Over the past 5 years, medical oncologists have witnessed the revolutionary impact of immunotherapy on patients with advanced urologic malignancies. Over the next 5 years, these therapies likely will similarly transform urologic surgical care. In the metastatic setting, the 2-year frontline progression-free survival rate for high-risk clear cell renal carcinoma has nearly doubled, from 17% with sunitinib (Sutent) to 30% with combination immunotherapy of ipilimumab (Yervoy) plus nivolumab (Opdivo).

 Overall survival (OS) at 2 years in the same study was 66% with immunotherapy compared with 53% for sunitinib. In refractory prostate cancer, the same combination, although given at different doses, was shown to have an objective response rate of 26% in docetaxel-naïve patients.

 In bladder cancer, multiple immunotherapy drugs have received FDA approval since 2016, and median OS was prolonged with pembrolizumab (Keytruda) immunotherapy to 10.3 months versus 7.4 months with chemotherapy.

 These therapies have led to long-term survival for many patients in the metastatic setting, for which the outlook has been historically poor. A logical extension of these clinical research efforts has been to insert immunotherapy earlier into the course of disease, including in the perioperative setting.

Early-stage bladder cancer is one of the most active areas of immunotherapy investigation. Recurrences of nonmuscle invasive bladder cancer (NMIBC) can be prevented with bacille Calmette-Guérin (BCG) immunotherapy, which clinicians have used for over 40 years. Yet up to 50% of patients either fail to respond or relapse within the first 5 years of treatment. Evidence of PD-L1 upregulation in the tumor microenvironment after BCG therapy has now been reported,

 and the exploration of PD-1 immune checkpoint blockade in early-stage tumors is under way. Additionally, investigators are evaluating the IDO inhibitor BMS-986205 in combination with nivolumab anti—PD-1 therapy in BCG-unresponsive NMIBC (NCT03519256). Prevention of recurrences or progressions could ultimately reduce the number of patients who develop muscle-invasive or metastatic urothelial cancer.

Table. Select Trials of Immuno-Oncology Agents in Urological Cancers (

For patients with localized urothelial cancer (T2-T4 disease), outcomes remain poor despite optimal neoadjuvant chemotherapy and surgery. In this setting, adjuvant studies with several anti—PD-1/PD-L1 antibody therapies are in progress for cisplatin-ineligible patients or patients with residual disease after neoadjuvant chemotherapy. Similarly, neoadjuvant immunotherapy studies are investigating anti–PD-1/PD-L1 therapy both alone and in combination with chemotherapy. Preliminary data from the PURE-01 and ABACUS studies indicated that pathologic complete response to pembrolizumab and atezolizumab (Tecentriq) was 42.0% and 29.0%, respectively.

 These same antibodies are being investigated in 2 large, randomized, phase III, 3-arm studies that include chemotherapy, combination chemotherapy and immunotherapy, and immunotherapy alone. These approaches could ultimately transform the prognosis for patients with newly diagnosed T2 and higher localized bladder cancer.

 In renal cancer, investigators are studying both adjuvant and neoadjuvant approaches. Adjuvant trials with atezolizumab, pembrolizumab, durvalumab (Imfinzi), and nivolumab with or without ipilimumab are accruing. Additionally, the perioperative PROSPER RCC trial is under way via cooperative groups to study nivolumab therapy both prior to and after nephrectomy. Investigators have hypothesized that starting immunotherapy treatment with the tumor intact can enhance antigen-specific T-cell reactivation compared with using therapy only postoperatively. Additionally, neoadjuvant therapy can lead to dramatic responses in patients with initially unresectable disease and can enable curative surgery.

 In the perioperative setting, the tyrosine kinase inhibitor therapies were largely unable to improve outcomes, with the controversial exception of sunitinib, which was approved for renal cancer in the adjuvant setting. Nonetheless, given its very different mode of action, anti—PD-1/PD-L1 immune checkpoint therapy has the potential to shift the paradigm of treatment in localized renal cancer.

Beyond sipuleucel-T (Provenge), immunotherapy in prostate cancer has been a challenge, but signs of hope are emerging. Investigators evaluated neoadjuvant ipilimumab with androgen-deprivation therapy in prostate cancer, and clinical or pathologic complete responses were not observed.

 However, upregulation of PD-L1 and VISTA inhibitory molecules on macrophages in treated tumors was observed as a potential mechanism of resistance. Results of a more recent study of combination ipilimumab and nivolumab in patients with metastatic prostate cancer have shown response rates of 25% in chemotherapy-naïve patients and 10% in patients with prior taxane therapy.

 Importantly, response rates were better in the chemotherapy-naïve cohort, whose patients are generally earlier in the disease course, when tumors are less refractory. This trend may support further investigation of combination immunotherapies at even earlier stages of prostate cancer, such as the perioperative setting. Indeed, some trials are even targeting the active surveillance population. One such trial involves administration of an adenoviral vector expressing the herpes simplex virus thymidine kinase gene concomitantly with the prodrug valacyclovir (Valtrex). This combination leads to tumor cell death and is intended to generate a tumor-specific in situ vaccination (NCT02768363). Preventing the development of advanced, invasive prostate cancer at a very early stage is an exciting prospect in improving outcomes in prostate cancer.

Given the shift in outcomes that urologic practices may see with immunotherapies, management of toxicities will, in parallel, become an important part of practice that clinicians could successfully manage through multidisciplinary teams or ongoing partnerships with medical oncologists and other specialists, such as gastroenterologists and rheumatologists. Clinical data indicate that immunotherapy given earlier in the disease course has the potential to have even higher efficacy than in the refractory metastatic setting. Thus, the promise of immunotherapy to transform care for patients with genitourinary cancer may be greatest in urologic care when cure is most attainable (

Tannir NM, Frontera OA, Hammers HJ, et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). 

. 2019;37(suppl 7):547. doi: 10.1200/JCO.2019.37.7_suppl.547.

Sharma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). 

. 2019;37(suppl 7):142. doi: 10.1200/JCO.2019.37.7_suppl.142.

Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. 

. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.

Hashizume A, Umemoto S, Yokose T, et al. Enhanced expression of PD-L1 in nonmuscle- invasive bladder cancer after treatment with bacillus Calmette-Guerin. 

. 2018;9(75):34066-34078. doi: 10.18632/oncotarget.26122.

Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). 

. 2018;36(suppl 15):4506. doi: 10.1200/ JCO.2018.36.15_suppl.4506.

Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. 

. 2018;36(34):3353-3360. doi: 10.1200/JCO.18.01148.

Labbate C, Hatogai K, Werntz R, et al. Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy. 

. 2019;7(1):66. doi: 10.1186/s40425-019-0546-8.

Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. 

. 2017;23(5):551-555. doi: 10.1038/nm.4308.

harma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). Presented at: 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 142.

Articles

Over the past 5 years, medical oncologists have witnessed the revolutionary impact of immunotherapy on patients with advanced urologic malignancies. Over the next 5 years, these therapies likely will similarly transform urologic surgical care.

Immune System Agents May Move Into Earlier Settings in GU Cancers

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses the management of TKI-associated adverse events in kidney cancer.

The adverse events associated with TKIs are very distinct from immunotherapy, says Sweis, and they include hypertension, hand foot syndrome, mouth sores, gastrointestinal (GI) upset, nausea, and loose stools. Unlike with immunotherapy, a patient who experiences an adverse event on TKI therapy can continue treatment on a lower dose, he adds. Even more chronic events can become better tolerated on a lower dose.

More aggressive intervention with antihypertensives is required for patients with hypertension; if that's not sufficient, the dose is reduced. For adverse events like GI upset, supportive medications like loperamide can be introduced to prevent loose stools, or anti-nausea meds can be administered. If neither of those medicines are effective, physicians can dose reduce. A high percentage of patients on TKIs have to be dose reduced, notes Sweis, but a dose reduction does not necessarily mean less efficacy.

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Dr. Sweis on the Management of TKI-Associated Adverse Events in Kidney Cancer

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses immunotherapy combinations in kidney cancer.

Several combinations of tyrosine kinase inhibitors (TKIs) and immunotherapies are being tested in the frontline setting, explains Sweis, including bevacizumab (Avastin) in combination with atezolizumab (Tecentriq). There are several others including pembrolizumab (Keytruda) plus axitinib (Inlyta), lenvatinib (Lenvima) plus pembrolizumab, avelumab (Bavencio) plus axitinib, as well as cabozantinib (Cabometyx) plus nivolumab (Opdivo). Physicians are awaiting data from their phase III trials to see how the field plays out.

Several of those combinations have received FDA breakthrough designations, adds Sweis. It is going to become difficult to select patients for the appropriate therapy, especially with the lack of comparative data in the field. The future of frontline kidney cancer treatment will require comparative studies of immunotherapy combinations versus TKI therapy, and potentially of immunotherapies in combination with TKIs. Answering these questions will require cooperation across the country as well as internationally, concludes Sweis.

Dr. Sweis on Immunotherapy Combinations in Kidney Cancer

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses the sequencing of therapies in the treatment of patients with prostate cancer.

Over the last few years, a number of different therapies have been granted FDA approval in this space. The area of prostate cancer that is evolving most quickly is the sequencing and timing of treatment. Sweis says this has been an area of confusion in the past, but recent advances have improved outcomes for patients in terms of survival and disease control. Therapies that were initially FDA approved in the metastatic castration-resistant setting are now being moved earlier on in treatment. These include enzalutamide (Xtandi), apalalutamide (Erleada), and abiraterone acetate (Zytiga). Even docetaxel is being investigated in an earlier setting.

Patients with metastatic castration-sensitive prostate cancer are now being treated more aggressively, due in large part to large international studies like CHAARTED and STAMPEDE, Sweis says.

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses the sequencing of therapies in prostate cancer.

Dr. Sweis on Sequencing of Therapies in Prostate Cancer

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses the frequency of immune-related adverse events (irAEs).

The frequency of irAEs depends on the type of immunotherapy and whether it is used as a single agent or combination, says Sweis. A single-agent immunotherapy can manifest in irAEs in up to 50% of patients. The majority of these side effects, notes Sweis, will be lower in intensity, such as a mild rash and some fatigue. A rash, says Sweis, can be treated with a topical steroid without a physician having to hold the therapy.

Additionally, physicians use a grading system to grade toxicities on a scale of 1 to 4, 4 being the most severe. Whether physicians have to hold therapy or administer steroids, or other advanced drugs that block the immune system, depends on the grade of the toxicity, says Sweis. For many grade 1 toxicities, physicians can continue with treatment. Grade 2 toxicities and above require more careful management that often require physicians to hold therapy and administer drugs that block the immune response. That applies to both monotherapies and combinations, explains Sweis.

Dr. Sweis on the Frequency of Immune-Related Adverse Events in Kidney Cancer

Randy F. Sweis, MD, instructor of medicine, University of Chicago Medicine, discusses the use of immunotherapy in genitourinary cancer.

In both bladder and kidney cancers, immunotherapy has become standard of care in practice, states Sweis. Currently-approved therapies include frontline nivolumab (Opdivo) and ipilimumab (Yervoy). Most patients who are diagnosed with these malignancies will be treated with an immunotherapy agent unless they have contraindications, explains Sweis.

Immunotherapy has adopted a greater role in the treatment paradigm over the past several years, which makes monitoring for immune-related adverse events very important. It is important for both patients and physicians to be aware of the potential side effects that can occur with immunotherapy use, notes Sweis. These side effects are more often than not different than what a patient might anticipate based on their understanding of historical treatments like chemotherapy. This understanding also extends to the various targeted therapies in kidney cancer, adds Sweis.

Dr. Sweis on Immunotherapy in Genitourinary Cancer

Randy F. Sweis, MD, clinical instructor, University of Chicago Medicine, discusses the emerging field of immunotherapy to treat patients with genitourinary (GU) malignancies.

GU cancers has had an interesting course of history, Sweis explains. While bacillus Calmette-Guérin is a standard immunotherapy that has long been available for patients with bladder cancer, Sweis says there was a lull in bladder cancer for quite some time. In kidney cancer, there was drug development with tyrosine kinase inhibitors, and in prostate cancer, patients have treatment options including androgen-targeted agents. However, bladder cancer remained quiet regarding FDA-approved drugs until the May 2016 approval of the PD-L1 inhibitor atezolizumab (Tecentriq).

Now, it is an exciting time to see anti—PD-1 therapies taking off in bladder cancer and renal cell carcinoma, where nivolumab (Opdivo) has also been approved as a treatment for patients.

Randy F. Sweis, MD, clinical instructor, University of Chicago Medicine, discusses the trend toward immunotherapy in the field of genitourinary malignancies.

Randy F. Sweis, MD