Bladder Cancer Immunotherapy: Establishing a Clinic of Excellence

Until recently, decades had elapsed with little progress in treating metastatic urothelial cancer (mUC). Cisplatin-based chemotherapy, the best available treatment option, had a median overall survival (OS) of 12-15 months, an overall response rate (ORR) of 50-60%, and was curative in about 10% of cases, but also was associated with potentially serious toxicities.12, 13, 2, 7, 3 

In addition, more than half of mUC patients were cisplatin-ineligible because of comorbidities such as poor performance status, renal insufficiency, neuropathy, hearing loss, or heart failure.4,5 In one study, up to 40% of cisplatin-ineligible mUC patients never received treatment,1 and outcomes among treated patients were poor: in a randomized phase II/III trial of 238 cisplatin-ineligible UC patients (EORTC study 30986), median OS were 9.3 months with gemcitabine-carboplatin and 8.1 months with methotrexate-carboplatin-vinblastine.7 For patients who progress after platinum-based chemotherapy, outcomes are very poor with survival in the range of 6-7 months. Consequently, the approval of immune checkpoint inhibitors marks the most important advance in treating mUC in more than 30 years.1 Although survival remains essentially unchanged in this nascent era of immunotherapy, inhibitors of the PD-1 pathway are active, with ORRs of about 15% to 20% in the second-line setting, and well-tolerated. Studies of novel checkpoint inhibitor combinations aim to improve survival, quality of life, and other key outcomes compared with chemotherapy or checkpoint monotherapy. How does immunotherapy work in mUC? Compared with most other cancers, UC is enriched for mutations linked to exposure to tobacco and environmental carcinogens.8 This high mutational burden promotes the formation of “neo-antigens,” foreign proteins that are recognizable by the host immune system.9 In the cancer immunity cycle, cancer cells die and release tumor neoantigens, which antigen-presenting cells uptake and then traffic to tumor-draining lymph nodes and present to naïve T cells.10 Primed, activated cytotoxic T cells then migrate back to tumor tissue, where they exert anti-tumor immune effects.10 Antibodies targeting programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) enhance this process by inhibiting the PD-1 checkpoint pathway, which enables the immune system to engage the tumor. This sounds well and good, but does it work in practice? A phase 1a trial of atezolizumab (15 mg/kg IV every 3 weeks for up to 1 year) in 85 mUC patients provided our first experience of checkpoint blockade in advanced UC.11 Approximately 30% of patients had a complete or partial response (CR or PR), and responses were rapid and durable, with a median time to first response of 42 days (range, 38-85 days); median duration of response was not reached.11 These results triggered many more trials, leading to the U.S. Food and Drug Administration (FDA) approvals of the 5 agents we have today. 

Currently, five immune checkpoint inhibitors are FDA- approved for the second-line treatment of locally advanced or mUC that has progressed during or after platinum-based chemotherapy: atezolizumab,14,22 pembrolizumab,9,19 nivolumab,16,21 durvalumab,17,20 and avelumab.24,19 These drugs have ORRs of 15%-21% and median OS times of 7-8 months. Atezolizumab and pembrolizumab are also approved for the first-line treatment of mUC in cisplatin-ineligible patients. Let’s review these immune checkpoint inhibitors in more detail. 

Second-Line Immunotherapy 
Atezolizumab 
In May 2016, atezolizumab, a monoclonal antibody targeting PD-L1, became the first immune checkpoint inhibitor to receive FDA approval in the mUC setting.22 Accelerated approval was based on the results of a single-arm, phase II, two-cohort trial of 310 patients (IMvigor 210) who received atezolizumab (1200 mg every 3 weeks) until loss of clinical benefit.28 Over a median follow-up of 17.5 months (range, 0.2-21.1 months), median time to first RECIST v1.1 response was 2.1 months (range, 1.6-8.3 months) among the 119 patients in the second-line cohort.28 Seven more patients developed a CR and PR with longer follow-up.28 These data illustrate some of the most important aspects of immune checkpoint inhibition: Patients often respond early, and ongoing treatment tends to induce additional responses. 

Atezolizumab’s accelerated FDA approval was contingent on further studies. Accordingly, the randomized, phase III IMVigor 211 trial enrolled 931 patients with platinum-refractory mUC who had progressed despite up to two prior lines of therapy that included platinum-based chemotherapy. Patients received either atezolizumab (1200 mg every 3 weeks) until loss of clinical benefit or investigator’s choice of chemotherapy (vinflunine, docetaxel, or paclitaxel every 3 weeks) until RECIST v1.1 progression.11 The primary endpoint was OS at the highest levels of PD-L1 expression (at least 5% of cells as measured by qualitative immunohistochemical analysis [IC 2/3]).11 

In May 2017, it was reported that IMVigor 211 missed this primary endpoint, which was partly attributed to the chemotherapy arm exceeding assumptions about OS on which the study was based.27 In the ICS 2/3 cohort, the hazard ratio [HR] for death was 0.87 and the 95% confidence interval [CI] crossed 1.0 (0.63 to 1.21; P = .41).36 Among ICS 2/3 patients, median OS was 11.1 (8.6 to 15.5) months with atezolizumab and 10.6 (8.4 to 12.2) months with chemotherapy, and 12-month OS rates were 46% (37% to 56%) and 41% (32% to 50%), respectively.36 

Although IMVigor 211 was reported as a negative study, it’s important to note that the hazard ratio in the intention-to-treat analysis favored atezolizumab and reached statistical significance (HR, 0.85; 95% CI, 0.73 to 0.99; P = .04). Regardless of treatment, survival curves were relatively higher in the ICS 2/3 cohort for both arms than in the intention-to-treat population, underscoring the fact that PD-L1 expression, as assessed by the SP142 assay on tumor infiltrating immune-cells, predicts for better outcomes in patients with mUC.48,49 Thus, using ICS 2/3 patients as the population of interest for the primary endpoint may have contributed to the negative results of IMVigor 211. 

Pembrolizumab 
Pembrolizumab, a monoclonal antibody targeting PD-1, was approved in May 2017 for patients with locally advanced or mUC and disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-based treatment.19 Approval was based on the international, phase III KEYNOTE-045 study, which compared second-line pembrolizumab with investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy in 542 such patients.24 

After a median follow-up of 14.1 months, median OS was 10.3 months (95% CI, 8.0 to 11.8 months) in the pembrolizumab arm and 7.4 months (6.1 to 8.3 months) in the chemotherapy arm. Estimated OS rates were 43.9% (37.8% to 49.9%) for pembrolizumab and 30.7% (25.0% to 36.7%) for chemotherapy, yielding a highly significant HR for death of 0.73 (95% CI, 0.59 to 0.91; P = .002).24 Pembrolizumab’s ORR was 21.1%, nearly twice that of chemotherapy (11.4%). Median duration of response (DOR) was not reached with pembrolizumab vs. 4.3 months with chemotherapy.24 

In an updated report of KEYNOTE-045 (data cutoff, May 19, 2017) at the 2017 annual meeting of the European Society for Medical Oncology (ESMO), OS rates were 33.2% for pembrolizumab and 19.7% for chemotherapy, further lowering the HR for death to 0.70 (95% CI, 0.57 to 0.86; P = .0003).29 Clearly, mUC patients can have durable responses to second-line immune checkpoint inhibition. 

Nivolumab 
Nivolumab, another anti-PD-1 antibody, was approved in February 2017 for treating patients with platinum-resistant locally advanced or mUC.21 Accelerated approval was based on the single-arm, phase II, open-label CheckMate 275 study of 270 such patients who had progressed despite platinum-based chemotherapy and whose tumor tissue samples were evaluable for PD-L1.30 Patients received nivolumab (3 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. Outcomes were enriched among patients with higher levels of PD-L1 expression: Median OS was 8.7 months (95% CI, 6.1 months to not reached) overall, 5.6 months (4.3 to 8.1 months) in patients with less than 1% PD-L1 expression, and 11.3 months (8.7 to NR) in patients with at least 1% PD-L1 expression.30 Similarly, ORR per RECIST v1.1 was 19.6% (95% CI, 15.0% to 24.9%) overall, 16.1% in patients with less than 1% PD-L1 expression, 23.8% in those with at least 1% PD-L1 expression, and 28.4% in those with at least 5% PD-L1 expression. Note, however, that second-line chemotherapy has about a 10% to 12% ORR in UC, making it less active than PD-1 pathway inhibition regardless of PD-L1 expression level. Thus, in the clinic, there is little value in testing PD-L1 expression in second-line mUC patients. 

Durvalumab 
Durvalumab, which targets PD-L1, received accelerated FDA approval in May 2017 for treating platinum-resistant locally advanced or mUC.20 Approval was based on data from 191 such patients who were part of a large phase I/II study (Study 1108) of durvalumab monotherapy (10 mg/kg every 2 weeks for 1 year) in patients with advanced solid tumors. The primary endpoints were safety and tolerability; key secondary endpoints included ORR per RECIST v1.1, disease control rate, DOR, PFS, and OS.31-34 Tumor assessments for PD-L1 expression occurred at weeks 6, 12, and 16 and every 8 weeks thereafter during treatment. Patients were offered retreatment with durvalumab upon disease progression.31-34 

So far, durvalumab is showing a tolerable safety profile and early and durable antitumor activity in several tumor types.31-34 Updated analyses of 191 patients reported in 2017 included response rates of 17.8% overall, 27.6% in PD-L1+ patients, and 5.1% in patients with low or undetectable PD-L1.35 

Avelumab 
Avelumab was approved by FDA in May 2017 for treating advanced or mUC in the post-platinum setting.18 Approval was based on the phase Ib JAVELIN Solid Tumor trial, which evaluated its safety and efficacy in 241 patients with confirmed mUC who were cisplatin-ineligible or who had progressed after platinum-based therapy.23 Patients received avelumab (10 mg/kg IV) every 2 weeks.23 The ORR was 18% in a preliminary analysis of data from 44 patients.23 Response rates were enriched in patients with high PD-L1 expression (54%) compared with patients with low expression (<5% tumor cells; 4%).23 

As a fully humanized monoclonal antibody, avelumab can cause infusion reactions, which are not typical with other immune checkpoint inhibitors.47 In the JAVELIN trial, 20.8% of patients developed an infusion reaction and 59% developed at least one treatment-emergent adverse event. These were usually of low to moderate (grade 1 or 2) severity and most commonly included infusion reactions, fatigue, nausea, asthenia, pyrexia, diarrhea, and pruritus. 

First-Line Options 
The FDA also has approved atezolizumab14 and pembrolizumab15 for the first-line treatment of advanced UC in cisplatin-ineligible patients. Approval of atezolizumab was based results from cohort 1 of the IMVigor 210 trial that consisted of 119 cisplatin-in- eligible patients with previously untreated mUC.37 The ORR was 23%, and 9% of patients had a CR37 which is notable when you compare this to the 36% ORR and 4% CR rate, with few, if any, durable responses historically observed with gemcitabine and carboplatin, as demonstrated in the EORTC Study 30986 of gem- citabine+carboplatin in cisplatin-ineligible mUC patients6 The median OS for atezolizumab was 15.9 months, which compares favorably to the 9-10 months observed with carboplatin-based regimens, thus, atezolizumab is showing promise in the first-line mUC setting. However, we need time for the data to mature and will be especially interested in the 5-year OS rate given that it was approximately 0% with gemcitabine-carboplatin. 

Approval of the first-line pembrolizumab in advanced and mUC was based on the results of the KEYNOTE-052 trial, in which 370 cisplatin-ineligible patients with treatment-naïve mUC, and ECOG PS scores of 0-2 received 200 mg pembrolizumab every 3 weeks.50 In the most recent report, 7% of patients had a CR and 22% had a PR, for a 29% ORR (95% CI, 25% to 34%) — about a 5% increase compared with the initial data cutoff approximately 5 months earlier.50 This improved ORR included 10 conversionsof PRs to CRs and 9 conversions of stable disease to PRs, again showing that once an anti-tumor immune response is generated, it can be long-lived. 

Pembrolizumab also elicited responses in 26% of patients with visceral metastases, compared with a 14% rate for atezolizumab in IMVigor 210. However, the KEYNOTE-052 data are relatively immature and we await results for the primary outcome of interest, survival. 

Enhancing Anti-Tumor Immunity Beyond PD-1/L1 Blockade 
Trials of PD-1 pathway inhibitors show that most patients with advanced or mUC do not respond to monotherapy, but that responders experience durable results. To enhance anti-tumor immunity and extend its benefits to more patients, we need to develop novel therapies or combination regimens. In the latter scenario, we might combine multiple checkpoint inhibitors or combine checkpoint blockade with chemotherapy, radiation, anti-angiogenic therapy, or agents that target fibroblast growth factor receptor 3 (FGFR3) or the DNA damage repair deficiency.38-40 

Several relevant trials of combination regimens are underway and should yield results in the next 1-2 years. Ipilimumab and tremelimumab, which target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), are in phase III trials in the first-line setting.1 Additionally, inhibitors of indoleamine 2,3-dioxygenase (IDO) appear to be active and very well tolerated when added to PD-1/ PD-L1 inhibitor therapy. 

Indoleamine-2,3-dioxygenase 
Indoleamine-2,3-dioxygenase (IDO), which is induced by interferon gamma (IFNγ), catalyzes the degradation of tryptophan to kynurenine.51 This metabolic pathway is activated as a consequence of effector T-cell activation, and the disrupted ratio of tryptophan to kynurenine is highly immunosuppressive to effector T-cells.51 

Ongoing studies of IDO-based agents include epacadostat (NCT02298153, NCT02318277), indoximod, (NCT03301636, BMS986205 (NCT03192943, NCT02658890), and PF-06840003.58 The most mature data exist for epacadostat, which was active and well-tolerated in combination with PD-1 blockade in phase I trials.52-54,41 For example, in the phase I ECHO-202/KN037 trial, pem- brolizumab+epacadostat had a 35% ORR in the mUC subgroup and its resembled that of single-agent PD-1 pathway inhibition.41 So far, responses seem to be at least as durable as with anti-PD-1 pathway monotherapy and with similar safety. These results have spurred plans for phase III trials of pembrolizumab+epacadostat in the second-line mUC setting and for first-line treatment of cisplatin-ineligible patients.41,55 

Localized Disease: Muscle-Invasive and Non-Muscle Invasive Bladder Cancer 
Muscle-invasive bladder cancer provides a unique platform for testing combinations of radiation and PD-1 blockade in patients with localized UC. Using these combinations earlier in the disease course could offer substantial traction, but it must be done in a rational manner. 

Chemoradiation is a standard treatment option for patients with localized UC who refuse radical cystectomy or who are not candidates for surgery. Radiation enhances T-cell priming, which can convert an uninflamed tumor to an inflamed one that may be more likely to respond to PD-1 blockade.58 In this sense, radiation can be immunogenic. In terms of which chemotherapy pairs best with radiation, an ideal treatment is highly radiosensitizing at very low doses, thereby minimizing the chances of depleting the immune cells we are trying to stimulate. In phase I and II trials, gemcitabine was highly radiosensitizing at less than 5% of the systemic dose.43 And studies from preclinical models suggest that gemicitabine may also deplete certain immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs).42

Other trials are investigating chemotherapy, radiotherapy, and PD-1 pathway inhibitor combinations in muscle-invasive bladder cancer. I am principal investigator for a multicenter phase II trial (NCT02621151) in which we are testing the addition of immunotherapy to chemoradiation in patients who refuse or are ineligible for radical cystectomy. The design of this trial is unique in that patients first receive lead-in treatment with a single dose of pembrolizumab (200 mg) followed by maximal transurethral resection of bladder tumor (TURBT). After 3-4 weeks, patients receive 4 weeks of hypofractionated radiation therapy at 52 Gy plus twice-weekly gemcitabine (27 mg/m2) and pembrolizumab (200 mg every 3 weeks for 3 doses). After another 12 weeks, patients undergo TUR of the tumor bed. Six patients are completing the safety lead-in component of this trial, after which an additional 48 patients will be enrolled. 

Additionally, trials are evaluating PD-1 pathway inhibitor therapy in non-muscle-invasive bladder cancer (NMIBC). Phase Ib or phase II studies are evaluating of atezolizumab alone or with Bacillus Calmette-Guerin (BCG) in patients with high-risk NMIBC (WO29635/NCT02792192), in patients with non-metastatic transitional cell carcinoma of the bladder (NCT02451423), and in BCG-unresponsive NMIBC (SWOG S1605/NCT02844816). Also, the phase II KEYNOTE-057 study is evaluating pembrolizumab in BCG-refractory high-risk NMIBC.46 

Toxicity 
Toxicity of immunotherapy remains a major concern and can affect nearly every organ system. Although the most frequent toxicities involve the skin, colon, endocrine organs, liver, and lungs, rarer toxicities, such as neuromuscular disorders and myocarditis, can be serious or even lethal.56 All these potential toxicities merit careful vigilance.56 

In studies to date, about 15% to 19% of patients who receive PD-1 pathway inhibitor monotherapy develop severe (grade 3-4) immune-related adverse effects (irAEs).56 Although these rates are better than what we see with chemotherapy, irAEs can be difficult to manage and will become more prevalent as combination checkpoint blockade becomes the standard of care in UC, and as patients with a history of autoimmunity (which was exclusionary in trials) choose these therapies. Right now, we have no reliable way to predict who will develop irAEs, or when they will occur. In all cases, irAEs need early detection and aggressive treatment with systemic corticosteroids to prevent life-threatening consequences. Tumor necrosis factor antagonists such as infliximab are highly effective in managing irAEs that are refractory to high- dose corticosteroids or that recur during or after steroid taper. Managing complex toxicities requires the early involvement of a specialist. 

Clinical Perspective 
In the clinic, we administer immune checkpoint inhibitors intravenously over 30 to 60 minutes as per the FDA label for each individual agent; no premedications are required. Dosing schedules vary from every 2 weeks to every 4 weeks based on the agent. Some debate persists about the relative efficacy of anti-PD-1 vs. anti-PD-L1 therapy, and it’s difficult to reach consensus on this question because we lack head-to-head trials. I recommend choosing what’s available, on formulary, and on label for the patient. In terms of monitoring, scans should be repeated every 8 to 10 weeks. Because responses to treatment tend to occur early, consider more frequent scans in your high-risk, highly symptomatic patients. Look for improvements in appetite, pain, energy, and sense of well-being after the second treatment dose. Patients who continue to progressing clinically with worsening symptoms at the time of the second or third dose are likely not responding, should have early repeat imaging and may need to discontinue treatment, and be offered an alternative therapy. 

Pseudoprogression, or “false growth,” is observed in less than 5% of patients who are undergoing treatment for mUC.33 This is a clinical diagnosis; we have no reliable way to distinguish false from real growth on a scan. Consider pseudoprogression when a scan shows progression despite clinical improvement and stable to improved labs. Without this disconnect, a scan showing progression is probably real. 

Questions also persist about how to sequence immunotherapy and chemotherapy. Without head-to-head trials, we lack a definite answer, but in my clinical experience, patients who are highly symptomatic and have a high disease burden should probably receive chemotherapy first to rapidly control their disease. 

Finally, keep in mind that the toxicity of immune checkpoint inhibitors varies in nature, severity, and timing. Patients can do well on immunotherapy for months and then develop severe, life-threatening irAEs. For all patients, remain a high degree of vigilance for toxicity throughout treatment and implement early, aggressive management if irAEs occur. 


Written by: Arjun Balar, MD. Director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center

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