Austin Poole

Systemic Immunotherapy for Urothelial Cancer: Current Trends and Future Directions

Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for first-line platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.

Independent Validation of Effect of HSD3B1 Genotype on Response to Androgen-Deprivation Therapy in Prostate Cancer

Independent Validation of Effect of HSD3B1 Genotype on Response to Androgen-Deprivation Therapy in Prostate Cancer Substantial advances have been made in the development of therapeutic biomarkers in various cancers, but not in prostate cancer. A germline inherited polymorphic variant (1245A→C) in the HSD3B1 gene was recently reported to correlate with shorter duration of response to androgendeprivation therapy (ADT) in hormone-sensitive prostate cancer (HSPC).1 The HSD3B1 gene encodes the enzyme 3βhydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen.2,3 In the study by Hearn et al,1 presence of 1 or more variant alleles of the HSD3B1 (1245C) was associated with decreased progression-free survival (PFS) compared with the absence of any variant alleles in 3 cohorts of men with prostate cancer treated with ADT: 2 cohorts with post-prostatectomy biochemical recurrence, and 1 cohort with metastatic HSPC (mHSPC) (total, n = 443). In the present analysis, we provide, to our knowledge, the first independent validation of these results, which have the potential to introduce the first predictive biomarker of response to therapy for this patient population.

Cisplatin-Based First-Line Therapy for Advanced Urothelial Carcinoma After Previous Perioperative Cisplatin-Based Therapy

BACKGROUND Outcomes with cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based chemotherapy are unclear. In this study we evaluated outcomes with a focus on the effect of time from previous cisplatin-based perioperative chemotherapy. PATIENTS AND METHODS Data were collected for patients who received cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based therapy. Cox proportional hazards models were used to investigate the prognostic ability of visceral metastasis, ECOG PS, TFPC, anemia, leukocytosis, and albumin on overall survival (OS). RESULTS Data were available for 41 patients from 8 institutions including 31 men (75.6%). The median age was 61 (range, 41-77) years, most received gemcitabine plus cisplatin (n = 26; 63.4%), and the median number of cycles was 4 (range, 1-8). The median OS was 68 weeks (95% confidence interval [CI], 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic effect on OS for PS > 0 versus 0 (hazard ratio [HR], 4.56 [95% CI, 1.66-12.52]; P = .003) and TFPC ≥ 78 weeks versus < 78 weeks (HR, 0.48 [95% CI, 0.21-1.07]; P = .072). The prognostic model for OS was internally validated with c-index = 0.68. Patients with TFPC < 52 weeks, 52 to 104 weeks, and ≥ 104 weeks had median survival of 42, 70, and 162 weeks, respectively. CONCLUSION Longer TFPC ≥ 78 weeks and ECOG PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC after previous perioperative cisplatin-based chemotherapy. The data support using TFPC ≥ 52 weeks to rechallenge with cisplatin-based first-line chemotherapy for metastatic disease.

Phase Ib/II Trial of Gemcitabine, Cisplatin, and Lenalidomide as First-Line Therapy in Patients With Metastatic Urothelial Carcinoma

BACKGROUND Outcomes with current chemotherapy in metastatic urothelial carcinoma (MUC) remain poor. Lenalidomide, an antiangiogenic and immunomodulatory agent, enhances the effects of chemotherapy in preclinical studies. In this phase Ib/II study, we sought to determine a tolerable dose of lenalidomide in combination with gemcitabine and cisplatin (GCL) in patients with MUC and to explore the safety and activity of this regimen. METHODS Patients with chemotherapy-naïve MUC received gemcitabine 1,000 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 every 21 days. In phase Ib, there were four planned escalating dose levels of lenalidomide (10, 15, 20, and 25 mg) daily on days 1-14. RESULTS Seven patients received GCL in phase Ib. The dose of lenalidomide was not escalated beyond 10 mg because of cytopenias requiring repeated dose delays and reductions. Two additional patients were enrolled in phase II, but the study was ultimately terminated due to poor tolerability and slow accrual. The most frequent grade ≥ 3 adverse events were cytopenias and diarrhea. Three of the nine patients experienced an objective response (one complete response, two partial responses). CONCLUSION Chronic administration of the GCL regimen was poorly tolerated because of additive and cumulative myelosuppression.

Incidence and Characterization of Antiandrogen Withdrawal Syndrome After Discontinuation of Treatment With Enzalutamide in Castration-resistant Prostate Cancer

Background Antiandrogen withdrawal syndrome (AAWS), manifested as a prostate‐specific antigen (PSA) decline after discontinuation of a first‐generation antiandrogen has been well characterized. The objective of the present study was to assess the incidence of AAWS with enzalutamide in men with metastatic castration‐resistant prostate cancer. Patients and Methods Patients from a single‐institution cohort with metastatic castration‐resistant prostate cancer who had discontinued enzalutamide after PSA or radiographic progression were included. AAWS after enzalutamide was defined as any PSA decline after discontinuation of enzalutamide. The baseline patient, disease, and treatment characteristics were compared between patients with and without AAWS after enzalutamide. Statistical analysis of the baseline characteristics included descriptive statistics using the Wilcoxon rank sum test and the Fisher exact test. The median duration of enzalutamide therapy was compared using the log‐rank test, and the progression‐free survival of the patients with AAWS was evaluated using the Kaplan‐Meier method. Results Of 47 eligible patients, 5 experienced AAWS after enzalutamide discontinuation. The PSA response in these 5 patients was 84%, 32%, 17%, 15%, and 15%. The median AAWS response time until subsequent PSA progression was 3.3 months. No patient, disease, or treatment characteristics differed among the patients with and without AAWS after enzalutamide discontinuation. Conclusion To the best of our knowledge, this is the largest reported cohort documenting the incidence and characterization of AAWS after enzalutamide to date. The AAWS frequency after enzalutamide was low and of short duration. No patient‐ or disease‐related characteristics were associated with AAWS with enzalutamide. The occurrence of AAWS after enzalutamide was not clinically meaningful. Thus, accounting for this phenomenon in clinical practice or trial designs could be unnecessary. Micro‐Abstract Antiandrogen withdrawal syndrome (AAWS) is a well‐reported phenomenon with first‐generation antiandrogens. AAWS is a less well‐defined phenomenon with the antiandrogen enzalutamide. The present retrospective evaluation of men with progression during enzalutamide therapy failed to demonstrate a clinically significant incidence of enzalutamide withdrawal. These findings argue against the need to account for AAWS with enzalutamide in clinical trial designs.

Survival Outcomes and Tumor IMP3 Expression in Patients with Sarcomatoid Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy (n = 19), immunotherapy (n = 4), cytotoxic chemotherapy (n = 1), and no treatment (n = 3). Median OS was 8.2 months (95% CI 3.8–14.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant (IMP3 negative 14.2 versus IMP3 positive 4.9 months; HR 0.46, 95% CI 0.16–1.21; P = 0.12). The study was limited by small sample size.

Effect of treatment dose reductions in the setting of hand-foot syndrome on survival outcomes in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor receptor inhibitors

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.

Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer

Micro‐Abstract The HSD3B1 (1245C) variant is predictive of response to ADT in castration sensitive prostate cancer (CSPC) and to ketoconazole in castration resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant would be predictive of response to abiraterone acetate (AA). In 76 men with metastatic CRPC, the HSD3B1 (1245C) variant was not predictive of response to first‐line AA. Background: The HSD3B1 gene encodes the enzyme 3&bgr;‐hydroxysteroid dehydrogenase‐1 (3&bgr;HSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration‐sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration‐resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression‐free survival in first‐line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression‐free survival on AA. Results: Seventy‐six men with metastatic CRPC treated with first‐line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first‐line AA. Conclusion: The HSD3B1 (1245C) variant does not predict response to first‐line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3‐keto‐5&agr;‐abiraterone) and antagonist (&Dgr;4‐abiraterone) on androgen signaling.

Rapid onset of hemophagocytic lymphohistiocytosis in a patient with refractory chronic lymphocytic leukemia treated with ibrutinib

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life threatening disorder characterized by excessive immune activation with resulting tissue injury [1]. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that has been approved for treatment of chronic lymphocytic leukemia (CLL) in both the front line and relapsed settings [2]. We report a case of a patient with CLL who died after developing rapid onset multiorgan failure after the initiation of ibrutinib secondary to HLH. The patient was a 54-year-old male diagnosed with CLL at age 40. Diagnosis was characterized by Rai stage 1 disease with symptomatic bulky abdominal lymphadenopathy. He lacked a history of splenomegaly, frequent infections or peripheral blood cytopenias. Prognostic evaluation demonstrated zap70 positivity, immunoglobulin heavy chain variable (IGHV) unmutated status and 11q22 deletion by peripheral blood fluorescent in situ hybridization (FISH). By age 47, he required initiation of treatment due to autoimmune hemolytic anemia and symptomatic abdominal lymphadenopathy. First line therapy consisted of six cycles of immunochemotherapy (R-CVP) leading to a partial response in 2008. Following his partial response, he was observed for five years of active therapy. In February 2013, progression was, yet again, demonstrated in the form of increased abdominal adenopathy: necessitating treatment with three cycles of bendamustine and rituximab (BR) with a resulting partial response. Given on-going symptoms, he was subsequently started on ibrutinib 420mg daily in December of 2014. Two days into therapy, he developed febrile neutropenia and a lower extremity deep vein thrombosis and ibrutinib was discontinued. An attempt was made to retreat the patient with BR in July 2015, however, no response was observed after three cycles. This led to a re-initiation of ibrutinib 420mg daily in November 2015. Five days into treatment, the patient noticed yellowing of the skin and sclera which progressively worsened. He was seen for a scheduled toxicity check on day 10 post ibrutinib therapy which revealed markedly abnormal liver function tests with a total bilirubin of 15.4mg/dL, aspartate transaminase (AST) of 1757U/L, alanine transaminase (ALT) of 2302U/L and alkaline phosphatase (ALP) 661mg/dL. A complete blood count demonstrated new onset grade III thrombocytopenia with a platelet count of 40,000/uL (Table 1). Viral serologies for hepatitis A, B, C as well as Epstein–Barr virus (EBV) were negative. EBV, hepatitis B and C DNA of the blood by polymerase chain reaction were also sent and were undetectable. An abdominal ultrasound failed to demonstrate any biliary pathology. Biopsy of his abdominal lymph node conglomerate confirmed CLL without evidence of Richter’s transformation. Autoimmune hepatitis panel including antinuclear antibody (ANA), anti-mitochondrial and antismooth muscle antibodies were negative. Serum ceruloplasmin level was normal at 29mg/dL while serum ferritin was elevated at 3264 ng/mL. In the context of the above findings, a liver biopsy was performed which showed acute fulminant hepatitis with necrosis along with extensive lymphocytic infiltration of the liver parenchyma with admixed eosinophils. The pathologic differential diagnosis included fulminant drug reaction versus acute viral hepatitis. Given the suspicion for drug-induced hepatitis, ibrutinib was discontinued and the patient was started on 1mg/kg of prednisone. Despite ibrutinib cessation and the addition of high dose steroids, the patient’s clinical condition continued to deteriorate requiring hospitalization at our institution for consideration of liver transplantation. Laboratory studies on admission, day 30 postibrutinib, revealed acute kidney injury and fulminant liver failure (Table 1). In the absence of a clear etiology for his liver failure, evaluation for HLH was initiated and steroids were continued. Ferritin returned at 12,485 ng/mL and fibrinogen was 111mg/dL. Soluble interleukin-2 (IL-2) receptor was increased at 4810 pg/mL. Unfortunately, the patient rapidly deteriorated and died due to HLH with acute liver failure and hepatorenal syndrome. Autopsy revealed involvement of CLL in the bone marrow, liver, and lymph nodes. In addition, extensive erythrophagocytosis was evident in the lymph nodes and bone marrow along with extensive hepatic central necrosis

867POUTCOMES WITH CISPLATIN-BASED FIRST-LINE THERAPY FOR ADVANCED UROTHELIAL CARCINOMA (UC) FOLLOWING PREVIOUS PERIOPERATIVE CISPLATIN-BASED THERAPY

ABSTRACT Aim: Outcomes with cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based chemotherapy are unclear. We conducted a retrospective study to evaluate outcomes and identify a threshold of time from prior cisplatin-based perioperative chemotherapy (TFPC) when repeating cisplatin-based chemotherapy may not be justified. Methods: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based therapy. The Kaplan-Meier method was used to estimate survival. Cox proportional hazards models were used to investigate the prognostic ability of variables on overall survival (OS). The multivariable model included patients with complete data for the all factors (visceral metastasis, ECOG performance status [PS], TFPC, anemia, leukocytosis, albumin). All tests and confidence intervals were two-sided and at p = 0.05 level of significance. Results: Individual level data for 40 patients from 8 institutions were obtained. The study included 33 men (77.5%), the median age was 61 years (range 41 to 71), the majority received gemcitabine plus cisplatin (N = 25, 62.5%) and the median number of cycles was 4 (range 1-8). The median OS was 70 weeks (95% CI: 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic impact on OS for PS >0 vs. 0 (HR 4.34 [1.52-12.36], p = 0.006) and TFPC ≥1.5 years vs. Conclusions: Longer TFPC ≥1.5 years and ECOG-PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC following prior perioperative cisplatin-based chemotherapy. The present analysis supports employing >1 year from prior perioperative cisplatin-based chemotherapy to re-challenge with cisplatin-based first-line chemotherapy for metastatic disease. Disclosure: All authors have declared no conflicts of interest.