From BCG to interferon gene therapy, physicians have treated bladder cancer with immunotherapy for decades. Treatment particulars generally depend on whether bladder cancer is non-muscle invasive, muscle-invasive, or metastatic. About 75% of patients have non-muscle invasive bladder cancer (NMIBC),1 which is considered high-risk if it consists of non-invasive papillary carcinoma (TaHG), carcinoma in situ (CIS), or T1 (minimally invasive) tumor of the lamina propria.2,3 For high-risk NMIBC, multiple peer-reviewed trials and meta-analyses support 1-3 years of intravesical immunotherapy with bacillus Calmette-Guérin (BCG) to significantly lower the risk of recurrence,4,5,6,7,8 progression, and death.9,10,11
However, patients need alternatives when high-risk NMIBC relapses or is BCG-refractory. Their primary and safest option remains radical cystectomy, often with neoadjuvant, platinum- based chemotherapy.12 However, they face complications, diminished quality of life, and recurrence. In fact, 20% to 50% of UC recurs after radical cystectomy,13,14,15,16 and up to 30% of patients who undergo cystectomy for lymph-node negative, extravesical (T3 or T4) disease die from recurrence within 2 years.17 Intravesical valrubicin is approved for BCG-refractory CIS when patients are not cystectomy candidates, but only about 8% of those who receive it have no evidence of disease at 1 year.18,19
Fortunately, novel intravesical therapies may soon improve the prognosis of BCG-refractory or relapsed NMIBC. Especially promising is rAd-IFNα/Syn 3 (Instiladrin), a recombinant adenoviral vector that delivers interferon alpha gene directly to the bladder. In a recent phase 2 trial, Instiladrin was well tolerated and 35% of patients remained free from recurrent high-grade tumors at month 12 month.20 If the ongoing phase 3 trial of Instiladrin (NCT02773849) yields similar results, they could be practice-changing.
For patients with advanced and metastatic urothelial carcinoma (mUC), chemotherapy has improved outcomes since the 1980s, when Dr. Allen Yagoda introduced methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).21 Today, dosedense MVAC or cisplatin-gemcitabine remain standard therapies
for mUC,22 but patients often experience toxicities that even experienced medical oncologists can find hard to manage.16 In addition, many patients are ineligible for intensive chemotherapy because of poor performance status, impaired renal or cardiac function, or other comorbidities. Until recently, these patients had few alternatives.23
This decades-long stagnancy ended in May 2016, when the U.S. Food and Drug Administration (FDA) approved atezolizumab (Tecentriq, Genentech), a monoclonal antibody targeting programmed death ligand-1 (PD-L1), for the treatment of locally advanced or mUC that progressed during or after platinum-based chemotherapy.23,24,25 Four more PD-1/PD-L1 pathway inhibitors quickly followed for second-line use in mUC: the anti-programmed death (PD-1) antibody nivolumab (Opdivo, Bristol-Myers Squibb),26,27 the anti-PD-1 antibody pembrolizumab (Keytruda, Merck),28,29 and the anti-PD-L1 antibodies avelumab (Bavencio, Pfizer and EMD Serono)30,31 and durvalumab (Imfinzi).32,33
In that same timeframe, atezolizumab34,35 and pembrolizumab29 also were approved for the first-line treatment of locally advanced or mUC in platinum-ineligible patients (pembrolizumab also is approved for treating unresectable or metastatic solid tumors that are microsatellite instability-high [MSI-H] or mismatch repair-deficient, based on genomic tissue analyses).36
Thus, within about a year, the FDA approved five checkpoint inhibitors for treating mUC. This is a phenomenal pace, considering that it took about 5 years to approve six therapies for metastatic, castration-resistant prostate cancer (sipuleucel-T [Provenge], denosumab [Xgiva], abiraterone [Zytiga], enzalutamide [Xtandi], and radium Ra 223 dichloride [Zofigo]).37,38,39,40,41 So many new treatment choices are exciting but also challenging for urologists and medical oncologists. Much new data need absorbing to identify the best candidates for treatment, especially because these approvals are mostly for late-stage UC, when patients tend to be frail or to have multiple comorbidities. Rates of objective response and immune-related adverse events (irAEs) also vary somewhat, and there no head-to-head trials yet to help clarify discrepancies.3
Another challenge is that immuno-oncologics in UC continue to evolve rapidly. Two brief examples illustrate this point. In May 2017, atezolizumab missed its primary OS endpoint when compared with chemotherapy in the phase 3 IMVigor 211 trial of patients with previously treated advanced disease,42 possibly because the chemotherapy arm exceeded assumptions about overall survival.43 In June 2018, a phase 2 trial showed that neoadjuvant pembrolizumab produced a nearly 40% complete pathologic response rate in patients with up to stage 3bN0M0 UC persisting after TURBT.44 Adverse events were uncommon and treatment with pembrolizumab did not delay radical cystectomy.
Clearly, urologists who treat bladder cancer need to know the history of immuno-oncology, current approvals, and future trends. This will help us better care for patients and educate and lead our teams.
Cytotoxic therapy dominated 20th century oncology, but immuno-oncology predates it. In the late 1800s, surgeon William Coley noted 47 reports of concomitant infections that led to cancer remissions. Ignoring ridicule from his peers, he began using a heat-killed mixture of Staphylococcus pyoges and S. marcecens to inject patients with sarcoma, in some cases obtaining results that are impressive even by today’s standards.45
Coley’s discovery laid the groundwork for research on cancer vaccines (1959), the role of T-cells in cellular immunity (1967), and the respective parts played by dendritic cells, major histocompatibility complex, and natural killer cells (1970s).45 By the late 20th century, researchers had confirmed the existence of T-cell mediated tumor-specific immune surveillance.45 In 2011, decades of research on an immune checkpoint protein known as cytotoxic T-lymphocyte antigen 4 (CTLA-4) culminated in the FDA approval of ipilimumab for stage IV melanoma.3,45 Subsequent research led to P1-pathway inhibitor approvals in advanced and mUC as well as other cancers.
Urologists have a strong historical precedent for using immuno-oncologics: BCG was one of the first immunotherapies for solid tumors,8 has been used for decades to treat bladder CIS,3,23,46,47 and remains the standard of care for high-risk NMIBC.3,48 Its primary mechanism of action is immunogenic, as it induces CD4(+) and CD8(+) T-lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells to kill tumor cells and to secrete soluble cytotoxic factors, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).49 Although BCG is also directly cytotoxic, this appears to be a secondary mechanism of action.49
Rationale and Use
Currently, immuno-oncologic therapy in UC targets the programmed death 1 (PD-1) checkpoint pathway, an inhibitory signaling system that limits the duration and extent of the immune system’s attack on tumor cells to prevent excessive peripheral tissue damage.3
Let’s briefly review this pathway. Within the tumor microenvironment, cytotoxic T-cells are activated by antigen presenting cells, such as dendritic cells, which process and present antigens by the major histocompatibility complex (MHC) or by directly binding the T-cell receptor.50 T-cells, natural killer cells, dendritic cells, and B-cells all express PD-1. When PD-1 on an active cytotoxic T-cell binds PD-L1 on a tumor cell, it is deactivated by means of T-cell apoptosis, anergy, functional exhaustion, or interleukin-10 (IL-10) production.50 The end result is a decrease in T-cell proliferation and anti-tumor activity with a corresponding increase in tumor cell survival and angiogenesis.3,50,51 In contrast, when PD-1 and PD-L1 are unbound, T-cell proliferation increases, and tumor cell survival and angiogenesis decrease.
Thus, the PD-1 checkpoint pathway is an important regulator of anti-tumor cellular immunity. Using monoclonal antibodies to inhibit either PD-1 or PD-L1 stops them from binding, which, in turn, enables tumor-killing T-cells to stay active.50,51 This is how PD-1 and PD-L1 blockers “take the brakes off” T-cells.3 The end result is heightened immune surveillance and T-cell mediated tumor cell killing.3
Practically speaking, immuno-oncologics in UC are administered intravenously.31,33,35,36,52 Fortunately, most urologists are comfortable with this route because of prior experience with sipuleucel-T, zoledronic acid, and radiopharmaceuticals.
Dose and schedule vary by agent. Options for fixed-dose therapy include pembrolizumab (200 mg every 3 weeks),36 nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks),52 and atezolizumab (1200 mg every 3 weeks).35 Weight-based dosing is used for avelumab (10 mg/kg every 2 weeks)31 and durvalumab (10 mg/kg q 2 weeks).33
Immune-related Adverse Events
Immuno-oncologic therapy can induce immune-related adverse events (irAEs) anytime during treatment and even after treatment ends.53,54 Prompt detection and intervention are crucial and usually induce complete resolution.55 All providers and patients need to be educated and vigilant.
Although irAEs can affect any organ system or tissue, they most often involve inflammation of the skin, endocrine glands, liver, colon, and lungs.55,53,56 Dermatologic irAEs (maculopapular rash, pruritus) are usually first to appear.54
Less common, but just as clinically important, are irAEs of the eye (episcleritis, conjunctivitis and uveitis), acute kidney injury (nephritis, granulomatous lesions and thrombotic microangiopathy), elevated amylase and lipase (usually asymptomatic), and neurologic abnormalities (most often peripheral neuropathy).55 Patients can also develop infusion reactions (fever or chills).55
In clinical trials to date, about 15% to 19% of patients have developed serious (grade 3-4) irAEs resulting from PD-1 pathway inhibitor monotherapy.50,56 However, autoimmunity was exclusionary in these trials, and rates of serious irAEs can be expected to rise as more patients with autoimmune diseases begin choosing immuno-oncologic therapy.
In one of the largest such cohort studies reported to date, nearly a third of 16 individuals with pre-existing rheumatic disease developed irAEs in response to checkpoint monotherapy.57 These resolved with corticosteroids and treatment discontinuation, underscoring the need to monitor patients closely.57
Researchers are seeking reliable biomarkers for irAEs, including germline genetics and variations in the microbiome.54 For now, we cannot reliably know which patients will develop irAEs or when.54,55
Treatment and Management
Moderate to severe irAEs are treated with temporary immunosuppression.54,55,58 First-line therapy usually consists of glucocorticoids, while infliximab is a second-line option for refractory cases.55,58 There have been no prospective trials of these regimens; practices are based on consensus opinion.54
Consider stopping the immuno-oncologic if irAEs are moderate or severe.54,55,58 It remains unclear whether it’s safe to re-start after a major irAE resolves.54 This probably depends on severity.54 So far, retrospective data suggest that patients can maintain responses to immuno-oncologic therapy even after stopping because of irAEs.54
When managing irAEs, foster strong partnerships with medical oncologists and other relevant specialists. Have a low threshold for referring patients or seeking consultations. Additionally, all support personnel should understand immuno-oncologic mechanisms of action, duration of risk, and “red flag” signs and symptoms.59
For patients and caregivers, reinforce the message that irAEs can develop anytime and require prompt notification and treatment.59 I suggest using a handout that categorizes irAEs by organ system, lists signs and symptoms, and highlights whom to notify and how. Also stress that treating irAEs does not reduce immuno-oncologic efficacy.54
Mechanism of Action
The exact pathophysiology of irAEs is unclear. Translational studies indicate that antibody, T-cell, and cytokine responses may be involved.54 Possible mechanisms include T-cell activity against antigens in both tumor and healthy tissue, increases in pre-existing autoantibodies or inflammatory cytokines, and enhanced complement-mediated inflammation.54
Studies have reported conflicting data on whether irAEs are a signal of treatment efficacy.54 However, patients can benefit from treatment without developing irAEs. There is some evidence that specific irAEs, such as vitiligo, are more closely linked with benefit.54
The use of immuno-oncologics in bladder cancer began with later-line use in advanced and metastatic disease. These cases can be challenging because patients tend to be older and to have significant comorbidities.
However, immuno-oncology in bladder cancer is starting to shift to earlier-stage and first-line use34 as previously occurred in prostate cancer60,61 and renal cell carcinoma.44 For example, a phase 1 trial (NCT02324582) of pembrolizumab monotherapy is recruiting patients with high-risk, BCG-naïve NMIBC. In nonmetastatic, BCG-refractory NMIBC, phase 1 and phase 2 trials are investigating single-agent nivolumab (NCT03106610) and pembrolizumab (KEYNOTE-057; NCT02625961). Depending on the results of such studies, immuno-oncologics might one day benefit many more UC patients than they do currently.
Muscle-Invasive Bladder Cancer
Other studies are investigating neoadjuvant or adjuvant immuno-oncologic therapy in muscle-invasive bladder cancer.
Trials that are recruiting include:
• A phase 2 trial (NCT03520491) of neoadjuvant nivolulmab-ipilimumab or nivolumab alone prior to radical cystectomy in chemotherapy-ineligible patients
• CheckMate-274 (NCT02632409), a phase 3 trial of adjuvant nivolumab versus observation alone post-cystectomy in patients with high-risk invasive carcinoma of the bladder or upper urinary tract
• AMBASSADOR (NCT03244384), a phase 3 trial of adjuvant pembrolizumab in muscle-invasive and locally advanced UC
• IMVigor 010 (NCT02450331), a phase 3 trial of adjuvant atezolizumab in high-risk muscle-invasive UC
Results from these studies are expected between 2018 and 2021.
Immuno-oncologic combinations are an especially “hot” research area, including in UC. For example, in the high-grade NMIBC setting, a phase 1 trial (NCT03258593) is evaluating durvalumab plus the antibody-drug conjugate vicinium. Patients in these combination trials might receive aggressive resection, radiation, and one or more immuno-oncologics, with or without chemotherapy. Such approaches appeal to sophisticated urologists who are prepared to work tandem with radiation oncologists.
In the metastatic setting, UC trial participants might receive multiple checkpoint inhibitors or a checkpoint inhibitor plus chemotherapy, radiation, anti-angiogenic therapy, or agents that target other pathways implicated in UC. The goal is to boost treatment response without significantly increasing toxicity.
Phase 3 trials with results expected in the next several years include:
• KEYNOTE-361(NCT02853305): pembrolizumab, with or without platinum-based chemotherapy, versus chemotherapy alone in advanced or mUC
• IMVigor 130 (NCT02807636): atezolizumab alone or with platinum-based chemotherapy in advanced or mUC
• DANUBE (NCT02516241) : durvalumab alone or with tremelimumab in treatment-naïve mUC
• CheckMate-901 (NCT03036098): nivolumab with ipilimumab or chemotherapy in treatment-naïve advanced or mUC
In May 2018, early data reviews of KEYNOTE-361 and
IMVigor 130 revealed decreased overall survival with pembrolizumab or atezolizumab monotherapy compared with chemotherapy in mUC patients with PD-L1-low expressing tumors. The FDA issued a drug safety alert and both trials have stopped enrolling PD-L1-low patients to their monotherapy arms.62 Such results add further credence to combination therapies in UC.
The relatively low response rate to anti-PD-1/PD-L1 monotherapy highlights the need for these novel combinations, but also for new immuno-oncologic targets. There are several promising candidates.
First, the fibroblast growth factor (FGF) family of transmembrane tyrosine kinase receptors has been implicated in UC, and FGFR3 is often overexpressed or mutated in NMIBC.63
Trials of anti-FGFR3 antibodies or antibody-drug conjugates in bladder cancer include:
• Two phase 1b trials of the anti-FGFR antibody B-701 in combination with pembrolizumab (NCT03123055) or docetaxel (NCT02401542) in locally advanced or mUC
• A phase 1 trial (NCT02529553) of the antibody-drug conjugate LY3076226 in FGFR3-mutated advanced or metastatic bladder cancer
A second target is indoleamine 2,3-dioxygenase (IDO), a cytosolic enzyme induced by interferon gamma (IFNγ) that catalyzes the metabolism of tryptophan to kynurenine.64 Less tryptophan within the tumor microenvironment leads to reduced effector T cell activity, downregulating the anti-tumor response.64
Consequently, researchers are studying IDO pathway inhibitors in several tumor types, including bladder cancer. Examples for UC include epacadostat (NCT02298153, NCT02318277), indoximod,65 BMS986205 (NCT03192943, NCT02658890), and PF-06840003.66
Data are most mature for epacadostat, which was active and well tolerated in combination with PD-1 inhibition in phase 1 trials. 67,68,69,70 In the phase 1 ECHO-202/KN037 trial (NCT02178722), for example, 35% of patients with mUC responded to combination therapy with pembrolizumab and epacadostat, whose safety resembled that of anti-PD-1 monotherapy.69 So far, responses also look at least as durable as for anti-PD-1 pathway monotherapy. Later-phase mUC trials will investigate pembrolizumab plus epacadostat for second-line treatment and for the first-line treatment of cisplatin-ineligible patients.70,71
A third investigational target is nectin-4, which is overexpressed in most UCs.72 In a phase 1 trial (EV-101; NCT02091999), the antibody-drug conjugate enfortumab-vedotin, which delivers a microtubule-disrupting agent to nectin-4-expressing tumor cells, produced an overall response rate of 33% and a median overall survival time of 12.5 months in chemotherapy-relapsed or cisplatin-ineligible mUC patients.72 Results from this phase 1 trial earned enfortumab-vedotin a breakthrough therapy designation from the FDA for patients with locally advanced or mUC previously treated with checkpoint inhibitors.73 Additional and later-phase trials are underway.
It is extremely challenging to power this many trials, so urologists should consider taking part whenever possible. By doing so, we can avoid the “late adapter” mentality that slowed our involvement in trials of immuno-oncologics in prostate cancer.
Multimodal, Integrative Care
Community-based urology in the United States has undergone a dramatic paradigm shift since 2010, when the first immunotherapy was approved for treating advanced PC.37 Urology practices are becoming larger, more sophisticated, and more specialized.
Consder the most recent (2017) census by the American Urological Association. Only 20% of urologists in private practice reported working solo, 41% practiced in groups of at least six urologists, and 16% were part of multispecialty groups.74 Nearly 40% of urologists reported subspecializing, usually in oncology.74
Urologists in larger and multimodal practices can focus solely on surgery or systemic therapy and can work with dedicated, trained support personnel. This model is ideal for incorporating immuno-oncologics into a bladder cancer armamentarium. One or two urologists can become physician champions, developing expertise and focusing solely on systemic genitourinary oncology with the support of highly skilled nurse champions.
Multimodal group practices are also ideal for immuno-oncologic therapy because they have the administrative infrastructure to obtain pre-authorizations and procurements and see enough patients to develop deep experience with treatment, education, and identification and management of irAEs.
As use of immuno-oncologists shifts to earlier-stage UC, academic centers will not be able to handle the volume of patients seeking these therapies. The shift away from “solo shops” will help urologists connect patients with immuno-oncologics and other therapies that require specialized care and follow-up.
As in prostate cancer, immuno-oncologic therapy of UC requires a specialized approach based on considerable focus and expertise. This is beyond the scope of most general urologists or general medical oncologists. However, many community-based urologists already have developed sophisticated prostate cancer clinics. The same opportunities now exist in bladder cancer.
Checkpoint inhibitors approved for the second-line treatment of advanced and mUC include the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech),25,26,27 the PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb),26,27 the anti-PD-1 antibody pembrolizumab (Keytruda, Merck),28,29 and the PD-L1 inhibitors avelumab (Bavencio, Pfizer and EMD Serono),30,31 and durvalumab (Imfinzi).32,33
Atezolizumab34,35 and pembrolizumab29 also are approved as first-line therapies for platinum-ineligible patients with locally advanced and mUC. However, they should not be used as monotherapy in platinum-eligible patients.
When discussing checkpoint inhibition in mUC, keep expectations reasonable. Only about 20% of patients respond to anti-PD-1/anti-PD-L1 monotherapy, but responses are durable, with median overall survival (OS) times of about 7 to 8 months.24,26,28,30,32
Immune-related adverse events can occur anytime during treatment or after treatment cessation. These events are manageable if quickly identified and treated. It’s vital to follow patients closely, thoroughly educate patients, caregivers, and personnel, and refer or consult when you need additional support.
The overarching goal of immuno-oncology is to significantly improve survival and quality of life across genotypic and phenotypic spectrums of cancer. With this in mind, researchers are investigating combination regimens, the optimal sequencing of treatment, and genetic signatures and other possible biomarkers of treatment response. Urologists who participate in trials can help advance these efforts and may also link help UC patients access earlier, more effective, and more tolerable therapy.
Written By: Neal Shore, MD, FACS
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