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Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers
Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Review article
Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers David M. Gill, M.D., Neeraj Agarwal, M.D.* Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT Received 20 September 2017; accepted 21 September 2017
Abstract The recent resurgence of immunotherapy has transformed the therapeutic field of advanced urologic cancers. In this seminars issue, we evaluate the role of emerging and recently approved immunotherapeutic agents in advanced prostate, urothelial, and renal cell carcinoma. In each of these fields, we discuss recent regulatory approvals as well as promising ongoing clinical trials. Finally, we discuss incidence and management of immune related adverse events specifically associated with PD-1/PD-L1 inhibitors. r 2017 Elsevier Inc. All rights reserved.
Keywords: Systemic immunotherapy; Urologic oncology; Checkpoint inhibitors; Cancer vaccines
Over the last 5 years, immunotherapy, especially with the checkpoint inhibitors (CPIs), has come to the forefront of cancer therapy with several agents garnering regulatory approval for various advanced cancers. Additionally, newer agents with novel mechanisms of action continue to be developed. However, in this context, urologic cancers have lagged behind until recently when approval of multiple programmed death receptor-1 (PD-1) axis inhibitors dramatically changed the treatment paradigms in advanced urothelial and renal cell carcinoma. This series of urologic oncology: seminars and original investigations includes 4 manuscripts evaluating the current and emerging therapeutic landscape of immunotherapy in urologic oncology. Articles from corresponding authors Drs Ravi Madan, Guru Sonpavde, and Moshe Ornstein will review the state of immunotherapy in advanced prostate, advanced urothelial cell, and advanced renal cell carcinoma, respectively. In addition, Dr Benjamin Maughan and colleagues will evaluate the toxicities of PD-1 and PD-L1 CPIs and will discuss the management of their adverse events in the setting of urologic oncology clinics. Though the treatment strategy for metastatic castrateresistant prostate cancer (mCRPC) has evolved over the Corresponding author: Tel.: þ1-801-213-5658; fax: þ1-801-585-0124. E-mail address: [email protected] (N. Agarwal). *
http://dx.doi.org/10.1016/j.urolonc.2017.09.023 1078-1439/r 2017 Elsevier Inc. All rights reserved.
past decade with regulatory approvals of abiraterone, enzalutamide, radium-223, and cabazitaxel, only 1 immunotherapeutic agent, sipuleucel-T, an autologous dendritic cell-based vaccine, has been approved. As CPIs have transitioned into clinical practice for other urologic cancers, these agents have yet to establish their roles in mCRPC. Dr Madan and colleagues will discuss why prostate cancer continues to be promising target for CPIs in spite of 2 large negative trials with ipilimumab in mCRPC [1,2]. They will describe emerging immunotherapies under investigation for advanced prostate cancer, such as novel vaccines and combinatorial therapies of CPIs with vaccines, androgen deprivation, docetaxel, and poly ADP ribose polymerase inhibitors [3]. In the setting of advanced urothelial carcinoma, Dr Sonpavde and colleagues will discuss how CPIs have solidified their role as standard of care for patients who are either ineligible or experience disease progression on or after platinum-based chemotherapy. This review includes the recent regulatory approvals of 5 agents targeting the PD1/PD-L1 axis in the postplatinum therapy setting, as well as the approval for 2 of these agents for those ineligible for cisplatin-based therapy owing to poor performance status or comorbidities [4,5]. In addition to discussing the role of PDL1 as a predictive biomarker, Dr Sonpavde and colleagues review ongoing trials investigating novel combination
2
D.M. Gill, N. Agarwal / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
regimens with CPIs, such as the one with novel indoleamine 2,3-dioxygenase (IDO1) inhibitor, epacadostat. Through conversion of tryptophan into kynurenine, the enzyme IDO1 subsequently allows immune tolerance and T cell evasion. Epacadostat inhibits this pathway and therefore prevents this immune checkpoint [6]. In contrast to advanced prostate and urothelial cancer, immunotherapy in the form of high-dose interleukin-2 and interferon-alfa have had an established role in patients with advanced renal cell carcinoma since the 1990s. However, until the recent introduction of CPIs, these agents were largely displaced by agents targeting vascular endothelial growth factor (VEGF), and mechanistic target of rapamycin (mTOR) pathways. Dr Ornstein and colleagues will review how nivolumab has obtained regulatory approval for the second-line treatment of advanced renal cell carcinoma, and will also discuss how focus has now shifted to the role of immunotherapy in the first-line therapy setting in these patients. He includes recently published data from IMmotion 150 investigators showing improved progression free survival with the combination of atezolizumab and bevacizumab compared to sunitinib in those with high PD-L1 expression [7]. IMmotion 151, which has fully accrued, will further evaluate these findings. Rapid shift in the treatment paradigm in the first-line therapy setting is expected given anticipated regulatory approval of the combinatorial regimen of ipilimumab and nivolumab which recently showed improved overall survival compared to sunitinib, a VEGF tyrosine kinase inhibitor, in treatment naïve patients with metastatic renal cell carcinoma. Current challenges of immunotherapy and multiple ongoing registration trials investigating the novel combination of CPIs with different mechanism of action or a CPI with an antiangiogenic agent in untreated patients are also reviewed. In this new era of immunotherapy, we are still learning about the acute and long-term toxicities of these novel agents. CPIs have been shown to alter peripheral tolerance leading to immune related adverse events (irAEs), which can involve any organ in a given patient. Clinical manifestations may range from thyroiditis leading to hypothyroidism, which are relatively easy to manage to like-threatening toxicities such as colitis, hepatitis, pneumonitis, and hypophysitis, which need to be recognized early and managed aggressively, often in conjunction with respective
specialists. Although less common than those seen with cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, grade 3-4 irAEs have been consistently been reported in up to 15% patients treated with PD-1/PD-L1 inhibitors. Dr Benjamin Maughan and colleagues will discuss the incidence, prevalence, and management of irAEs specifically in the context of treatment with PD-1/PD-L1 inhibitors in the urologic oncology clinics. With the exception of endocrinopathies, most irAEs are reversible with appropriate and timely treatment. However, different immunosuppressive agents and doses are indicated based on the organ involved and grade of toxicity. Accordingly, as the use of PD-1 axis inhibitors becoming more widespread, it is imperative that practitioners who prescribe these agents are aware of the potential toxicities, recognize them early, and initiate prompt management. References [1] Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, Van den Eertwegh AJ, 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;15:700–12. [2] Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 2016;35:40–7. [3] Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708. [4] Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatinineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389: 67–76. [5] O'Donnell PH, Grivas P, Balar AV, et al. Biomarker findings and mature clinical results from KEYNOTE-052: first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). J Clin Oncol 2017;35:4502. [6] Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 2016;37: 193–207. [7] Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol 2017;35:4505.
Review article
Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers David M. Gill, M.D., Neeraj Agarwal, M.D.* Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT Received 20 September 2017; accepted 21 September 2017
Abstract The recent resurgence of immunotherapy has transformed the therapeutic field of advanced urologic cancers. In this seminars issue, we evaluate the role of emerging and recently approved immunotherapeutic agents in advanced prostate, urothelial, and renal cell carcinoma. In each of these fields, we discuss recent regulatory approvals as well as promising ongoing clinical trials. Finally, we discuss incidence and management of immune related adverse events specifically associated with PD-1/PD-L1 inhibitors. r 2017 Elsevier Inc. All rights reserved.
Keywords: Systemic immunotherapy; Urologic oncology; Checkpoint inhibitors; Cancer vaccines
Over the last 5 years, immunotherapy, especially with the checkpoint inhibitors (CPIs), has come to the forefront of cancer therapy with several agents garnering regulatory approval for various advanced cancers. Additionally, newer agents with novel mechanisms of action continue to be developed. However, in this context, urologic cancers have lagged behind until recently when approval of multiple programmed death receptor-1 (PD-1) axis inhibitors dramatically changed the treatment paradigms in advanced urothelial and renal cell carcinoma. This series of urologic oncology: seminars and original investigations includes 4 manuscripts evaluating the current and emerging therapeutic landscape of immunotherapy in urologic oncology. Articles from corresponding authors Drs Ravi Madan, Guru Sonpavde, and Moshe Ornstein will review the state of immunotherapy in advanced prostate, advanced urothelial cell, and advanced renal cell carcinoma, respectively. In addition, Dr Benjamin Maughan and colleagues will evaluate the toxicities of PD-1 and PD-L1 CPIs and will discuss the management of their adverse events in the setting of urologic oncology clinics. Though the treatment strategy for metastatic castrateresistant prostate cancer (mCRPC) has evolved over the Corresponding author: Tel.: þ1-801-213-5658; fax: þ1-801-585-0124. E-mail address: [email protected] (N. Agarwal). *
http://dx.doi.org/10.1016/j.urolonc.2017.09.023 1078-1439/r 2017 Elsevier Inc. All rights reserved.
past decade with regulatory approvals of abiraterone, enzalutamide, radium-223, and cabazitaxel, only 1 immunotherapeutic agent, sipuleucel-T, an autologous dendritic cell-based vaccine, has been approved. As CPIs have transitioned into clinical practice for other urologic cancers, these agents have yet to establish their roles in mCRPC. Dr Madan and colleagues will discuss why prostate cancer continues to be promising target for CPIs in spite of 2 large negative trials with ipilimumab in mCRPC [1,2]. They will describe emerging immunotherapies under investigation for advanced prostate cancer, such as novel vaccines and combinatorial therapies of CPIs with vaccines, androgen deprivation, docetaxel, and poly ADP ribose polymerase inhibitors [3]. In the setting of advanced urothelial carcinoma, Dr Sonpavde and colleagues will discuss how CPIs have solidified their role as standard of care for patients who are either ineligible or experience disease progression on or after platinum-based chemotherapy. This review includes the recent regulatory approvals of 5 agents targeting the PD1/PD-L1 axis in the postplatinum therapy setting, as well as the approval for 2 of these agents for those ineligible for cisplatin-based therapy owing to poor performance status or comorbidities [4,5]. In addition to discussing the role of PDL1 as a predictive biomarker, Dr Sonpavde and colleagues review ongoing trials investigating novel combination
2
D.M. Gill, N. Agarwal / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
regimens with CPIs, such as the one with novel indoleamine 2,3-dioxygenase (IDO1) inhibitor, epacadostat. Through conversion of tryptophan into kynurenine, the enzyme IDO1 subsequently allows immune tolerance and T cell evasion. Epacadostat inhibits this pathway and therefore prevents this immune checkpoint [6]. In contrast to advanced prostate and urothelial cancer, immunotherapy in the form of high-dose interleukin-2 and interferon-alfa have had an established role in patients with advanced renal cell carcinoma since the 1990s. However, until the recent introduction of CPIs, these agents were largely displaced by agents targeting vascular endothelial growth factor (VEGF), and mechanistic target of rapamycin (mTOR) pathways. Dr Ornstein and colleagues will review how nivolumab has obtained regulatory approval for the second-line treatment of advanced renal cell carcinoma, and will also discuss how focus has now shifted to the role of immunotherapy in the first-line therapy setting in these patients. He includes recently published data from IMmotion 150 investigators showing improved progression free survival with the combination of atezolizumab and bevacizumab compared to sunitinib in those with high PD-L1 expression [7]. IMmotion 151, which has fully accrued, will further evaluate these findings. Rapid shift in the treatment paradigm in the first-line therapy setting is expected given anticipated regulatory approval of the combinatorial regimen of ipilimumab and nivolumab which recently showed improved overall survival compared to sunitinib, a VEGF tyrosine kinase inhibitor, in treatment naïve patients with metastatic renal cell carcinoma. Current challenges of immunotherapy and multiple ongoing registration trials investigating the novel combination of CPIs with different mechanism of action or a CPI with an antiangiogenic agent in untreated patients are also reviewed. In this new era of immunotherapy, we are still learning about the acute and long-term toxicities of these novel agents. CPIs have been shown to alter peripheral tolerance leading to immune related adverse events (irAEs), which can involve any organ in a given patient. Clinical manifestations may range from thyroiditis leading to hypothyroidism, which are relatively easy to manage to like-threatening toxicities such as colitis, hepatitis, pneumonitis, and hypophysitis, which need to be recognized early and managed aggressively, often in conjunction with respective
specialists. Although less common than those seen with cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, grade 3-4 irAEs have been consistently been reported in up to 15% patients treated with PD-1/PD-L1 inhibitors. Dr Benjamin Maughan and colleagues will discuss the incidence, prevalence, and management of irAEs specifically in the context of treatment with PD-1/PD-L1 inhibitors in the urologic oncology clinics. With the exception of endocrinopathies, most irAEs are reversible with appropriate and timely treatment. However, different immunosuppressive agents and doses are indicated based on the organ involved and grade of toxicity. Accordingly, as the use of PD-1 axis inhibitors becoming more widespread, it is imperative that practitioners who prescribe these agents are aware of the potential toxicities, recognize them early, and initiate prompt management. References [1] Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, Van den Eertwegh AJ, 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;15:700–12. [2] Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 2016;35:40–7. [3] Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708. [4] Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatinineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389: 67–76. [5] O'Donnell PH, Grivas P, Balar AV, et al. Biomarker findings and mature clinical results from KEYNOTE-052: first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). J Clin Oncol 2017;35:4502. [6] Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 2016;37: 193–207. [7] Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol 2017;35:4505.