What You Need to Remember According to the Clinical Oncologist

Madrid, Spain (UroToday.com) Dr. James provided an oncologist’s perspective on several important highlights for clinical practice from major conferences in 2018. The age-standardized five-year survival for bladder cancer has not significantly changed in the last twenty years.1 This unfortunate stagnation requires the introduction of better drug therapies to improve outcomes, especially in the setting of muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer.

According to the European Association of Urology (EAU) guidelines, radical cystectomy is the standard of care for patients with MIBC. Cisplatin-based neoadjuvant chemotherapy should be offered to eligible patients only. The question of whether there is a role for neoadjuvant immunotherapy in MIBC is important and needs to be answered. The first two studies mentioned by Dr. James attempt to answer this question.

The two studies were the phase two study investigating the safety and efficacy of neoadjuvant atezolizumab in MIBC (ABACUS study)2, and the phase two PURE-01 study, which is the preoperative pembrolizumab before radical cystectomy for MIBC: interim clinical and biomarker finding.3. In the ABACUS trial MIBC patients with no positive nodes or metastases, who were not fit or were unwilling to receive neoadjuvant cisplatin chemotherapy, were given two cycles of 1200 mg of Atezolizumb and then underwent radical cystectomy. The primary endpoints included pathological complete response and increase in CD8 count. Secondary endpoints included safety and radiological response. Of 74 patients enrolled in the trial, nine patients (12.1%) had grade 3 or 4 complications induced by mepolizumab, and ten patients (13.5%) had surgical grade 3 or 4 complications, with one patient (1.3%) enduring treatment-related death. The pathological complete response rate was 40% for PD-L1 positive patients and 16% for PD-L1 negative patients. 

In the similar MIBC patients were given three cycles of Pembrolizumab 200 mg and then underwent radical cystectomy. The primary endpoint was identical, and the results demonstrated a 40% pathological complete response rate. Dr. James concluded from both these studies that neoadjuvant Atezolizumab and Pembrolizumab seem promising in this area of unmet need (30-40% pathological complete response), but long-term follow-up is needed.

Next, Dr. James discussed whether immune checkpoint inhibitor therapy is associated with cardiovascular adverse events. An exploratory observational study, assessing data from 59 prospective trials (with over 21,000 patients), including studies analyzing the immune checkpoint inhibitors: Atezolizumab, Avelumab, Durvalumab, Nivolumab, and Pembrolizumab, and their combinations as well. The study assessed the relative risk of a variety of cardiovascular endpoints including congestive heart failure, arrhythmia, myocarditis, vasculitis, bleeding, hypertension, sudden cardiac death, peripheral vascular disease, pericarditis, and ischemia. The relative risk of the immune combination therapy was quite high for each of these endpoints, ranging between 0.35-11.14, as seen in table 1.4 In summary, these data suggest that the combination of immune checkpoint inhibitor therapy is associated with an increased incidence of cardiovascular adverse effects, when compared to immune checkpoint inhibitor monotherapy.



Table 1- The relative risk of cardiovascular endpoints for monotherapy or combined immunotherapy

The next question discussed was whether there are emerging promising non-immunotherapy strategies in advanced urothelial carcinoma. The 1st study discussed was the: “First results from the primary analysis population of the phase two study of erdafitinib in patients with metastatic or unresectable urothelial carcinoma and FGFR alterations (BLC2001 study)”5

Another study discussed at the same session was the updated results from the enforumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer. The fibroblast growth factor receptor 3 (FGFR3) is an oncogene harboring mutation in 70% of patients with non-muscle invasive bladder cancer (NMIBC) and 40% of MIBC patients. In the BLC2001study metastatic or surgically unresectable urothelial carcinoma patients were screened for FGFR fusion mutations and then randomized to either 10 mg/d for seven days or 6 mg every day of erdafitinib, which is an FGFR inhibitor. The primary endpoint was objective response rate (ORR). The trial, which included 99 patients, demonstrated an ORR of 40.4% with a complete response rate of 3% and partial response in 37.4% of patients. The median time to response was 1.4 months, and no grade 4 or 5 complications were reported. 

The second discussed study (the EV-101) included metastatic urothelial carcinoma patients with a previous chemotherapy treatment or patients who were cisplatin ineligible. Enfortumab vedotin, is an antibody-drug conjugate designed for the treatment of cancer expressing Nectin-4, which is a cellular adhesion molecule involved in calcium independent cellular adhesion. This drug was given to patients on day 1,8, 15 and every 28 days during the study period. The ORR was 41%, the complete response was 4%, and partial response was 37%. Median time on therapy was 24 weeks, and 5% of patients had grade 5 complications. Dr. James concluded that both enrdafitinib and enforumab vedotin are well tolerated and show promising ORR in phase 1 and two studies of urothelial metastatic patients.

Dr. James concluded his talk and emphasized that the role of PD1 targeting keeps expanding - and trials with bladder preservation are warranted, to try to finally improve the stagnant survival rates.

Presented by: Nick James, The University of Warwick, London, UK

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the Global Conference on Bladder Cancer 2018 - September 20-21, 2018 Madrid, Spain 

References:

  1. Rafael MG et al. European Journal of Cancer 2015
  2. Powles TJ et al. J. Clin Oncol 2018; 36 (Suppl 15): abstract 4506
  3. Necchi A. J Clin Oncol 2018; 36(Suppl 15): abstract 4507
  4. Amiri-Kordestani L et al. ASCO 2018, abstract 3009 (data from poster included)
  5. Siefler-Radtke AO et al. J Clin Oncol 2018; 36 (Suppl 15): abstract 4503
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