ASCO GU 2019 Bladder Cancer

ASCO GU 2019 Bladder Cancer

ASCO GU 2019: Phase II Trial of Pembrolizumab for Patients with High-Risk Non-Muscle Invasive Bladder Cancer Unresponsive to BCG

San Francisco, CA (UroToday.com) The primary management for non-muscle invasive bladder cancer is surgical resection via transurethral resection of bladder tumor (TURBT). Unfortunately, many patients will have disease recurrence or progression. According to the European Organization for Research and Treatment risk tables (EORTC), after a median follow up of 3.9 years, 47.8% had at least one recurrence with a median time to first recurrence of 2.7 years, and 11% of patients had progression to muscle-invasive disease.1 For low-risk patients, a single dose of intravesical chemotherapy or surveillance may be sufficient. However, for high-risk patients, first line intravesical Bacillus Calmette-Guerin (BCG) therapy is standard of care, as recommended by the American Urological Association (AUA), the European Association of Urology (EAU), and the Canadian Urological Association (CUA) bladder cancer guidelines.2-4

ASCO GU 2019: PIVOT-02 Study of NKTR-214 with Nivolumab in Metastatic Urothelial Carcinoma

San Francisco, CA (UroToday.com) Immune checkpoint inhibitors are approved both in the first line and second line for patients with metastatic urothelial carcinoma. In the first line, KEYNOTE 052 showed that pembrolizumab has significant anti-tumor activity for cisplatin ineligible patients with UC1, for a 38% objective response rate for patients with a combined positive score of 10% or more (PD-L1 positive). Further analysis last year found that the benefit to checkpoint inhibition in the first line was restricted to patients with a high PD-L1 expression, as defined by CPS≥10 or PD-L1 IC ≥5%. In the second line, KEYNOTE 045 improved median overall survival compared with chemo (10.3 v 7.4 months; HR, 0.70; P < 0.001)2.

ASCO GU 2019: Gemcitabine-Carboplatin versus Gemcitabine-Oxaliplatin In Cisplatin Un-Fit Advanced Urothelial Carcinoma: Randomized Phase II Study-COACH Study

San Francisco, CA (UroToday.com) The first line chemotherapy in advanced metastatic urothelial carcinoma is cisplatin-based. The two most accepted options are gemcitabine + cisplatin (GC) or Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC).  In patients who are unfit to receive cisplatin-based chemotherapy (approximately 30-50% of patients), the available options include gemcitabine and carboplatin, or immune checkpoint inhibitors such as pembrolizumab or atezolizumab for patients with high PD-L1 expression. Gemcitabine and carboplatin have been shown to harbor significant adverse events such as neutropenia (52.5%), thrombocytopenia (48.3%), febrile neutropenia (4.2%), grade 3 or 4 infections (11.8%), and severe acute toxicity (9.3%).1,2

ASCO GU 2019: CheckMate 9UT - Nivolumab or Nivo Plus BMS-986205 with or without Intravesical Bacillus Calmette-Guerin in BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer

San Francisco, CA (UroToday.com) Immune checkpoint inhibitors, including the anti-PD1 monoclonal antibody nivolumab, have demonstrated favorable tolerability and efficacy profiles, ushering a new treatment paradigm for advanced bladder cancer. Nivolumab has a meaningful clinical benefit in patients with advanced bladder cancer, whose disease progressed or recurred following treatment with platinum-based chemotherapy (objective response rate of 20%), and a manageable safety profile. However, an unmet need exits for new effective treatment options in an earlier stage of the disease, including patients with BCG-unresponsive, high risk- non-muscle invasive bladder cancer (NMIBC). 

ASCO GU 2019: POTOMAC Study - Durvalumab and BCG versus BCG Alone in High-risk, BCG-Naïve Non Muscle-Invasive Bladder Cancer

San Francisco, CA (UroToday.com) Urothelial carcinoma is the most common type of cancer of the bladder, urethra, and urachus, accounting for 90% of primary malignancies of the urinary tract. Standard treatment for patients with high-risk tumors is transurethral resection (TURBT) followed by intravesical BCG. Despite the efficacy of BCG, recurrence rates are as high as 50% in the first three years of follow-up and can be even higher for aggressive histologic subtypes.  Antitumor immune response has been shown with the targeting of the programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1). The response rates have shown to be doubled with immunotherapy targeting PD-1 and PD-L1 compared to standard chemotherapy.

ASCO GU 2019: Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer

San Francisco, CA (UroToday.com) Patients with high-risk muscle-invasive bladder cancer (MIBC) have a poor prognosis. Radical cystectomy remains the standard treatment for these patients. However, even though the surgical technique has been significantly refined and improved, mortality from metastatic recurrence after surgery remains considerably high. Many MIBC patients are ineligible for cisplatin-based chemotherapy (almost 50%) or have persistent MIBC despite neoadjuvant chemotherapy (NAC). Additional treatments are therefore needed for these patients. 

ASCO GU 2019: Ramucirumab Exposure-Response Relationship in RANGE: Trial in Advanced Platinum-Refractory Urothelial Carcinoma

San Francisco, CA (UroToday.com)  Patients with advanced or metastatic, platinum-refractory urothelial carcinoma (UC) have limited treatment options. RANGE is an international, randomized, double-blind, phase 3 trial that assessed the safety and efficacy of treatment with docetaxel plus either ramucirumab (RAM), a human IgG1 VEGFR-2 antagonist, or placebo. It was demonstrated that docetaxel plus RAM was associated with superior progression free survival (PFS) compared to docetaxel chemotherapy alone in platinum-refractory advanced UC, validating the VEGF-2 pathway as a therapeutic target in the treatment of such patients. The present study reports the exposure-response and overall survival relationships for RAM in the RANGE study. 

ASCO GU 2019: Pembrolizumab in Muscle-Invasive and Locally Advanced Urothelial Carcinoma - AMBASSADOR versus Observation

San Francisco, CA (UroToday.com) Patients with high-risk muscle-invasive bladder cancer (MIBC) have a poor prognosis. Adjuvant cisplatin-based neoadjuvant chemotherapy has been shown to improve survival, but a large number of these patients are resistant to chemotherapy and develop recurrent disease. Due to renal insufficiency, many patients are also not cisplatin-eligible.  Therefore, there is a need to develop additional treatment options.

ASCO GU 2019: A Phase III, Randomized, Open-label, Multicenter, Global Study of Durvalumab and BCG versus BCG Alone in High-risk, BCG-naïve Non-muscle-invasive Bladder Cancer Patients - POTOMAC

San Francisco, CA (UroToday.com) While the standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) is currently maximal transurethral resection of the bladder tumor (TURBT), followed by an induction course of BCG, recurrence rates can reach as high as 50% in this patient population. Because recurrence rates are high after induction BCG alone, the Dr. Maria De Santis from Charite University Hospital in Berlin, Germany, and her group sought to evaluate if combination anti-PD1 or anti-PDL-1 agents with BCG would lead to decreased recurrence rates and improved cancer-specific outcomes.

ASCO GU 2019: ATLAS: A Phase II Open-Label Study of Rucaparib in Patients with Locally Advanced or Metastatic Urothelial Carcinoma

San Francisco, CA (UroToday.com) In the Trials in Progress Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, Testicular, and Adrenal Cancers, at the Annual ASCO GU 2019 meeting in San Francisco, CA, Petros Grivas, MD, PhD presented ATLAS: A phase II open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma (mUC).

ASCO GU 2019: Perioperative Immunotherapy in Urothelial Carcinoma: State of Existing Evidence

San Francisco, CA (UroToday.com) During the general session on challenges and advances in perioperative and local therapy for urothelial carcinoma at the Annual ASCO GU 2019 meeting in San Francisco, CA, Dr. Necchi, a medical oncologist at Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy presented on updates in immunotherapy developments in adjuvant and neoadjuvant setting of muscle-invasive bladder cancer (MIBC). He started his talk by pointing out that pilot studies in NSCLC and melanoma have proven the safety and activity of short courses of preoperative immunotherapy. In MIBC, cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care (SoC) for MIBC, but the adherence to SoC is poor, selection criteria are based on clinical staging which is not accurate, and there are no good predictive biomarkers.

ASCO GU 2019: Updated Results of Keynote 057: Pembrolizumab for Patients with High-risk Nonmuscle Invasive Bladder Cancer Unresponsive to BCG

San Francisco, CA (UroToday.com) Dr. Arjun Balar presented updated results of the Keynote-057 trial of Pembrolizumab for high risk non-muscle invasive bladder cancer (NMIBC) patients who were unresponsive to Bacillus Calmette-Guerin (BCG) therapy. This was a single arm open-label phase 2 study.

First, an introduction and review of BCG unresponsive high-risk NMIBC. Adequate BCG therapy is defined as at least 5-6 instillations of induction BCG + at least 2 of 3 doses of maintenance therapy or 2 of 6 doses of a second induction course.

ASCO GU 2019: Randomized Phase III Trial of Adjuvant Sequential Chemotherapy plus Radiotherapy versus Adjuvant Radiotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy: Urothelial Carcinoma Subgroup Analysis.

San Francisco, CA (UroToday.com) For patients with muscle-invasive urothelial carcinoma, surgery may provide long term cure for up to 50% of patients. However, a substantial number of patients, especially those with locally advanced disease, will have disease recurrence and the five year overall survival for patients with tumor invasion beyond the bladder is 40%1. Thus, neoadjuvant chemotherapy is recommended for all patients who are willing and medically fit to receive chemotherapy. 

ASCO GU 2019: Sacituzumab Govitecan (IMMU-132) in Patients with Previously Treated Metastatic Urothelial Cancer

San Francisco, CA (UroToday.com) Sacituzumab govitecan (SG) is a humanized antibody-drug conjugate, made from anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.1 Trop-2 is transmembrane glycoprotein encoded by the Tacstd2 gene, and is differentially expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast, colonic, prostate, and lung cancer.2 In hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC), the overall response rate was 31% by local assessment, and the clinical benefit rate (PR+SD > 6 months) was 48%.3 In an early phase study with metastatic non-small cell lung cancer, 47 patients were treated and the objective response rate was 19% with a median response duration of 6.0 months.4

ASCO GU 2019: Challenges of Therapy in Upper-Tract Urothelial Carcinoma

San Francisco, CA (UroToday.com)  Dr. Matin, a Urologic Oncologist at The University of Texas MD Anderson Cancer Center, Houston, presented on challenges of therapy in upper-tract urothelial carcinoma (UTUC). He started his talk with current challenges in the management of UTUC which includes risk stratification, endoscopic management, renal dysfunction, neoadjuvant and adjuvant chemotherapy, and lymph node dissection.

ASCO GU 2019: Trimodality Therapy is the Best Option for Muscle-Invasive Bladder Cancer

San Francisco, CA (UroToday.com)  Dr. Jason Efstathiou provided the argument for trimodal therapy (TMT) for muscle-invasive bladder cancer (MIBC) during the Challenges and Advances in Perioperative and Local Therapy for Urothelial Carcinoma session at GU ASCO. Dr. Jeanny Aragon-Ching from the Inova Schar Cancer Institute started the debate by presenting a case of a 64-year-old healthy male who presented with hematuria and underwent a CT scan demonstrating a 4-cm tumor at the left posterior wall. There was no hydronephrosis and no clinical lymphadenopathy. The patient’s eGFR was 74 ml/min. Cystoscopy confirmed the tumor and no other mass was notable on examination under anesthesia. Complete transurethral resection of the bladder tumor achieved an R0 resection. The clinical pathology was T2 high-grade urothelial cancer with pathology showing carcinoma with squamous features.

ASCO GU 2019: Interim Analysis of Ibrutinib Plus Paclitaxel for Patients with Metastatic Urothelial Carcinoma Previously Treated with Platinum-Based Chemotherapy

San Francisco, CA (UroToday.com)  Patients with advanced urothelial carcinoma who progress on platinum-based chemotherapy generally have a poor prognosis and limited treatment options. Immunotherapy has recently moved into both the first and second line space1. However, the majority of patients do not respond to immune checkpoint inhibition. For example, in KEYNOTE-045, only 21% of patients had an objective response with pembrolizumab. The objective response rates for chemotherapy remain low – in that same study where the control group received investigators choice of chemotherapy which included paclitaxel, docetaxel, or vinflunine, the ORR was only 11.4%. Thus, there is an unmet need for additional therapies for patients who have progressed on platinum-based chemotherapy. 

ASCO GU 2019: Fierce-21: Phase II Study of Vofatamab, a Selective Inhibitor of FGFR3, as Salvage Therapy in Metastatic Urothelial Carcinoma

San Francisco, CA (UroToday.com)  Dr. Necchi presented the Fierce-21 phase 2 study of vofatamab, a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma. Patients with metastatic urothelial carcinoma who have failed platinum-based chemotherapy have a poor prognosis. Approximately 20% of these patients harbor fibroblast growth factor receptor 3 (FGFR3) mutations or fusions. FGFR3 alterations have been shown preclinically to be oncogenic drivers of bladder cancer. FGFR3 inhibitors are revolutionizing the clinical management of metastatic urothelial carcinoma in biomarker-selected and potentially poor immunoncology responding patients.  

ASCO GU 2019: Radical Cystectomy is the Best Option for Muscle-Invasive Bladder Cancer

San Francisco, CA (UroToday.com) The Challenges and Advances in Perioperative and Local Therapy for Urothelial Carcinoma session was highlighted by a debate regarding the optimal treatment of muscle-invasive bladder cancer. Dr. Jeanny Aragon-Ching from the Inova Schar Cancer Institute started the debate by presenting a case of a 64-year-old healthy male who presented with hematuria and underwent a CT scan demonstrating a 4-cm tumor at the left posterior wall. There was no hydronephrosis and no clinical lymphadenopathy. The patient’s eGFR was 74 ml/min. Cystoscopy confirmed the tumor and no other mass was notable on examination under anesthesia. Complete transurethral resection of the bladder tumor achieved an R0 resection. The clinical pathology was T2 high-grade urothelial cancer with pathology showing carcinoma with squamous features. At this point in the presentation, Dr. Aragon-Ching polled the audience, who overwhelmingly voted (73% vs 27% for trimodal therapy) that radical cystectomy was the best treatment of choice.

ASCO GU 2019: Multimodality Treatment in Challenging Cases of Urothelial Carcinoma: Case Panel Discussion

San Francisco, CA (UroToday.com) In this case panel discussion, 3 patient cases were reviewed highlighting important points in the management of bladder cancer. The text below includes a summary of each case presented and key points made by the panelists.

Case 1: Small Cell Bladder Cancer: 65-year-old man who presents feeling lethargic, 10 lb weight loss, poor appetite. He has microscopic hematuria. Cystoscopy and subsequent TURBT demonstrates small cell bladder cancer.