Publications by authors named "Andrew W Hahn"

56 Publications

Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies.

Oncologist 2021 Mar 31. Epub 2021 Mar 31.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Introduction: Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs.

Methods: We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used.

Results: Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity.

Conclusion: Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs.

Implications For Practice: As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.
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http://dx.doi.org/10.1002/onco.13770DOI Listing
March 2021

Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial.

Invest New Drugs 2021 Mar 26. Epub 2021 Mar 26.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030-4009, USA.

Background: Treatment options for unresectable, locally advanced or metastatic penile squamous cell carcinoma (SCC) are limited. Previous studies have shown that 40-62% of patients with penile SCC express PD-L1. We report three cases of locally advanced or metastatic penile SCC treated with pembrolizumab.

Case Presentations: Herein, we present three patients with recurrent, locally advanced or metastatic penile SCC who progressed on a platinum-based chemotherapy triplet and were treated with pembrolizumab, administered as part of a phase II clinical trial for rare tumors (NCT02721732). One patient with a microsatellite instability high (MSI-H) tumor experienced a durable partial response to pembrolizumab, underwent surgical consolidation, and remains disease-free 38.7 months later. Two patients experienced progressive disease within 3 months of beginning pembrolizumab. No one experienced a grade 3 or worse treatment-related adverse event.

Conclusion: In sum, single-agent pembrolizumab was well tolerated as salvage therapy in a small cohort of patients with unresectable, locally advanced or metastatic penile SCC. Pembrolizumab produced an objective response in an MSI-H tumor, yet it did not control disease in two patients with MSS penile SCC. Rationale combination therapies, including pembrolizumab, warrant further investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT02721732 . Registered March 23, 2016.
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http://dx.doi.org/10.1007/s10637-021-01100-xDOI Listing
March 2021

Successful Recruitment of Black Men to Prostate Cancer Clinical Trials-A Lesson in Achievement.

JAMA Netw Open 2021 01 4;4(1):e2034652. Epub 2021 Jan 4.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.34652DOI Listing
January 2021

Drug and alcohol use among people living with HIV in care in the United States by geographic region.

AIDS Care 2021 Jan 23:1-8. Epub 2021 Jan 23.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Substance use in the U.S. varies by geographic region. Opioid prescribing practices and marijuana, heroin, and methamphetamine availability are evolving differently across regions. We examined self-reported substance use among people living with HIV (PLWH) in care at seven sites from 2017-2019 to understand current regional substance use patterns. We calculated the percentage and standardized percentage of PLWH reporting current drug use and at-risk and binge alcohol use by U.S. Census Bureau geographic region and examined associations in adjusted logistic regression analyses. Among 7,686 PLWH, marijuana use was the most prevalent drug (30%), followed by methamphetamine/crystal (8%), cocaine/crack (7%), and illicit opioids (3%). One-third reported binge alcohol use (32%). Differences in percent of current use by region were seen for marijuana (24-41%) and methamphetamine/crystal (2-15%), with more use in the West and Northeast, and binge alcohol use (26-40%). In adjusted analyses, PLWH in the Midwest were significantly less likely to use methamphetamine/crystal (aOR: 0.13;0.06-0.25) or illicit opioids (aOR:0.16;0.05-0.53), and PLWH in the Northeast were more likely to use cocaine/crack (aOR:1.59;1.16-2.17), compared to PLWH in the West. Understanding differences in substance use patterns in the current era, as policies continue to evolve, will enable more targeted interventions in clinical settings among PLWH.
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http://dx.doi.org/10.1080/09540121.2021.1874274DOI Listing
January 2021

Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes.

Mol Cancer Res 2021 03 15;19(3):395-402. Epub 2020 Dec 15.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. , and alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in were almost mutually exclusive of . More than half (64%) of patients with an alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type . The reverse relationship was observed in patients harboring an alteration. IMPLICATIONS: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0751DOI Listing
March 2021

Validation of prognostic scoring systems for patients with metastatic renal cell carcinoma enrolled in phase I clinical trials.

ESMO Open 2020 11;5(6):e001073

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Background: For patients with metastatic renal cell carcinoma (mRCC) who progress on standard-of-care therapies, there is an unmet need for novel treatments. Phase I clinical trials are designed to test the safety, toxicity and optimal dosing of novel agents. Herein, we analysed the outcomes of patients with mRCC enrolled in phase I trials and assess the utility of prognostic scores.

Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center (MDACC). Survival outcomes were calculated using Cox proportional hazard model. Prognostic value of the International Metastatic RCC Database Consortium (IMDC), Royal Marsden Hospital (RMH) and MDACC scores was assessed using the likelihood ratio (LR) χ test and the c-index.

Results: Among 82 patients with mRCC who received treatment, 21 patients participated in more than one trial, resulting in 106 trial participants (TP). Median prior therapies was two. For all TPs, median overall survival (OS) was 31.2 months, progression-free survival (PFS) was 5.9 months and objective response rate was 22%. Median OS and PFS were significantly shorter with increasing IMDC, RMH and MDACC scores. The RMH and MDACC scores outperformed the IMDC score for predicting OS (RMH LR χ=8.64; MDACC LR χ=7.74; IMDC LR χ=2.36) and PFS (RMH LR χ=17.5; MDACC LR χ=20.3; IMDC LR χ=4.28).

Conclusions: The RMH and MDACC prognostic scores can be used to predict OS for patients with mRCC in phase I trials and may guide patient selection. Patients with mRCC should be considered for phase I trials.
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http://dx.doi.org/10.1136/esmoopen-2020-001073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684827PMC
November 2020

Pathogenic Germline DNA Repair Gene and Mutations in Men With Metastatic Prostate Cancer.

JCO Precis Oncol 2020 4;4. Epub 2020 Mar 4.

Department of Medicine and the Duke Cancer Institute, Duke University School of Medicine, Durham, NC.

Purpose: Germline mutations in DNA repair (DR) genes and susceptibility genes and have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood.

Patients And Methods: To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, , and in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses.

Results: All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; /, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene . It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or G84E mutations.

Conclusion: These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.
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http://dx.doi.org/10.1200/PO.19.00284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446531PMC
March 2020

Circulating-tumor DNA as predictor of enzalutamide response post-abiraterone treatment in metastatic castration-resistant prostate cancer.

Cancer Treat Res Commun 2020 14;24:100193. Epub 2020 Jul 14.

Department of Internal Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans 70112, LA, USA. Electronic address:

Background: The crossover from abiraterone acetate (AA) to enzalutamide (ENZA) is a frequent approach in clinical practice. Our aim was to explore the role of genomic alterations as putative biomarkers of response to sequential AA followed by ENZA in mCRPC and their association with clinical outcomes.

Patients And Methods: This was a multi-center, retrospective analysis of mCRPC patients with circulating-tumor DNA (ctDNA) post-AA and prior to ENZA treatment. Objectives of this analysis were to assess PSA response, time to PSA progression (TTP) and overall survival (OS) in mCRPC patients treated with ENZA following progression on AA with respect to genomic aberrations detected by ctDNA.

Results: A total of 28 patients with mCRPC were identified. Median time between AA and ENZA was 3.1 months and median initial PSA prior to ENZA was 35.0 ng/mL. Nine patients (32.1%) achieved PSA responses to ENZA. Most patients (79.0%) achieved confirmed PSA progression with median TTP of 1.6 months (95% CI, 0.7-2.4). Somatic alterations in AR genes were detected in 36.0% of patients with other common alterations detected including 39.0% TP53, 11.0% DNA repair, and 11.0% PTEN. A lack of AR alterations was associated with better PSA response to ENZA (p = 0.04).

Conclusion: While lack of AR alterations in ctDNA was associated with more favorable outcomes, the present dataset is insufficient to recommend the use of ctDNA to impact clinical decision-making in this setting. Further understanding of the implications of the genomic phenotype in ctDNA of castration-resistant tumors and the potential therapeutic implications is required.
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http://dx.doi.org/10.1016/j.ctarc.2020.100193DOI Listing
May 2021

The rapidly evolving treatment landscape of advanced prostate, bladder, and renal cell carcinomas.

Cancer Treat Res Commun 2020 4;24:100190. Epub 2020 Jul 4.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ctarc.2020.100190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334643PMC
May 2021

Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer.

Eur Urol 2020 11 2;78(5):652-656. Epub 2020 Jul 2.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address:

Recently, mutations in speckle-type pox virus and zinc finger protein (SPOP) gene (mutant SPOP [mtSPOP]) have been associated with improved outcomes to abiraterone in the castration-resistant setting. We hypothesized that mtSPOP would be associated with improved outcomes to systemic therapy in men with de novo metastatic castration-sensitive prostate cancer (d-mCSPC). Retrospective data of newly diagnosed d-mCSPC patients were collected from four institutions. Eligibility criteria included standard androgen deprivation therapy without intensification, and SPOP mutational status (mtSPOP or wild-type SPOP [wtSPOP]) determination by targeted next-generation sequencing from tumor biopsies. A total of 121 men (25 mtSPOP [21%] and 96 wtSPOP [79%]) were included. After adjusting for covariates, mtSPOP was significantly associated with better median progression-free survival (35 vs 13 mo; adjusted hazard ratio [HR] 0.47; p =  0.016) and overall survival (97 vs 69 mo; adjusted HR 0.32; p =  0.027), with similar HR and p value on the univariate analysis. These findings, upon external validation, may assist with counseling and prognostication in the clinic, and inform the design of future clinical trials in this setting. PATIENT SUMMARY: : Presence of tumor mutation in speckle-type pox virus and zinc finger protein (SPOP) gene was associated with improved survival outcomes in men with de novo metastatic castration-sensitive prostate cancer receiving standard androgen deprivation therapy.
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http://dx.doi.org/10.1016/j.eururo.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572891PMC
November 2020

Potential Roles for PD-1 Inhibition and Cabozantinib in Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma.

Oncologist 2020 03 15;25(3):186-188. Epub 2019 Oct 15.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

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http://dx.doi.org/10.1634/theoncologist.2019-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066721PMC
March 2020

A Phase I Study of Alpha-1,3-Galactosyltransferase-Expressing Allogeneic Renal Cell Carcinoma Immunotherapy in Patients with Refractory Metastatic Renal Cell Carcinoma.

Oncologist 2020 02 6;25(2):121-e213. Epub 2019 Sep 6.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Lessons Learned: HyperAcute Renal immunotherapy was well tolerated and demonstrated antitumor activity in patients requiring salvage-line treatment for metastatic renal cell carcinoma (mRCC). HyperAcute Renal immunotherapy was safely administered with concomitant salvage-line treatments for mRCC, and it may be a candidate for inclusion in novel combinations for salvage treatment of mRCC because of its unique mechanism of action.

Background: HyperAcute Renal (HAR) immunotherapy exploits a naturally occurring barrier to xenotransplantation and zoonotic infections in humans to immunize patients against metastatic renal cell carcinoma (mRCC) cells. HAR consists of two allogeneic renal cancer cell lines genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity.

Methods: Patients with refractory mRCC were eligible for this phase I dose-escalation trial. Concomitant treatment was permitted after the initial 2 months of HAR monotherapy. HAR was injected intradermally weekly for 4 weeks then biweekly for 20 weeks, totaling 14 immunizations. The primary endpoint was safety and determination of a maximum tolerated dose (MTD).

Results: Among 18 patients enrolled, two grade 3 adverse events (AEs) were attributed to HAR, lymphopenia and injection site reaction, and no grade 4/5 AEs occurred. The recommended phase II dose (RP2D) was 300 million cells. One patient had a partial response and eight patients had stable disease, for a disease control rate of 50% (9/18). Median overall survival with low-dose HAR was 14.2 months and was 25.3 months with high-dose HAR.

Conclusion: In pretreated mRCC, HAR immunotherapy was well tolerated and demonstrated antitumor activity. HAR immunotherapy may be a candidate for inclusion in novel combinations for salvage treatment of mRCC.
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http://dx.doi.org/10.1634/theoncologist.2019-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011628PMC
February 2020

Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration-resistant Prostate Cancer.

Clin Cancer Res 2020 05 14;26(9):2104-2110. Epub 2020 Jan 14.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Purpose: Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC.

Patients And Methods: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.

Results: Thirty-nine men were randomized to RE ( = 27) or enzalutamide ( = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51-0.81; = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide ( = 0.024), correlated with decline in BMMs.

Conclusions: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2591DOI Listing
May 2020

Potential Roles for PD-1 Inhibition and Cabozantinib in Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma.

Oncologist 2019 Oct 15. Epub 2019 Oct 15.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

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http://dx.doi.org/10.1634/theoncologist.2019-0657DOI Listing
October 2019

First-line Treatment of Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis.

Eur Urol Oncol 2019 Nov 4;2(6):708-715. Epub 2019 Oct 4.

Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Context: No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis.

Objective: To indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group.

Evidence Acquisition: An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. "Clinically relevant" studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes.

Evidence Synthesis: We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves [SUCRA] 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease.

Conclusions: The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice.

Patient Summary: Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.
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http://dx.doi.org/10.1016/j.euo.2019.09.002DOI Listing
November 2019

Patterns of treatment in metastatic renal cell carcinoma for older versus younger patients.

J Geriatr Oncol 2020 05 8;11(4):724-726. Epub 2019 Aug 8.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jgo.2019.07.002DOI Listing
May 2020

The Role of PD-L1 Testing in Advanced Genitourinary Malignancies.

Eur Urol Focus 2020 01 11;6(1):11-13. Epub 2019 Mar 11.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address:

In accordance with US Food and Drug Administration recommendations, tumor PD-L1 expression should be assessed in all patients with platinum-ineligible metastatic urothelial carcinoma (mUC), and patients with low PD-L1 expression should not receive single-agent immune checkpoint inhibition treatment. By contrast, PD-L1 should not be tested in metastatic renal cell carcinoma and platinum-refractory mUC.
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http://dx.doi.org/10.1016/j.euf.2019.03.003DOI Listing
January 2020

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study.

Lancet Oncol 2019 04 28;20(4):581-590. Epub 2019 Feb 28.

Abramson Cancer Center, Philadelphia, PA, USA.

Background: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.

Methods: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.

Findings: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.

Interpretation: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(18)30907-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849381PMC
April 2019

Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors.

Drugs Aging 2019 05;36(5):395-401

Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Suite 2161, Salt Lake City, UT, 84112, USA.

Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.
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http://dx.doi.org/10.1007/s40266-019-00644-1DOI Listing
May 2019

Time from definitive therapy to onset of metastatic disease predicts outcomes in men with metastatic hormone sensitive prostate cancer.

Urol Oncol 2019 06 13;37(6):352.e19-352.e24. Epub 2019 Feb 13.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. Electronic address:

Purpose: Contemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC.

Methods: This multicenter retrospective study included men initiating systemic therapy with ADT for new mHSPC. Kaplan-Meier and COX proportional hazard models assessed time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) by receipt of prior DT.

Results: Of the 253 men with new mHSPC, 115 (45%) had received prior DT. In a multivariate analysis, increasing years from DT to the start of ADT was an independent predictor of time to mCRPC (per year: hazard ratio 0.91 95% confidence interval 0.84-0.99, P = 0.020) and improved OS (per year: hazard ratio 0.87, 95% confidence interval 0.74-0.99, P = 0.0025) in patients with new mHSPC, and may assist with risk stratification in these patients at time of mHSPC.

Conclusion: Time from DT to start of ADT is an independent predictor of time to mCRPC and OS in men with new mHSPC, and may assist with risk stratification of these patients for systemic therapy selection.
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http://dx.doi.org/10.1016/j.urolonc.2019.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857455PMC
June 2019

Evolution of the genomic landscape of circulating tumor DNA (ctDNA) in metastatic prostate cancer over treatment and time.

Cancer Treat Res Commun 2019 6;19:100120. Epub 2019 Feb 6.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive Suite 5726, Salt Lake City, UT 84112, USA. Electronic address:

Background: Targeted therapies have shown promise for men with metastatic castration-resistant prostate cancer (mCRPC). Due to the difficulty with obtaining tumor tissue in bony metastases, liquid biopsies are a promising alternative to guide treatment selection. While concurrent tissue next-generation sequencing (tNGS) and liquid biopsy has high concordance, it is unknown whether the genomic landscape of metastatic prostate cancer (mPC) changes over time or treatment. Herein, we hypothesize that the genomic landscape of mPC evolves with new treatments and/or time between tests.

Patients And Methods: Men with mPC from the University of Utah with matched tNGS and liquid biopsy were included. Clinical data was collected retrospectively. Exonic regions from 69 genes covered by both platforms were included for analysis. Paired t tests were used to assess number of genomic alterations (GAs) between testing platforms. Number of alterations was assessed by time and number of treatments between testing by multivariate nonparametric trend tests.

Results: 101 men with mPC were eligible and included. In men with no new treatments and ≤ 1 year between tests, a similar number of GAs were detected in both tests (2.0 vs. 2.2). In contrast, men with ≥ 1 new treatment between tests had significantly more GAs after treatment (5.0 vs. 2.4, p = 0.005). Total number of GAs was correlated with number of new treatments between testing (p = 0.003) and not time between testing (p = 0.76).

Conclusion: The genomic landscape of mPC evolves with subsequent therapies. This finding suggests that contemporary tumor genomic profile upon disease progression may optimize guidance towards subsequent therapy selection.
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http://dx.doi.org/10.1016/j.ctarc.2019.100120DOI Listing
September 2019

Management of Nonmetastatic Castration-Resistant Prostate Cancer: Recent Advances and Future Direction.

Curr Treat Options Oncol 2019 02 11;20(2):14. Epub 2019 Feb 11.

Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Opinion Statement: Nonmetastatic castration-resistant prostate cancer (nmCRPC) comprises a relatively narrow niche of advanced prostate cancer, but the treatment landscape for men with nmCRPC has drastically changed over the past year. Prior to the SPARTAN and PROSPER trials, men with nmCRPC were commonly treated with first-generation androgen receptor antagonists, such as bicalutamide or flutamide, or with estrogens or ketoconazole, none of which were associated with any proven survival benefit. The SPARTAN trial evaluated apalutamide versus placebo for men with nmCRPC and found that apalutamide significantly improved metastasis-free survival (MFS), the primary endpoint of this trial. Similarly, the PROSPER trial showed that enzalutamide significantly improved MFS compared with placebo for men with nmCRPC. In both trials, the data for overall survival was immature at the time of analysis. The SPARTAN and PROSPER trials led to the approval of apalutamide and enzalutamide, respectively, for men with nmCRPC. More recently, the phase 3 trial ARAMIS showed that darolutamide, a novel androgen receptor antagonist, also improves MFS compared with placebo for men with nmCRPC, and this trial is expected to garner regulatory approval for darolutamide in the nmCRPC setting. Novel imaging modalities are becoming more prevalent for the diagnostic evaluation of men with prostate cancer and are more sensitive than conventional bone or CT scans for detection of oligometastatic disease that previously was undetected. These modalities are likely to reduce the incidence and prevalence of nmCRPC in the near future. Ultimately, the treatment options for men with nmCRPC have significantly improved over the past 2 years.
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http://dx.doi.org/10.1007/s11864-019-0611-zDOI Listing
February 2019

Predictive genomic markers of response to VEGF targeted therapy in metastatic renal cell carcinoma.

PLoS One 2019 25;14(1):e0210415. Epub 2019 Jan 25.

Department of Internal Medicine, Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, United States of America.

Background: First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection.

Methods: From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed.

Results: Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner.

Conclusion: In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210415PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347137PMC
October 2019

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.

Cancer 2019 05 8;125(9):1459-1469. Epub 2019 Jan 8.

Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.

Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.

Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.

Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.

Conclusions: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.
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http://dx.doi.org/10.1002/cncr.31959DOI Listing
May 2019

Germline Variant in and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

Mol Cancer Ther 2019 03 26;18(3):726-729. Epub 2018 Dec 26.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of are common and predict improved response to first-line abiraterone acetate in men with mCRPC.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0739DOI Listing
March 2019

Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment.

Am Soc Clin Oncol Educ Book 2018 May;38:363-371

From the Division of Oncology, University of Utah/Huntsman Cancer Institute, Salt Lake City, UT; Division of Oncology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Division of Hematology/Oncology, University of California-San Francisco, Helen Diller Comprehensive Cancer Center, San Francisco, CA.

The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. With multiple treatment options available for patients with mCSPC, treatment selection to optimize patient outcomes has become increasingly difficult. Here, we review the clinical trials involving ADT plus docetaxel or abiraterone and provide clinicians with guidelines for treatment. Although surgery and/or radiation are standard of care for localized, intermediate- and high-risk prostate cancer, these treatments are not routinely used as part of initial treatment plans for patients with de novo mCSPC. Recent clinical data are challenging that dogma, and we review the literature on the addition of surgery and radiation to systemic therapy for mCSPC. Finally, the standard of care for oligometastatic prostate cancer (a subset of mCSPC with limited metastases) has not been established compared with that for some other cancers. We discuss the recent studies on metastasis-directed therapy for treatment of oligometastatic prostate cancer.
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http://dx.doi.org/10.1200/EDBK_200967DOI Listing
May 2018

DNA Damage Repair (DDR) Mutations and the Utility of High-Risk Genetics Clinics in Metastatic Castration-Refractory Prostate Cancer (mCRPC).

World J Oncol 2018 Aug 6;9(4):119-122. Epub 2018 Sep 6.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Germline pathogenic variants (PVs) in DNA-repair genes have garnered increasing attention in metastatic prostate cancer, and more patients are having somatic and germline DNA testing performed. Interpretation of germline DNA testing is a novel challenge for many clinicians, and the results of germline DNA-repair gene testing have significant implications for men with advanced prostate cancer and their children and siblings. Here, we report the case of a man with metastatic castration-refractory prostate cancer and a pathogenic, germline variant. We discuss the significance of his referral to a high-risk genetics clinic and the unique targeted therapy that he responded to.
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http://dx.doi.org/10.14740/wjon1144wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134990PMC
August 2018

Targeting Endoglin to Treat Metastatic Renal Cell Carcinoma: Lessons from Osler-Weber-Rendu Syndrome.

Oncologist 2019 02 23;24(2):143-145. Epub 2018 Aug 23.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

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http://dx.doi.org/10.1634/theoncologist.2018-0443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369955PMC
February 2019

Treatment of metastatic renal cell carcinoma in older patients: A network meta-analysis.

J Geriatr Oncol 2019 01 1;10(1):149-154. Epub 2018 Jun 1.

Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. Electronic address:

Introduction: More than half of patients diagnosed with renal cell carcinoma (RCC) are age 65 or older. However, older patients are often unable to meet eligibility criteria for clinical trial enrollment due to multiple factors, such as comorbidities and polypharmacy, which leads to under-representation of this population in clinical trials. Given this, efficacy data from the registration trials may not apply to older patients. Our objective was to evaluate the efficacy of first-line and salvage-line treatment in older patients, and compare efficacy between older and younger patients with metastatic RCC (mRCC).

Methods: Pivotal phase three clinical trials for first-line and salvage-line treatments were included if they reported overall survival (OS) or progression-free survival (PFS) results stratified by age (
Results: In the first-line setting, data suggests that Nivolumab plus Ipilimumab is the most efficacious treatment for older patients (PFS hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.23-1.45, probability best 39.7%). In the salvage-line setting, Cabozantinib is likely the most efficacious therapy for older patients (PFS HR 0.15, 95% CI 0.08-0.28, probability best 77.2%). Evidence suggests that the majority of first-line treatments have worse efficacy in older patients compared to younger patients.

Conclusion: For older patients, first-line Nivolumab plus Ipilimumab and salvage-line Cabozantinib may offer the best survival outcomes. Most first-line drugs for mRCC have inferior performance in older patients compared to their younger counterparts.
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http://dx.doi.org/10.1016/j.jgo.2018.05.010DOI Listing
January 2019