

Clin Genitourin Cancer 2021 04 14;19(2):167-175. Epub 2020 Nov 14.

Urologic Oncology Branch, Center for Cancer Research, Mayo Clinic, Rochester, MN.

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.
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http://dx.doi.org/10.1016/j.clgc.2020.10.005DOI Listing
April 2021

Introduction by the Guest Editor: Challenges and Opportunities for the Next Era of Development in Kidney Cancer.

Cancer J 2020 Sep/Oct;26(5):363-364

From the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CA.

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http://dx.doi.org/10.1097/PPO.0000000000000478DOI Listing
September 2021

Comparison of Large, Medium, and Small Solid Tumor Gene Panels for Detection of Clinically Actionable Mutations in Cancer.

Target Oncol 2020 08;15(4):523-530

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Next-generation sequencing of gene panels has supplanted single-gene testing for cancer molecular diagnostics in many laboratories. Considerations for the optimal number of genes to assess in a panel depend on the purpose of the testing.

Objective: To address the optimal size for the identification of clinically actionable variants in different-sized solid tumor sequencing panels.

Patients And Methods: Sequencing results from 480 patients with a large, 315 gene, panel were compared against coverage of a medium, 161 gene, and small, 50 gene, panel.

Results: The large panel detected a total of 2072 sequence variants in 480 patient specimens; 61 (12.7%) contained variants for which there is therapy approved by the US Food and Drug Administration, 89 (18.5%) had variants associated with an off-label therapy, and 312 (65.0%) contained variants eligible for a genomically matched clinical trial. The small panel covered only 737 of the 2072 variants (35.5%) and somewhat fewer therapy-related variants (on-label 88.5%, off-label 60.7%). The medium-size panel included 1354 of the 2072 (65.3%) variants reported by the large panel. All 318 patients with a clinically actionable variant would have been identified by the medium panel.

Conclusions: The results demonstrate that a carefully designed medium size gene panel is as effective as a large panel for the detection of clinically actionable variants and can be run by most molecular pathology laboratories.
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http://dx.doi.org/10.1007/s11523-020-00743-9DOI Listing
August 2020

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

Clin Genitourin Cancer 2020 12 11;18(6):425-428. Epub 2020 May 11.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address:

The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfront treatment of mCSPC. Notably, a subset of patients in these more recent trials were treated with a combination of docetaxel, ADT, and androgen receptor signaling inhibitors or maintenance androgen receptor signaling inhibitors after docetaxel and ADT that provided an initial glimpse into the efficacy of these triplet or maintenance strategies. We discuss the implications of these recent findings and place them in context of the current mCSPC treatment landscape.
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http://dx.doi.org/10.1016/j.clgc.2020.05.003DOI Listing
December 2020

COVID-19 and androgen-targeted therapy for prostate cancer patients.

Endocr Relat Cancer 2020 09;27(9):R281-R292

Department of Medicine, Cedars-Sinai Cancer, Los Angeles, California, USA.

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.
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http://dx.doi.org/10.1530/ERC-20-0165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546583PMC
September 2020

Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma.

Clin Cancer Res 2020 05 7;26(10):2327-2336. Epub 2020 Feb 7.

Argos Therapeutics Inc., now CoImmune Inc., Durham, North Carolina.

Purpose: Rocapuldencel-T is an autologous immunotherapy prepared from mature monocyte-derived dendritic cells (DC), coelectroporated with amplified tumor RNA plus CD40L RNA. This pivotal phase III trial was initiated to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC).

Patients And Methods: Patients received either Rocapuldencel-T plus standard of care (SOC) or SOC treatment alone. The primary objective compared overall survival (OS) between groups. Secondary objectives included safety assessments, progression-free survival (PFS), and tumor responses based on RECIST 1.1 criteria. Exploratory analyses included immunologic assessments and correlates with OS.

Results: Between 2013 and 2016, 462 patients were randomized 2:1, 307 to the combination group and 155 to the SOC group. Median OS in the combination group was 27.7 months [95% confidence interval (CI) 23.0-35.9] and 32.4 months (95% CI, 22.5-) in the SOC group HR of 1.10 (95% CI, 0.83-1.40). PFS was 6.0 months and 7.83 months for the combination and SOC groups, respectively [HR = 1.15 (95% CI, 0.92-1.44)]. The ORR was 42.7% (95% CI, 37.1-48.4) for the combination group and 39.4% (95% CI, 31.6-47.5) for the SOC group. Median follow up was 29 months (0.4-47.7 months). On the basis of the lack of clinical efficacy, the ADAPT trial was terminated on February 17, 2017. Immune responses were detected in 70% of patients treated with Rocapuldencel-T, and the magnitude of the immune response positively correlated with OS. In addition, we report the survival-predictive value of measuring IL-12 produced by the DC vaccine and the observation that high baseline numbers of T regulatory cells are associated with improved outcomes in DC-treated patients, but are associated with poor outcomes in patients receiving SOC treatment. No serious adverse events attributed to the study medication have been reported to date.

Conclusions: Rocapuldencel-T did not improve OS in patients treated with combination therapy, although the induced immune response correlated with OS. Moreover, we identified two potential survival-predictive biomarkers for patients receiving DC based immunotherapy, IL-12 produced by the DC vaccine and higher numbers of T regulatory cells present in the peripheral blood of patients with advanced RCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2427DOI Listing
May 2020

The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC).

J Immunother Cancer 2019 12 20;7(1):354. Epub 2019 Dec 20.

Georgetown, Lombardi Comprehensive Cancer Center, Research Building, Room E501 3970 Reservoir Road NW, Washington, DC, 20057, USA.

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.
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http://dx.doi.org/10.1186/s40425-019-0813-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924043PMC
December 2019

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2020 02 14;26(4):793-803. Epub 2019 Nov 14.

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

Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients.

Patients And Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW ( = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies.

Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired mutation elsewhere, suggesting a possible alternate mechanism of resistance.

Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024660PMC
February 2020

Wearable activity monitors to assess performance status and predict clinical outcomes in advanced cancer patients.

NPJ Digit Med 2018 5;1:27. Epub 2018 Jul 5.

1Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA USA.

An objective evaluation of patient performance status (PS) is difficult because patients spend the majority of their time outside of the clinic, self-report to providers, and undergo dynamic changes throughout their treatment experience. Real-time, objective activity data may allow for a more accurate assessment of PS and physical function, while reducing the subjectivity and bias associated with current assessments. Consenting patients with advanced cancer wore a wearble activity monitor for three consecutive visits in a prospective, single-cohort clinical trial. Provider-assessed PS (ECOG/Karnofsky) and NIH PROMIS® patient-reported outcomes (PROs) were assessed at each visit. Associations between wearable activity monitor metrics (steps, distance, stairs) and PS, clinical outcomes (adverse events, hospitalizations, survival), and PROs were assessed using correlation statistics and in multivariable logistic regression models. Thirty-seven patients were evaluated (54% male, median 62 years). Patients averaged 3700 steps, 1.7 miles, and 3 flights of stairs per day. Highest correlations were observed between average daily steps and ECOG-PS and KPS (  0.63 and   0.69, respectively  < 0.01). Each 1000 steps/day increase was associated with reduced odds for adverse events (OR: 0.34, 95% CI 0.13, 0.94), hospitalizations (OR: 0.21 95% CI 0.56, 0.79), and hazard for death (HR: 0.48 95% CI 0.28-0.83). Significant correlations were also observed between activity metrics and PROs. Our trial demonstrates the feasibility of using wearable activity monitors to assess PS in advanced cancer patients and suggests their potential use to predict clinical and patient-reported outcomes. These findings should be validated in larger, randomized trials.
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http://dx.doi.org/10.1038/s41746-018-0032-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550281PMC
July 2018

Brain Metastases in Renal Cell Carcinoma: Immunotherapy Responsiveness Is Multifactorial and Heterogeneous.

J Clin Oncol 2019 08 20;37(23):1987-1989. Epub 2019 Jun 20.

1Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1200/JCO.19.00639DOI Listing
August 2019

Role of Biomarkers in Prediction of Response to Therapeutics in Metastatic Renal-Cell Carcinoma.

Clin Genitourin Cancer 2019 06 15;17(3):e454-e460. Epub 2019 Jan 15.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address:

Renal-cell carcinoma remains one of the elusive cancers that lacks a biomarker. It is the eighth most commonly diagnosed malignancy in the United States, and the incidence has slowly trended upward. In addition to the increase in newly diagnosed cases, the prevalence and overall survival of individuals with kidney cancer also has increased substantially. This formal review synopsizes the literature regarding the current treatment landscape, the utility of biomarkers in renal-cell carcinoma, and future directions regarding next-generation sequencing of circulating tumor DNA.
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http://dx.doi.org/10.1016/j.clgc.2019.01.004DOI Listing
June 2019

Developments in the use of tyrosine kinase inhibitors in the treatment of renal cell carcinoma.

Expert Rev Anticancer Ther 2019 03 4;19(3):259-271. Epub 2019 Feb 4.

a Department of Medicine, Division of Hematology and Oncology , Cedars-Sinai Medical Center , Los Angeles , CA , USA.

Introduction: Renal cell carcinoma (RCC) is among the most commonly diagnosed solid malignancies, but until recently there were few systemic treatment options for advanced disease. Since 2005, the treatment landscape has been transformed by the development of several novel systemic therapies. In particular, tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway have been instrumental in improving outcomes in patients with metastatic disease. Areas covered: The armamentarium of TKIs available for the treatment of RCC has expanded in recent years. The most active area of research at this time is the development of treatment regimens combining newer-generation TKIs and immune checkpoint inhibitors. Emerging data point to a role for combination therapy in the frontline management of advanced RCC. Other ongoing areas of research include the use of TKIs in the adjuvant setting and the role of cytoreductive nephrectomy within a changing treatment landscape. Expert opinion: Although TKIs and immune checkpoint inhibitors have incrementally improved outcomes for patients with advanced RCC, long-term survival remains poor. The development of regimens combining these agents represents the next step in the evolution of the field. For the clinician, this will offer exciting possibilities and novel challenges.
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http://dx.doi.org/10.1080/14737140.2019.1573678DOI Listing
March 2019

Highlights in kidney cancer from the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Authors:
Robert A Figlin

Clin Adv Hematol Oncol 2018 06;16(6):423-425

Cedars-Sinai Medical Center, Los Angeles, California.

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June 2018

Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group.

Clin Genitourin Cancer 2018 08 4;16(4):298-304. Epub 2018 May 4.

Memorial Sloan Kettering Cancer Center, Department of Oncology, New York, NY.

Background: Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting.

Materials And Methods: A retrospective analysis was performed on data from sunitinib-treated patients (n = 375) in the pivotal phase III trial of sunitinib versus interferon-α as first-line treatment for mRCC. Objective response rates (ORRs) were determined from independently reviewed radiologic assessments. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and median overall survival (OS) according to patient risk group.

Results: Median PFS (95% confidence interval [CI]) was 14.1 (13.4-17.1), 10.7 (10.5-12.5), 2.4 (1.1-4.7), and 10.6 (8.1-10.9) months in sunitinib-treated patients in the IMDC favorable (n = 134), intermediate (n = 205), poor (n = 34), and intermediate + poor (n = 239) risk groups, respectively. Median OS (95% CI) was 23.0 (19.8-27.8), 5.1 (4.3-9.9), and 20.3 (16.8-23.0) months in sunitinib-treated patients in IMDC intermediate, poor, and intermediate + poor risk groups, respectively, and was not reached in the favorable risk group (>50% of patients were alive at data cutoff). ORRs (95% CI) was 53.0% (44.2%-61.7%), 33.7% (27.2%-40.6%), 11.8% (3.3%-27.5%), and 30.5% (24.8%-36.8%) in sunitinib-treated patients in IMDC favorable, intermediate, poor, and intermediate + poor risk groups, respectively.

Conclusion: Results of this retrospective analysis show differences in patient outcomes for PFS, OS, and ORR on the basis of IMDC prognostic risk group assignment for patients with mRCC.
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http://dx.doi.org/10.1016/j.clgc.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690431PMC
August 2018

Highlights in renal cell carcinoma from the Sixteenth International Kidney Cancer Symposium: commentary.

Authors:
Robert A Figlin

Clin Adv Hematol Oncol 2018 Jan;16 Suppl 1(1):21-23

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California.

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January 2018

Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma.

J Clin Oncol 2018 03 19;36(9):867-874. Epub 2017 Dec 19.

Kevin D. Courtney and James Brugarolas, University of Texas Southwestern Medical Center; Naseem J. Zojwalla, Ann M. Lowe, Keshi Wang, Eli M. Wallace, and John A. Josey, Peloton Therapeutics, Dallas, TX; Jeffrey R. Infante, TN Oncology and Sarah Cannon Research Institute, Nashville, TN; Elaine T. Lam, University of Colorado Cancer Center, Aurora, CO; Robert A. Figlin, Cedars-Sinai Medical Center, Los Angeles, CA; Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Toni K. Choueiri, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.
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http://dx.doi.org/10.1200/JCO.2017.74.2627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946714PMC
March 2018

Adjuvant Pazopanib Does Not PROTECT Against Recurrence of High-Risk, Initially Localized Renal Cell Cancer but Does Provide Novel Insights.

J Clin Oncol 2017 12 25;35(35):3895-3897. Epub 2017 Oct 25.

Grant D. Stewart, University of Cambridge, Cambridge, United Kingdom; Bradley C. Leibovich, Mayo Clinic, Rochester, MN; Sylvie Negrier, University of Lyon, Lyon, France; and Robert A. Figlin, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1200/JCO.2017.75.4242DOI Listing
December 2017

Predicting Real-World Effectiveness of Cancer Therapies Using Overall Survival and Progression-Free Survival from Clinical Trials: Empirical Evidence for the ASCO Value Framework.

Value Health 2017 Jul - Aug;20(7):866-875. Epub 2017 May 16.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Objectives: To measure the relationship between randomized controlled trial (RCT) efficacy and real-world effectiveness for oncology treatments as well as how this relationship varies depending on an RCT's use of surrogate versus overall survival (OS) endpoints.

Methods: We abstracted treatment efficacy measures from 21 phase III RCTs reporting OS and either progression-free survival or time to progression endpoints in breast, colorectal, lung, ovarian, and pancreatic cancers. For these treatments, we estimated real-world OS as the mortality hazard ratio (RW MHR) among patients meeting RCT inclusion criteria in Surveillance and Epidemiology End Results-Medicare data. The primary outcome variable was real-world OS observed in the Surveillance and Epidemiology End Results-Medicare data. We used a Cox proportional hazard regression model to calibrate the differences between RW MHR and the hazard ratios on the basis of RCTs using either OS (RCT MHR) or progression-free survival/time to progression surrogate (RCT surrogate hazard ratio [SHR]) endpoints.

Results: Treatment arm therapies reduced mortality in RCTs relative to controls (average RCT MHR = 0.85; range 0.56-1.10) and lowered progression (average RCT SHR = 0.73; range 0.43-1.03). Among real-world patients who used either the treatment or the control arm regimens evaluated in the relevant RCT, RW MHRs were 0.6% (95% confidence interval -3.5% to 4.8%) higher than RCT MHRs, and RW MHRs were 15.7% (95% confidence interval 11.0% to 20.5%) higher than RCT SHRs.

Conclusions: Real-world OS treatment benefits were similar to those observed in RCTs based on OS endpoints, but were 16% less than RCT efficacy estimates based on surrogate endpoints. These results, however, varied by tumor and line of therapy.
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http://dx.doi.org/10.1016/j.jval.2017.04.003DOI Listing
July 2017

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials.

Clin Genitourin Cancer 2017 Jun 20. Epub 2017 Jun 20.

Gustave Roussy, Villejuif Cedex, France.

Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months.

Patients And Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months ("others"). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology.

Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P < .0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m, and low neutrophil-to-lymphocyte ratio were associated with LTR.

Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.
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http://dx.doi.org/10.1016/j.clgc.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736765PMC
June 2017

Targeted therapies for renal cell carcinoma.

Nat Rev Nephrol 2017 Aug 10;13(8):496-511. Epub 2017 Jul 10.

Urologic Oncology Program &Translational Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Department of Pharmacy Services, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.

The management of patients with metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. Nephrectomy remains an important intervention for localized RCC but systemic therapy is the mainstay of treatment for patients who relapse after surgery or who have metastatic RCC. Before 2005, medical therapies for RCC were limited to cytokine therapies, which are very toxic and benefit only a small percentage of patients. In 2017, therapeutic agents now include kinase and immune checkpoint inhibitors. Contemporary research with these agents is now focusing on combinatorial and perioperative therapy. The field is now faced with the evolving challenge of how to select the best therapy for each patient during their natural history of disease, which has created a strong interest in modern sequencing and molecular approaches to identify biomarkers to personalize treatments. New therapeutic agents and approaches are associated with different toxicities and financial burdens, which require consideration of value by measuring clinical benefit, toxicity, and the cost of each drug with an organized framework. In this Review, we discuss the mechanisms underlying RCC and how improved molecular understanding helped the development of therapies, as well as biomarkers of response to treatment. We also discuss the value of these agents and their impact on personalization of therapy and drug development for RCC.
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http://dx.doi.org/10.1038/nrneph.2017.82DOI Listing
August 2017

Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.

Clin Genitourin Cancer 2017 10 27;15(5):526-533. Epub 2017 Feb 27.

Baylor Sammons Cancer Center-Texas Oncology, Dallas, TX.

Background: Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule.

Patients And Methods: Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial. Associations between 9 SNP variants (CXCL8, LOXL2, CCDC26, SH3GL2, CLLU1, IL2RA, AURKB, and 2 SNPs on Chromosomes 7 and 12) and progression-free survival (PFS), objective response rate, and overall survival were assessed using Kaplan-Meier analysis, Cox proportional hazard model, and the Fisher exact test.

Results: CXCL8 rs1126647 A/A versus A/T (P = .004) or T/T (P < .0001) and SH3GL2 rs10963287 C/C versus C/T (P = .005) or T/T (P = .018) were associated with improved overall survival in all patients. CLLU1 rs525810 A/A genotype versus A/G (P = .014) or G/G (P = .048) was associated with improved PFS in the continuous daily dosing arm. IL2RA rs7893467 T/G versus T/T was associated with improved PFS (P = .034) in the 4-weeks-on/2-weeks-off arm and objective response rate (P = .034) in all patients. No significant associations between improved efficacy and genotype were found for other SNPs.

Conclusion: Germline variants in CLLU1, IL2RA, CXCL8, and SH3GL2 warrant further retrospective study in independent cohorts of patients with metastatic RCC treated with vascular endothelial growth factor-class inhibitors, to test their biological significance and potential clinical fitness as biomarkers to guide treatment.
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http://dx.doi.org/10.1016/j.clgc.2017.02.006DOI Listing
October 2017

Circulating tumor cells in prostate cancer: beyond enumeration.

Clin Adv Hematol Oncol 2017 Jan;15(1):63-73

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Circulating tumor cells (CTCs) are a population of rare cancer cells that have detached from the primary tumor and/or metastatic lesions and entered the peripheral circulation. Enumeration of CTCs has demonstrated value as a prognostic biomarker, and newer studies have pointed to information beyond enumeration that is of critical importance in prostate cancer. Technologic advances that permit examination of the morphology, function, and molecular content of CTCs have made it possible to measure these factors as part of liquid biopsy. These advances provide a way to study tumor evolution and the development of resistance to therapy. Recent breakthroughs have created new applications for CTCs that will affect the care of patients with prostate cancer.
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January 2017

Recent Advances in the Medical Treatment of Recurrent or Metastatic Renal Cell Cancer.

Drugs 2017 Jan;77(1):17-28

Urologic Oncology Program and Translational Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.

Renal cell carcinoma (RCC) historically has had limited treatment options in the metastatic setting but in the last decade, a significant arsenal of new therapies has emerged. Specifically, targeted anti-angiogenic therapies through vascular endothelial growth factor (VEGF) inhibition and immunotherapy through PD-1 inhibition have become the foundation of metastatic RCC treatment increasing not only progression-free survival but also an improved overall survival with improved toxicity profiles compared with older therapies such as IL-2 and interferon. With the development of these newer medications, the optimal sequence and pairing of treatments is not yet well understood but important studies are ongoing as this information will allow for more effective and safe treatment of patients.
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http://dx.doi.org/10.1007/s40265-016-0665-1DOI Listing
January 2017

Adjuvant treatment for renal cell carcinoma: do we finally have a major breakthrough?

Clin Adv Hematol Oncol 2016 Nov;14(11):907-914

Cedars-Sinai Medical Center, Los Angeles, California.

Clinical parameters can be used to identify patients at greatest risk for recurrence following nephrectomy for clinically localized renal cell carcinoma (RCC). Molecular tools are being developed to improve risk stratification. An increasing list of available treatments for metastatic RCC continues to provide hope that an effective adjuvant therapy will be identified for patients with high-risk, clinically localized disease. In a phase 3 adjuvant therapy trial (S-TRAC), sunitinib increased median disease-free survival in patients with clear cell RCC who were at very high risk. This is the first positive phase 3 adjuvant therapy trial using a targeted therapy. However, a much larger phase 3 trial comparing sunitinib, sorafenib, and placebo (ASSURE) was negative. Careful review of recent adjuvant therapy trials reveals insights about who may benefit from adjuvant therapy and provides lessons for future trial design.
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November 2016

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.

J Immunother Cancer 2016 15;4:81. Epub 2016 Nov 15.

Georgetown-Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, Research Building, Room E501, Washington, DC 20057, USA.

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.
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http://dx.doi.org/10.1186/s40425-016-0180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109802PMC
February 2018

Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma.

Oncologist 2017 01 2;22(1):41-52. Epub 2016 Nov 2.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

The oral multikinase inhibitor sunitinib malate was approved by the U.S. Food and Drug Administration in January 2006 for use in patients with advanced renal cell carcinoma (RCC). Since then, it has been approved globally for this indication and for patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. As we mark the 10-year anniversary of the beginning of the era of targeted therapy, and specifically the approval of sunitinib, it is worthwhile to highlight the progress that has been made in advanced RCC as it relates to the study of sunitinib. We present the key trials and data for sunitinib that established it as a reference standard of care for first-line advanced RCC therapy and, along with other targeted agents, significantly altered the treatment landscape in RCC. Moreover, we discuss the research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers, plus the extent to which this research has contributed to the overall understanding and management of RCC. We also explore the key learnings regarding study design and data interpretation from the sunitinib studies and how these findings and the sunitinib development program, in general, can be a model for successful development of other agents. Finally, ongoing research into the continued and future role of sunitinib in RCC management is discussed.

The Oncologist: 2017;22:41-52 IMPLICATIONS FOR PRACTICE: Approved globally, sunitinib is established as a standard of care for first-line advanced renal cell carcinoma (RCC) therapy and, along with other targeted agents, has significantly altered the treatment landscape in RCC. Research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers has contributed to the overall understanding and management of RCC. Key learnings regarding study design and data interpretation from the sunitinib studies and the sunitinib development program, in general, can be a model for the successful development of other agents.
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http://dx.doi.org/10.1634/theoncologist.2016-0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313263PMC
January 2017

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.

Clin Genitourin Cancer 2017 04 18;15(2):291-299.e1. Epub 2016 Aug 18.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Background: The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib.

Patients And Methods: Patients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan-Meier methods, and Pearson χ tests.

Results: The patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression-free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05).

Conclusion: INTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.
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http://dx.doi.org/10.1016/j.clgc.2016.08.013DOI Listing
April 2017

Third-Line Treatment Options for Kidney Cancer.

Oncology (Williston Park) 2016 09;30(9):813-5

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September 2016

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials.

Clin Genitourin Cancer 2016 10 27;14(5):406-414. Epub 2016 Apr 27.

Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events.

Patients And Methods: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia.

Results: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant.

Conclusion: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.
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http://dx.doi.org/10.1016/j.clgc.2016.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063024PMC
October 2016
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