Publications by authors named "Amishi Y Shah"

24 Publications

  • Page 1 of 1

The evolving treatment landscape of advanced urothelial carcinoma.

Curr Opin Oncol 2021 May;33(3):221-230

Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas.

Purpose Of Review: Bladder cancer is the 10th most common cancer in the world and the 6th most common cancer among men. In the past few years, several new agents have been approved for the treatment of urothelial tumors. In this paper, we review the evolving treatment landscape of advanced urothelial carcinoma (UC).

Recent Findings: Since 2016, the Food and Drug Administration (FDA) has approved five immunotherapies targeting programmed cell death 1/programmed cell death 1 legend, an antinectin-4 antibody drug conjugate (ADC), and a fibroblast growth factor receptor (FGFR) inhibitor for the treatment of patients with advanced UC. Moreover, there are multiple targeted agents, immune checkpoint inhibitors (ICI), ADCs, and their combinations currently being tested in clinical studies with the goal of obtaining FDA approval.

Summary: Precision oncology efforts continue to advance our understanding of the UC biology and transform the existing treatment paradigms. An enlarging arsenal of treatment options promises further personalization of UC therapy.
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http://dx.doi.org/10.1097/CCO.0000000000000722DOI Listing
May 2021

Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.

Oncologist 2021 Mar 31. Epub 2021 Mar 31.

Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.

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-TKI), but limited data exist on the efficacy of Len +/- Eve after progression on immune checkpoint inhibitors (ICI) and VEGFR-TKI.

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 v1.1. Descriptive statistics and the Kaplan-Meier method were used.

Results: 55 patients were included in the analysis. 81.8% had clear-cell histology (ccRCC) and 76.4% had IMDC intermediate-risk disease. Median number of prior therapies was 4 (range, 2-10); all patients had prior ICI and VEGFR-TKI, and 80% were previously treated with ICI and ≥2 VEGFR-TKI, 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% 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.

Conclusions: Len +/- Eve demonstrated meaningful clinical activity and tolerability in heavily pre-treated patients with mRCC after disease progression with prior ICI and VEGFR-TKI.
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http://dx.doi.org/10.1002/onco.13770DOI Listing
March 2021

Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction.

Front Oncol 2021 4;11:621591. Epub 2021 Mar 4.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology.
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http://dx.doi.org/10.3389/fonc.2021.621591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970171PMC
March 2021

Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.

Int J Cancer 2021 Mar 19. Epub 2021 Mar 19.

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

Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.
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http://dx.doi.org/10.1002/ijc.33560DOI Listing
March 2021

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
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http://dx.doi.org/10.1056/NEJMoa2026982DOI Listing
March 2021

A Durable Response With the Combination of Nivolumab and Cabozantinib in a Patient With Metastatic Paraganglioma: A Case Report and Review of the Current Literature.

Front Endocrinol (Lausanne) 2020 27;11:594264. Epub 2020 Nov 27.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Introduction: Pheochromocytomas and sympathetic paragangliomas (PPGL) are neuroendocrine catecholamine-secreting tumors that are usually localized. Metastatic disease is rare and systemic treatment consists of conventional chemotherapy and high-specific-activity iodine-131-MIBG which was approved by the FDA in 2018. Although chemotherapy combinations still have value in specific settings, the debilitating side effects of treatment with only modest benefit have limited their use. With the introduction of a new generation of targeted therapy and immunotherapy patients with metastatic PPGL may have improved therapeutic options.

Areas Covered: The current paper presents a case of a patient with metastatic PPGL who received multiple lines of systemic treatment. Despite progression on previous single agent cabozantinib and single agent pembrolizumab on separate clinical trials, the patient has exhibited a major response to the combination of cabozantinib and nivolumab for the past 22 months. In addition, we will review the available therapies for metastatic PPGL and discuss novel agents under clinical development.

Conclusion: Newer targeted therapies and immunotherapy options are under clinical development with promising results for patients with PPGL.
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http://dx.doi.org/10.3389/fendo.2020.594264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731902PMC
November 2020

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

Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.

J Natl Compr Canc Netw 2020 Dec 14:1-9. Epub 2020 Dec 14.

2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes.

Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis.

Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018).

Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.
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http://dx.doi.org/10.6004/jnccn.2020.7647DOI Listing
December 2020

Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies.

Cancer 2021 Mar 20;127(6):840-849. Epub 2020 Nov 20.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616).

Methods: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1).

Results: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related.

Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing.

Lay Summary: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.
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http://dx.doi.org/10.1002/cncr.33328DOI Listing
March 2021

Outcomes of patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation to immune checkpoint inhibitors.

Urol Oncol 2021 02 10;39(2):134.e9-134.e16. Epub 2020 Nov 10.

The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Introduction: Metastatic renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with poor survival outcomes. We aimed to analyze the efficacy and safety of immune checkpoint inhibitors (ICI) in patients with sRCC comparing clear-cell (sccRCC) to non-clear cell epithelial histology (snccRCC).

Methods: We performed retrospective analysis of sRCC patients who received ICI at MD Anderson Cancer Center (n = 48, 41 with ccRCC and 7 with nccRCC) to determine the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, we performed a prespecified multivariable Cox regression comparing survival outcomes between sccRCC and snccRCC.

Results: The ORR for the entire cohort was 35.4% (95% confidence interval [CI]: 23.4%, 49.6%), including 8 (16.7%) patients (95% CI: 8.7%, 29.6%) who achieved a complete remission. The disease control rate was 52% (95% CI: 38.3%, 65.5%). In patients with sccRCC, the ORR was 39% (95% CI: 25.7%, 54.3%) and disease control rate 58.5% (43.4%, 72.2%). Among 7 snccRCC patients, only one (14.3%) achieved an objective partial response. At a median follow-up of 51.1 months, the median PFS was 4.9 months (95% CI: 2.7, 16.3) and the median OS was 28.4 months (95% CI: 15.8, NA) for the entire cohort. For patients with sccRCC, the median PFS was 8.9 months, with median OS of 30.1 months, compared with median PFS of 2.3 months (HR 0.25 [95% CI: 0.08, 0.78]; P= 0.0145) and median OS of 6.7 months (HR 0.13 [95% CI 0.04, 0.44]; P=0.0009) for patients with snccRCC.

Conclusion: ICIs appear to be effective in sccRCC while the treatment of snccRCC remains challenging.
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http://dx.doi.org/10.1016/j.urolonc.2020.10.019DOI Listing
February 2021

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.

Nat Med 2020 12 12;26(12):1845-1851. Epub 2020 Oct 12.

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

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.
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http://dx.doi.org/10.1038/s41591-020-1086-yDOI Listing
December 2020

Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors.

Eur Urol Oncol 2021 Feb 28;4(1):102-111. Epub 2019 Nov 28.

University of Calgary, Calgary, Canada. Electronic address:

Background: Immuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied.

Objective: To describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy.

Design, Setting, And Participants: A retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation.

Intervention: Patients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs).

Outcome Measurements And Statistical Analysis: Outcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group.

Results And Limitations: Among 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30-0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs.

Conclusions: Targeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy.

Patient Summary: Patients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment.
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http://dx.doi.org/10.1016/j.euo.2019.11.001DOI Listing
February 2021

Real-World Experience With Cabozantinib in Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis.

J Adv Pract Oncol 2019 May-Jun;10(4):333-339. Epub 2019 Mar 1.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cabozantinib inhibits tyrosine kinase activity at the MET, AXL, and VEGF receptors and is approved for front-line therapy in metastatic clear cell renal cell carcinoma. Little off-protocol data exist on tolerability and response. The objective of this retrospective study was to assess off-protocol tolerability and response rates in patients with metastatic clear cell renal cell carcinoma being treated with cabozantinib. Data on baseline disease characteristics and treatment details were retrospectively gathered for patients with metastatic clear cell renal cell carcinoma treated with cabozantinib at The University of Texas MD Anderson Cancer Center from 2015 to 2017. A blinded radiologist determined the best response according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Descriptive statistics were utilized. Cabozantinib has a high disease control rate (92%), even as a late line of therapy in metastatic clear cell renal cell carcinoma. However, careful monitoring is warranted, as many patients require treatment breaks and dose reductions for therapy-related toxicity.
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http://dx.doi.org/10.6004/jadpro.2019.10.4.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520741PMC
March 2019

Current and Future Landscape of Immune Checkpoint Inhibitors in Urothelial Cancer.

Oncology (Williston Park) 2019 Jan;33(1):11-8

Immune checkpoint inhibitors have revolutionized the field of oncology, providing a novel mechanism for anticancer therapy. Programmed death 1-targeting antibodies pembrolizumab and nivolumab and programmed death ligand 1 (PD-L1)-targeting antibodies atezolizumab, durvalumab, and avelumab have been approved for use in advanced urothelial cancer in the post-platinum setting or in the upfront setting in platinum-ineligible patients. While this represents a significant step forward in management of urothelial cancers, most patients do not have an objective response to these therapies. PD-L1 expression is not a consistently predictive biomarker, but is recommended for checkpoint utilization in select circumstances. We report here a summary of known data and the differences between these agents, as well as future avenues to explore with immuno-oncologic agents in urothelial cancer. Much work is ongoing to better understand resistance mechanisms, to maximize efficacy with combination strategies, to find improved predictive biomarkers, to assess curative-intent strategies, and to better manage toxicity with these agents.
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January 2019

Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis.

Eur J Cancer 2018 11 28;104:188-194. Epub 2018 Oct 28.

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

Background: Cabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC).

Methods: This is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1.

Results: With a median follow-up of 20.6 months (95% confidence interval [CI]: 11.4-28.8), median PFS was 8.6 months (95% CI: 6.1-14.7), and median OS was 25.4 months (95% CI: 15.5-35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity.

Conclusion: In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.
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http://dx.doi.org/10.1016/j.ejca.2018.08.014DOI Listing
November 2018

Survival Rates and Health Care Costs for Patients With Advanced Bladder Cancer Treated and Untreated With Chemotherapy.

Clin Genitourin Cancer 2018 08 27;16(4):e909-e917. Epub 2018 Mar 27.

Division of Surgery, Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Systemic chemotherapy has long been the standard of care for advanced bladder cancer, but its cost implications are poorly understood. The objective of this analysis was to estimate survival and health care costs for patients with stage IV bladder cancer who did or did not receive chemotherapy.

Patients And Methods: This was a retrospective cohort study of patients identified in the Surveillance, Epidemiology, and End Results-Medicare database with a new primary diagnosis of stage IV bladder cancer between January 2007 and December 2011. Survival and health care visits and costs following the date of diagnosis were determined for treated and untreated patients. Costs were expressed in 2016 US dollars.

Results: A total of 1215 patients were diagnosed with stage IV bladder cancer, of whom 411 (33.8%) were treated with chemotherapy and 804 (66.2%) were untreated. Median overall survival was 10 months longer for treated than for untreated patients: 13.2 (95% confidence interval, 12.3-14.1) months versus 3.2 (95% confidence interval, 3.0-3.5) months. Treated patients had fewer per-patient-per-month (PPPM) health care visits than untreated patients (7.5 vs. 10.2, P < .01) and lower total PPPM health care costs ($10,707 vs. $18,935). Overall mean total lifetime costs were greater for treated than for untreated patients ($139,893 vs. $66,829, P < .05), which was driven by an approximate 4-fold increase in life expectancy for the treated patients.

Conclusion: Approximately two thirds of patients diagnosed with stage IV bladder cancer were not treated with systemic chemotherapy. Increasing the percentage of treated patients in this population could potentially extend overall survival while simultaneously lowering PPPM costs.
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http://dx.doi.org/10.1016/j.clgc.2018.03.002DOI Listing
August 2018

Five new therapies or just one new treatment? A critical look at immune checkpoint inhibition in urothelial cancer.

Immunotherapy 2017 09;9(10):781-784

Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, 1515 Holcombe, Unit 1374, Houston, TX 77030, USA.

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http://dx.doi.org/10.2217/imt-2017-0073DOI Listing
September 2017

Phase 2 Trial of Capecitabine, Gemcitabine, and Bevacizumab in Sarcomatoid Renal-Cell Carcinoma.

Clin Genitourin Cancer 2017 Aug 10. Epub 2017 Aug 10.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Patients with sarcomatoid renal-cell carcinomas (sRCC) have poor outcomes and limited treatment options. Preclinical and clinical data suggest susceptibility to cytotoxic agents and vascular endothelial growth factor-targeted therapies. We designed a phase 2 trial to evaluate the efficacy and safety of capecitabine, gemcitabine, and bevacizumab in sRCC.

Patients And Methods: Patients with metastatic or unresectable sRCC were eligible for inclusion. Patients received oral capecitabine 800 mg/m twice daily on days 1 to 21 of a 28-day cycle, intravenous gemcitabine 900 mg/m on days 1 and 15, and intravenous bevacizumab 10 mg/kg on days 1 and 15. Primary end points were progression-free survival and time to treatment failure (TTF). Secondary end points were safety, objective response rate, and overall survival.

Results: Thirty-four patients were enrolled onto the trial. One patient was excluded from survival analysis and 4 from response analysis as a result of missing data. Median progression-free survival was 5.5 months (95% confidence interval [CI], 3.4-7.7), median TTF was 4.2 months (95% CI, 2.4-6.0), and median overall survival was 12 months (95% CI, 10.6-13.4). Objective response rate was 20% (5 partial responses, 1 complete response), and disease control rate was 73%. Thirty-one (91%) of the 34 patients discontinued treatment. The most common reason for treatment discontinuation was progressive disease, which occurred in 24 patients (71%). The most common grade 3 toxicity was rash (including hand-foot syndrome) in 24% patients.

Conclusion: The combination of capecitabine, gemcitabine, and bevacizumab is an option for patients with sRCC; however, response rates are low. Novel therapies are needed to improve outcomes in patients with sRCC.
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http://dx.doi.org/10.1016/j.clgc.2017.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809227PMC
August 2017

Editorial Comment.

Urology 2017 11 1;109:132. Epub 2017 Sep 1.

The University of Texas, MD Anderson Cancer Center, Austin, TX.

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http://dx.doi.org/10.1016/j.urology.2017.06.049DOI Listing
November 2017

Non-clear cell renal cell carcinomas: biological insights and therapeutic challenges and opportunities.

Clin Adv Hematol Oncol 2017 May;15(5):409-418

University of Texas MD Anderson Cancer Center, Houston, Texas.

The non-clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare-variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next-generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes. Both of these trials compared everolimus with sunitinib and provided evidence suggesting that frontline sunitinib is superior to everolimus in terms of progression-free survival. Renal medullary and collecting duct carcinomas do not respond to targeted agents, supporting the use of platinum-based chemotherapy as frontline therapy. Clinical evidence is currently emerging on the efficacy of c-MET inhibitors in patients with papillary type 1 RCC harboring germline mutations. Data on the activity of immune checkpoint inhibitors in this setting are lacking; however, several trials are ongoing in this space. The management of patients with nccRCC likely will improve in the future with histology-driven trials, which may pave the way for personalized therapies based on the molecular characterization of these orphan kidney cancer subtypes. Efforts must also be made to establish in vitro and animal models for testing hypotheses generated through extensive genomic analysis. Ultimately, collaborative national and international studies are urgently needed to improve therapeutic strategies in patients with metastatic disease.
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May 2017

Optimizing management of upper tract urothelial carcinoma.

Urol Oncol 2017 07 1;35(7):492-498. Epub 2017 Jun 1.

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

Upper tract urothelial cancer (UTUC) is a rare cancer of the urothelium, comprising only a fraction of cases as compared to urothelial tumors of the bladder. As a result, systemic treatment approaches in bladder cancer are often applied to patients with UTUC. Given the anatomical location of these tumors, the age, the comorbid conditions of these patients with UTUC, and the need for radical nephroureterectomy for treatment, most patients have substantial impairment of renal reserve. There is growing evidence for the benefit of perioperative chemotherapy in this disease. Patients with UTUC have high rates of microsatellite instability and fibroblast growth factor receptor 3 mutations as compared to their bladder counterparts presenting unique, important subsets in UTUC. Immune checkpoint inhibitors targeting the programmed death receptor 1 and ligand have provided a new second-line treatment option for patients with UTUC and appear particularly well suited for patients with microsatellite instability. More work in understanding the molecular gene signatures and its relationship to response to chemotherapy, immunotherapy, and targeted therapy is needed to continually optimize care for patients with all stages of disease. Advances in UTUC are possible, when one accounts for the unique clinical and biological features of this disease.
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http://dx.doi.org/10.1016/j.urolonc.2017.05.009DOI Listing
July 2017

Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study.

BJU Int 2017 12 9;120(6):782-792. Epub 2016 Dec 9.

MD Anderson Cancer Center, Houston, TX, USA.

Objective: To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS).

Patients And Methods: RMC is a rare and aggressive malignancy that afflicts young patients with sickle cell trait; there are limited data on management to date. This is a study of patients with RMC who were treated in 2000-2015 at eight academic institutions in North America and France. The Kaplan-Meier method was used to estimate OS, measured from initial RMC diagnosis to date of death. Cox regression analysis was used to determine predictors of OS.

Results: In all, 52 patients (37 males) were identified. The median (range) age at diagnosis was 28 (9-48) years and 49 patients (94%) had stage III/IV. The median OS for all patients was 13.0 months and 38 patients (75%) had nephrectomy. Patients who underwent nephrectomy had superior OS compared to patients who were treated with systemic therapy only (median OS 16.4 vs 7.0 months, P < 0.001). In all, 45 patients received chemotherapy and 13 (29%) had an objective response; 28 patients received targeted therapies, with 8-week median therapy duration and no objective responses. Only seven patients (13%) survived for >24 months.

Conclusions: RMC carries a poor prognosis. Chemotherapy provides palliation and remains the mainstay of therapy, but <20% of patients survive for >24 months, underscoring the need to develop more effective therapy for this rare tumour. In this study, nephrectomy was associated with improved OS.
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http://dx.doi.org/10.1111/bju.13705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857178PMC
December 2017

Clinical and pathological complete remission in a patient with metastatic renal cell carcinoma (mRCC) treated with sunitinib: Is mRCC curable with targeted therapy?

Urol Case Rep 2015 Mar;3(2):18-20

MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1374; Houston, TX 77030.

We report a patient with metastatic clear-cell renal cell carcinoma (mRCC) who presented with primary tumor in situ in the left kidney and metastases to bone, liver, lungs, and brain. After over 5 years of sunitinib therapy and subsequent cytoreductive left nephrectomy, the patient achieved radiographic complete response (CR) and had pathologic CR in the nephrectomy specimen. Durable clinical and pathological CRs are possible with targeted agents, even with primary tumor in situ and widely disseminated metastases. Ongoing research will define the optimal duration of systemic therapy in exceptional responders and identify the molecular determinants of response and resistance.
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http://dx.doi.org/10.1016/j.eucr.2014.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477704PMC
March 2015

Actinic cheilitis: a treatment review.

Int J Dermatol 2010 Nov;49(11):1225-34

Department of Dermatology, Baylor College of Medicine, Houston, TX 77005, USA.

All other factors being equal, the presence of actinic cheilitis, a pre-invasive malignant lesion of the lips, doubles the risk of squamous cell carcinoma developing in this anatomic area. Various forms of local ablation,immunomodulation and surgical extirpation have been proposed as therapeutic interventions. This paper critically evaluates the available medical literature to highlight the evidence-based strength of each recommended therapy for actinic cheilitis. Vermilionectomy remains the gold standard for efficacy; trichloroacetic acid application is easy and convenient, but the least efficacious overall.
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http://dx.doi.org/10.1111/j.1365-4632.2010.04580.xDOI Listing
November 2010