Over the last decade, the accelerated pace of understanding and drug development for advanced genitourinary malignancies, together with positive clinical trials, has led to a significant evolution in oncologic practice. This development is perhaps best illustrated by the current treatment paradigm for patients with metastatic renal cell carcinoma (mRCC), where application of targeted agents inhibiting vascular endothelial growth factor and mammalian target of rapamycin pathways are most commonly used. In the last few years, the focus has shifted to immuno-oncology, which is one of the hottest fields, and the current and future role of immunotherapy in the treatment of urologic cancers appears promising.
This month’s column summarizes recent data for immune-based agents across the major organ sites.
Immunotherapy in urologic oncology
Harnessing the immune system has a long history in the treatment of urologic cancers. Since the first report by Morales and colleagues in 1976, the intravesical instillation of Bacillus Calmette-Guérin (BCG) has become the mainstay of adjuvant treatment for non-muscle invasive bladder cancers after endoscopic resection.1 BCG remains the standard of care in reducing risks of cancer recurrence and progression, even when compared with other intravesical agents.
Until the previously mentioned targeted agents were introduced, the management of mRCC relied on immune activation with cytokines, such as interferon and interleukin-2 (IL-2). Even today, high-dose IL-2 plays a role in treatment, with a partial or complete response in up to 15 percent of selected patients.2 In April 2010, the U.S. Food and Drug Administration (FDA) approved sipuleucel-T, first in class as a therapeutic autologous vaccine, for the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). The treatment is a cell-based immunostimulant where a patient’s antigen-presenting cells (primarily dendritic) are extracted via leukapheresis, incubated with a prostate acid phosphatase and GM-CSF fusion protein, and then infused back into the patient, whereby the mature dendritic cells activate the patient’s own T cells, yielding a 4.1-month overall survival benefit when compared with placebo.3
The latest generation of more specific immunotherapeutic agents includes immune checkpoint inhibitors, which target one of several sites of actions within the regulatory pathway (see Figure 1).4 These drugs affect programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Blocking interaction of CTLA-4 and B7 on the T cell and dendritic cell, respectively, and PD-1 and PD-L1 on the T cell and tumor, respectively, releases the brakes on the immune system and permits T-cell activation.
Figure 1. Mechanism of checkpoint blockade
Prostvac is a prostate cancer vaccine, which in phase II trials led to an 8.5-month improvement in median overall survival over placebo.5 It is based on two viral vectors engineered to express and, thus, target PSA as the tumor-specific antigen, along with three costimulatory transgenes. Interestingly, and similar to sipuleucel-T, PSA response to treatment was not correlated with outcomes and suggests that PSA may not be a useful biomarker in patients treated with immunotherapy.
A phase III trial of nearly 1,300 patients with mCRPC is under way, which compares Prostvac alone or in combination with GM-CSF against placebo with the endpoint of overall survival. This trial has completed accrual, and results should be reported in late 2017.6
Other ongoing phase II trials combine Prostvac with docetaxel and other immunotherapies, such as ipilimumab.
Researchers expressed initial excitement for the strategy of inhibiting CTLA-4, with preclinical evidence suggesting efficacy in controlling tumor growth in a variety of cancers. The FDA has approved ipilimumab, a fully human IgG1 monoclonal antibody targeting CTLA-4, for the first-line and second-line treatment of advanced melanoma, but its role for mCRPC remains to be determined. Unfortunately, in two phase III trials, ipilimumab did not improve overall survival in men with mCRPC.
One study, CA184-095, randomized 400 men who were chemotherapy-naïve to ipilimumab or placebo (2:1 ratio). Although progression-free survival was longer in the ipilimumab arm, results showed the therapy had no effect on overall survival.7
Another study, CA184-043, compared ipilimumab with placebo in approximately 800 men with mCRPC previously treated with radiotherapy and docetaxel chemotherapy.8 Again, no improvement in overall survival (hazard ration 0.85, p = 0.053) was observed; however, there was a suggestion of benefit in those patients with more favorable disease.
Studies are under way to determine whether combining ipilimumab with other agents improves efficacy.
Renal cell carcinoma
Although high-dose IL-2 has demonstrated benefit in patients with mRCC and has been FDA approved since 1992, its routine use has been limited by significant toxicity and replaced by agents targeting angiogenesis. The completed phase III ADAPT (The Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma) trial accrued 462 patients with mRCC. This study compares standard therapy alone with standard therapy plus rocapuldencel-T, an autologous dendritic cell-based vaccine. Although the final results are pending, the independent data monitoring committee recently recommended that the study be discontinued due to futility based on the planned interim analysis.
In November 2015, nivolumab received FDA approval for the treatment of patients with mRCC who had progressed on antiangiogenic therapy. Nivolumab, a monoclonal antibody that neutralizes the PD-1 protein, was tested in a phase III study (CheckMate 025) of 821 patients, which showed that median overall survival was significantly longer with nivolumab compared with everolimus (hazard ratio 0.73, p = 0.002).9 In addition, the objective response rate for nivolumab was 21.5 percent versus 3.9 percent for everolimus. The benefit of nivolumab was consistent across prognostic factors, including risk group, age, and number/sites of metastases. In addition, the survival benefit was not dependent on the expression of PD-L1 on tumor cells. Thus, nivolumab is now one of the preferred (category 1) options in second-line therapy for mRCC.
Additional studies are under way to examine the role of other checkpoint inhibitors, such as pembrolizumab and atezolizumab, both alone and in combination with agents, such as interferon, pazopanib, and bevacizumab. In addition to efficacy, side effects and tolerability need to be carefully considered, as illustrated by data recently presented regarding significant hepatotoxicity and more than 80 percent grade 3/4 adverse events in patients with RCC receiving both pazopanib and pembrolizumab.10
Urothelial carcinoma of the bladder
Perhaps the greatest strides have been made in the treatment of advanced bladder cancer, where the mainstay had been cisplatinum-based combination chemotherapy. The absence of promising agents, combined with the challenges of completing clinical trials in this space, had led to little progress over three decades. However, the FDA has approved five immunotherapy drugs in the last year.
Atezolizumab targets and binds to PD-L1 and demonstrated a 15 percent objective response rate. The median duration of response was not reached with median follow-up of 11.7 months in the phase II IMvigor 210 trial, which included patients with advanced or metastatic bladder cancer with progression after previous platinum-based chemotherapy.11 A second platinum-ineligible cohort within the study also showed encouraging results, with a 23 percent objective response rate and median overall survival of 15.9 months.12 These findings led to accelerated FDA approval for both first-line and second-line treatment in bladder cancer; however, preliminary reports on the phase III IMvigor 211 trial data do not support a significant improvement in overall survival in the second-line setting, which was the primary endpoint. The ongoing phase III IMvigor 130 trial seeks to confirm the findings in the platinum-ineligible population.
Avelumab and durvalumab are both FDA approved in patients with disease progression after prior chemotherapy and demonstrated objective response rates of 13 percent and 17 percent, respectively.13,14 Durvalumab is being evaluated as first-line therapy alone and in combination with tremelimumab in the phase III Danube trial. Pembrolizumab is also approved in this space based on results from KEYNOTE-045, with improvement in overall survival from 7.4 to 103 months (hazard ratio 0.73, p = 0.002).15 The benefit was independent of measurement of PD-L1 expression.
The anti-PD-1 nivolumab was the second agent approved by the FDA as a second-line agent after a prior platinum-containing regimen. CheckMate 275 confirmed the findings from the phase 1/2 trial (CheckMate 032), with an objective response in 20 percent of patients and complete response rate of 2.6 percent, with mediation duration of response of 10.3 months.16
The efficacy of novel immunotherapeutics, particularly checkpoint inhibitors, hold promise for a wide variety of tumor types. The next critical steps will be identifying the patients most likely to benefit from therapy and to develop and validate relevant biomarkers. In addition, these drugs will likely be used in combination with many others to optimize outcomes while minimizing side effects.
Open Alliance trials can be viewed on the Alliance for Clinical Trials in Oncology website.
- Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
- Law TM, Motzer RJ, Mazumdar M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer. 1995;76(5):824-832.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
- Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974-1982.
- Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099-1105.
- S. National Institutes of Health. A randomized, double-blind, phase 3 efficacy trial of Prostvac-V/F +/- GM-CSF in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (prospect). Available at: clinicaltrials.gov/ct2/show/NCT01322490. Accessed June 26, 2017.
- Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naïve castration-resistant prostate cancer. J Clin Oncol. 2017;35:40-47.
- Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700-712.
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
- American Society of Clinical Oncology. Meeting abstracts. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). Available at: abstracts.asco.org/199/AbstView_199_180924.html. Accessed June 26, 2017.
- Rosenberg JE, Hoffman-Censitis J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicenter, phase 2 trial. Lancet. 2016;387:1909-1920.
- Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicenter, phase 2 trial. Lancet. 2017;389:67-76.
- Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017;35(19):2117-2124. doi:10.1200/JCO.2016.71.6795.
- Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119-3125.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as a second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
- Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.