Urothelial cancer (UC), also known as transitional cell carcinoma, is the 5th most common cancer in the United States, and it arises more commonly in the bladder than in other parts of the urinary tract. An estimated 79,030 new cases of UC are expected in 2017. Of these cases, there will be about 12,240 deaths in men and 4630 in women. Bladder cancer accounts for approximately 5% of all new cancers. For the past 30 years, bladder cancer-related mortality had remained unchanged.1,2
The standard of care for first-line treatment of advanced/metastatic UC had been and remains platinum-based chemotherapeutic regimens. The 5-year survival rate is about 15%.1,2 A quantum leap was made with the advent of immune checkpoint inhibitors. These compounds and their mechanisms of action and potential clinical uses have been the subject of numerous review publications.3-5
Briefly, once activated by an antigen through an appropriate antigen-presenting cell, T‑cells upregulate the expression of cell-surface proteins, which are “immune checkpoints” that help to control immune response. Several checkpoint proteins have been identified: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1), and PD-1 programmed death-ligand-1 (PD-L1). PD-L2 has been less studied, and its precise role remains elusive. Drugs that inhibit these immune checkpoint proteins have demonstrated significant clinical activity across tumor types. These proteins are thought to operate at different stages of an immune response.3-5
The PD-1 pathway is located in the tumor microenvironment, where it dampens ongoing immune responses after T-cells have been activated. CTLA-4 is expressed only on T-cells, whereas PD-1 is expressed on a broad range of cells that include activated and “exhausted” (nonfunctional) T‑cells, tumor-infiltrating T-cells, antigen-presenting cells, B‑cells, dendritic cells, and macrophages. The PD-1 pathway consists of the PD-1 receptor and its 2 ligands—PD-L1 and PD-L2.3-5
Many types of tumors express PD-L1, including UC. The PD-1/PD-L1 pathway is considered the main route of escape from the immune system. The PD-L2 ligand is expressed by a more limited cell population and has not been well-studied. Notably, UC carries one of the highest mutational loads of all studied cancers, making it a candidate for immune checkpoint blockade, mainly due to production of “neoantigens.” Mutant proteins result in the production of abnormal antigens, called neoantigens, which the immune system can recognize as foreign because of their novelty.3-5
Two years ago, there were no therapies approved by the U.S. Food and Drug Administration (FDA) for locally advanced or metastatic UC that previously progressed on platinum-based chemotherapy. Second-line chemotherapy had only modest response rates and concern of toxicity. In May 2016, the FDA gave accelerated approval to atezolizumab, a PD-L1 inhibitor, for use in advanced UC patients who have progressed on a platinum-based regimen.6,7 During the past year, we have seen a dizzying rate of approvals by the FDA for immune checkpoint inhibitors to treat metastatic UC in patients whose disease progressed despite platinum-based chemotherapy. Four additional immune checkpoint inhibitors are now available in that setting: 2 anti-PD-1s, nivolumab and pembrolizumab, and 2 anti-PD-L1s, avelumab and durvalumab. Moreover, atezolizumab and pembrolizumab are both FDA-approved for cisplatin-ineligible patients who have not received chemotherapy for advanced UC.
KEY CLINICAL TRIALS
Atezolizumab is a humanized, engineered immunoglobulin G1 monoclonal antibody that inhibits binding of PD-L1 to receptors PD-1 and B7-1, thereby restoring anti-cancer T-cell activity and reinvigorating suppressed immune cells.
Atezolizumab’s accelerated approval was based on the results of a phase II, global, multicenter, single-arm 2-cohort trial of 310 patients.7,8 Cohort 1 consisted of patients who were treatment-naïve in the metastatic setting and considered to be cisplatin-ineligible. Cohort 2 comprised those with inoperable locally advanced or metastatic UC whose disease had progressed after prior platinum-based chemotherapy.7 Patients enrolled in Cohort 2 received a fixed dose of 1200 mg intravenous atezolizumab administered every 3 weeks. Results of Cohort 2 were reported first, forming the basis of the FDA’s accelerated approval. Atezolizumab conferred significant clinical benefit to patients in this cohort (IMvigor 210 Cohort 2 [NCT02108652]) who progressed during or following platinum-based treatment.7 Analyses included the association between gene expression profiling, CD8+ T‑cell infiltration, and mutation load, with independent review facility-assessed objective response. Patient tumor samples were prospectively and centrally assessed for PD-L1 expression by immunohistochemistry using the SP142 assay. The PD-L1, tumor-infiltrating immune cell (IC) status was defined by the percentage of PD-L1-positive ICs: IC0 (< 1%); IC1 (≥ 1% but < 5%); and IC2/3 (≥ 5%). The patients were evenly distributed among these groups.7
According to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the primary analysis, treatment with atezolizumab resulted in a meaningful objective response rate (ORR) for each immunohistochemistry (IHC) group. After a median follow-up of 11.7 months, the ORRs were 26% in the IC2/3 group, 18% in the IC1/2/3 group, and 15% in all patients. This corresponded to 15 individuals with complete response (CR) by RECIST 1.1 and 16 patients (5%) with CR by modified RECIST by investigator review. Of PD-L1-negative patients, 8% to 13% responded (depending on the criteria used), including two who had CR. At data cut-off, ongoing responses were reported in 38 (84%) of the 45 responding patients, and the median time to response was 2.1 months. According to RECIST 1.1, median progression-free survival (PFS) was 2.1 months in all patients and was similar across PD-L1 IC groups. However, when the immune-related response criteria were used, median PFS increased in all groups. The effect was most pronounced in the IC2/3 group: median PFS was 4.0 months in that group, 2.9 months in the IC1/2/3 group, and 2.7 months overall. Median overall survival (OS) was 11.4 months in the IC2/3 group, 8.8 months in the IC1/2/3 group, and 7.9 months overall. Atezolizumab was well-tolerated, with mostly mild or moderate treatment-related adverse events (AEs).7
Clinical data from Cohort 1 were presented later.9 Cohort 1 included 119 patients who were ineligible for first-line cisplatin because of renal impairment (GFR > 30 but < 60 mL/min), ≥grade II hearing loss or peripheral neuropathy, or Eastern Cooperative Oncology Group Performance Status 2. The ORR was 23%, which included a 9% CR rate after median follow-up of 17.2 months.9 Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median PFS was 2.7 months, and median OS was 15.9 months, respectively. Tumor mutation load was strongly associated with response.9 Toxicity profile was similar to Cohort 2. Atezolizumab was FDA-approved (accelerated approval) as first-line therapy in cisplatin-ineligible patients who have not received chemotherapy for advanced disease.
Recently, the results of the randomized, phase III trial with atezolizumab vs. chemotherapy in patients who progressed on or after platinum-based chemotherapy were presented.10 The trial did not meet its primary endpoint of OS benefit with atezolizumab in those with high PD-L1 expression (IC2/3 group); however, there was a statistically significant OS difference in the entire study population favoring atezolizumab. Patients with high PD-L1 expression appeared to have longer OS compared with the overall study population, suggesting that based on this assay, PD-L1 expression may be a favorable prognostic rather than predictive biomarker. Individuals on vinflunine fared better than expected in the study’s statistical assumptions; publication of results is pending.
Nivolumab is fully human IgG4 PD-1 immune checkpoint inhibitor antibody. The FDA granted accelerated approval to nivolumab in patients with locally advanced or metastatic UC who have disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.11 Patients with advanced or metastatic solid tumors had been enrolled in a 2-stage, multiarm, phase I/II trial (CheckMate 032) of nivolumab alone or in combination. After results of patients enrolled in nivolumab monotherapy were reported,12 the pivotal study (CheckMate 275) was conducted to confirm and expand the findings. CheckMate 275 formed the basis of approval for nivolumab.13
CheckMate 275 is a single-arm study treating 270 patients with locally advanced or metastatic UC who progressed during or following platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. They received nivolumab, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was ORR confirmed by blinded independent review committee using RECIST 1.1 in all treated patients and by tumor PD-L1 expression (≥ 5% and ≥ 1%).13 Confirmed ORR was 19.6% in all comers, and 28.4% in patients with PD-L1 expression of 5% or more. For those with a PD-L1 expression of 1% or higher, ORR was 23.8%, and it was 16.1% for patients with a PD-L1 expression of below 1%. Median duration of response was not reached in the entire trial population. At the time of analysis, responses were ongoing in 77% of 52 patients who had confirmed response. The recommended dose and schedule for nivolumab for the above indication is 240 mg intravenously every 2 weeks. Grade 3-4 treatment-related AEs occurred in 18% of patients, most commonly fatigue and diarrhea, while 3 deaths were attributed to study therapy.13 Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable UC.12,13
Pembrolizumab is another PD-1 immune inhibitor that is a humanized monoclonal IgG4-kappa isotype antibody against PD-1. The FDA granted regular approval to pembrolizumab for patients with locally advanced or metastatic UC who have disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.14
Approval for pembrolizumab as second-line indication was based on data from the KEYNOTE-045, which was an open-label, international, phase III trial of 542 patients with advanced UC that recurred or progressed after platinum-based chemotherapy. Patients were randomized to receive either pembrolizumab at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy. The co-primary endpoints were OS and PFS. All patients were assessed as well as people who had tumor PD-L1 combined positive score (CPS) of at least 10.15 The median OS in the total population was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group. The median OS among patients who had a tumor PD-L1 combined positive score of at least 10 was 8.0 months in the pembrolizumab group and 5.2 months in the chemotherapy group. The duration of PFS did not differ between the 2 groups. Fewer treatment-related AEs of any grade were reported with pembrolizumab than with chemotherapy (60.9% vs. 90.2%), and there were also fewer AEs of grade 3-5 reported with pembrolizumab than with the chemotherapy group (15.0% vs. 49.4%).15 A report on longer follow-up confirmed the published report.16
First-line pembrolizumab is being studied in KEYNOTE-052, a multicenter, phase II trial of patients with advanced UC who were ineligible for cisplatin. An early analysis was presented on the first 100 patients after a median follow-up of 8 months.17 The recommended pembrolizumab dose and schedule for the treatment of UC is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. PD-L1 expression was not an entry criterion, but it was prospectively assessed in tumor and immune cells as a putative biomarker. Efficacy and safety were assessed in the 370 patients who had one or more doses of pembrolizumab.17-20 After a median follow-up time of 9.5 months, the ORR was 29%.19 Response was observed across subgroups; precisely 27 patients achieved (7%) CR and 81 (22%) partial response. Another 67 patients (18%) had stable disease as best response. Median time to response was 2 months (range, 1-9). When the data were reported, 67% of responses were ongoing with 82% of responses lasting for at least 6 months. Median duration of response had not yet been reached. A small proportion of patients experienced grade 3 or higher drug-related AEs (19%). Results confirmed that pembrolizumab elicits clinically meaningful, durable responses in cisplatin-ineligible advanced UC. Consistent with PD-1 pathway biology, biomarkers, for example, gene expression profiling (GEP) and PD-L1 CPS showed association with response.19 Pembrolizumab was well-tolerated across cisplatin-ineligible patients, including the elderly and those with poor performance status, providing a new first-line treatment option (like atezolizumab), including for chemotherapy-unfit patients.20 The FDA granted accelerated approval to pembrolizumab as first-line therapy in those who are cisplatin-unfit and have not received chemotherapy for advanced UC based on the KEYNOTE-052 clinical trial.21
Avelumab is a fully human anti–PD-L1 IgG1 antibody that inhibits PD-1/PD-L1 interactions while leaving the PD-1/PD-L2 pathway intact. This agent differs from the 4 other anti–PD-L1/PD-1 antibodies in that it has an additional mechanism of action of antibody-dependent, cell-mediated cytotoxicity in vitro.22 The FDA granted accelerated approval to avelumab for patients with locally advanced or metastatic UC whose disease progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy.22,23 Approval was based on data from an open-label, single-arm, multicenter study that enrolled patients with locally advanced or metastatic UC whose disease progressed on or after platinum-based therapy or within 12 months of a platinum-containing neoadjuvant or adjuvant chemotherapy regimen.22 Exactly 44 individuals received avelumab 10 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. All patients received pre-medication with an antihistamine and acetaminophen prior to each avelumab administration, with the primary objectives being safety and tolerability. Secondary objectives included confirmed ORR by RECIST 1.1, PFS, OS, and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on 5% or more of tumor cells. Grades 3/4 treatment-related AEs happened in 6.8% of patients and included asthenia, AST elevation, creatine phosphokinase elevation, and anorexia. The confirmed ORR by independent central review was 18.2%. Median duration of response was not reached, while responses were ongoing in 6 patients, including 4 of 5 CRs; 7 out of 8 patients who responded had PD-L1-positive tumors. The median PFS was 11.6 weeks, and the median OS was 13.7 months, respectively. The authors concluded that avelumab was well-tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.22
Durvalumab is a human IgG1‑kappa monoclonal antibody targeting PD-L1. The FDA granted accelerated approval to durvalumab for the treatment of patients with locally advanced or metastatic UC who have disease progression during or after platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.24 Durvalumab had demonstrated a manageable safety profile in early-phase trials. The most common AEs in at least 15% of patients were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection The recommended dose of durvalumab is 10 mg/kg, administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.24-27 Approval was based on a single-arm phase I/II trial of patients including those with locally advanced or metastatic UC whose disease progressed on/after, or were ineligible for, or refused prior chemotherapy.25-27 . As of October 24, 2016 (data cut-off), 191 patients had received treatment; median follow-up was 5.8 months. Grade 3/4 treatment-related AEs occurred in 6.8% of patients; grade 3/4 immune-mediated AEs occurred in 2.1% of patients. Confirmed ORR as assessed by blinded independent central review per RECIST 1.1 was 17.8%, which included 7 CRs. When analyzed by PD-L1 expression status, the confirmed ORR was 27.6% in patients with a high PD-L1 score and 5.1% in patients with a low/negative PD-L1 score, respectively.
CHOOSING A CHECKPOINT INHIBITOR
Choosing the appropriate immune checkpoint blocker is probably largely based on efficacy, safety, level of evidence, treatment interval, patient convenience, available guidelines, local care paths, insurance coverage, and cost. While it is inappropriate to compare different trials, the efficacy and safety of the 5 agents appear relatively comparable, while no comparative cost-effectiveness data are available, and treatment frequency is either 2 or 3 weeks. Based on the level of evidence, the only medication with improved OS benefit over chemotherapy in a randomized, phase III trial is pembrolizumab, and this will probably be the most used agent in the post-platinum treatment setting; the other 4 drugs have comparable phase I/II trials data. In the cisplatin-ineligible first-line setting, currently only atezolizumab and pembrolizumab are FDA-approved based on phase II, single-arm trials data.
For patients with metastatic UC who are treatment-naïve, either cisplatin-based chemotherapy or a clinical trial is the recommended initial treatment. If the patient is cisplatin-ineligible due to impaired renal function, poor performance status, notable hearing loss, neuropathy, or heart failure, the options include immunotherapy, for example, atezolizumab, or pembrolizumab, or non-cisplatin chemotherapy, for instance, gemcitabine/carboplatin or single-agent chemotherapy, or clinical trial. For those who have received platinum-based chemotherapy and immunotherapy, a clinical trial is the preferred option; otherwise, chemotherapy with single-agent taxane (United States), vinflunine (European Union), or other medications are frequently used.
Combination therapies with other immune checkpoint inhibitors, chemotherapy, radiation, targeted, and anti-angiogenic therapies, and such are being tested in many cancer types, including UC.28 One example with recently presented data includes pembrolizumab with epacadostat.29 The latter is an orally available hydroxyamide and an inhibitor of indoleamine 2,3-dioxygenase, an intracellular enzyme that initiates the breakdown of tryptophan in the tumor microenvironment and suppresses T-cell-mediated immune surveillance. So far, pembrolizumab with epacadostat was generally well-tolerated and was associated with higher response rate compared with those previously reported with PD-1-inhibitor monotherapy in advanced UC.29 Moreover, the ipilimumab-with-nivolumab combination has shown promising results that support the design of a phase III trial in the first-line setting comparing that combination to platinum-based chemotherapy.30 There are 3 additional first-line, large, randomized, phase III trials with durvalumab, atezolizumab, or pembrolizumab, comparing platinum-based chemotherapy with immunotherapy (or their combination in two of those trials). Moreover, there are 2 randomized trials that test whether switch maintenance immunotherapy may benefit patients who had received platinum-based chemotherapy as first line without progression (pembrolizumab vs. placebo; avelumab vs. observation). There are also numerous other trials evaluating several combination strategies in different disease settings.
From studies on immune checkpoint blockers, it is becoming increasingly apparent that standard efficacy measurements may not keep up with modern immunotherapy. Response rates and other historic surrogates of efficacy in trials of metastatic UC chemotherapy (e.g., PFS) assessed at early time points might not fully capture the benefit of these agents. In some trials the number of responses may increase over time showing atypical kinetics and delayed responses; however most responses are rapid and durable. Benefit may be noted even in the absence of classical RECIST 1.1 response, an observation common to immunotherapy but not to chemotherapy trials, which may impact the optimal timing of initial restaging scans. RECIST 1.1. criteria have been the standard used to assess radiologic response, although utilization of immune-related RECIST may result in a longer PFS. The potential adoption of the latter in more clinical trials and the broader community practice as well as its impact on decision making and outcomes is an area of active discussion. Treatment-discontinuation timing is often a hard decision, especially in the absence of clinical progression and available subsequent standard treatment options or clinical trials. Rates of pseudoprogression do not appear frequent, but they may be underestimated in UC.
A substantial proportion of patients treated with immune checkpoint inhibitors may have little or no benefit. The establishment of valid predictors of treatment response is becoming a priority.31,32 Immune checkpoint inhibitors are more active in tumors with higher mutation load and/or microsatellite instability (MSI-high)/mismatch repair deficiency across tumor types.33-35 Accumulating data from The Cancer Genome Atlas and other datasets indicates that UC carries one of the highest mutation loads, which may explain at least partially why a number of UC tumors may respond to immunotherapy.31-35 The optimal method and cut-off of high vs. low mutational load are being debated; there is variability among the different assays used and reports.
Additional data suggest that gene expression signatures can be used to separate UC into molecular subtypes that may correlate with differential responses to immunotherapy.7 The analysis of an 18-gene T-cell inflamed GEP signature from the Keynote 052 trial showed significant associations with response. An appreciable number of additional responders were captured using T-cell inflamed GEP vs. PD-L1 immunohistochemistry.19
Moreover, the presence of germline (which is much higher than previously expected in UC and will increase need and usage of genetic counseling) or somatic DNA repair gene mutations appears to have a strong correlation with response to immune checkpoint inhibitors, probably traceable to the generation of neoantigens.36-38 Last but not least, PD-L1 protein expression is clearly a suboptimal biomarker with contradictory results in the different studies, mainly depending on the assay, methodology, cell types measured, and cut-off used. An expanding number of clinical, pathologic, molecular, and imaging biomarkers are being explored, but they need to demonstrate clinical utility before entering clinical practice.
A NEW PARADIGM
Cancer care has always centered on the organ on which the tumor originated. Even in this age of personalized medicine, drugs that target specific tumor types are the norm. In May 2017, the FDA granted the first tissue site-agnostic approval to pembrolizumab for patients with unresectable or metastatic, MSI-high, or mismatch repair-deficient solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. The approval was based on data from 149 individuals with MSI-high or mismatch repair-deficient cancers enrolled across 5 uncontrolled, multi-cohort, multi-center, single-arm clinical trials. Precisely 90 patients had colorectal cancer and 59 were diagnosed with one of 14 other cancer types and treated with pembrolizumab. The ORR was 39.6%, including 7.4% CR and 32.2% partial response rates, and was 36% in those with colorectal cancer and 46% with other tumor types.39 There are also an increasing number of clinical trials that are evaluating “precision or personalized medicine” approaches targeted to the molecular makeup of the tumor based on specific biomarkers, regardless of the organ of tumor origin. Such trials may be either “umbrella type,” which evaluate the clinical utility of several biomarkers and therapies in the same tumor type, or “basket type,” which assess biomarkers and therapies in several tumor types.
In conclusion, at the era of molecular medicine, deeper understanding of tumor biological and immunologic underpinnings can further refine the efficacy of immunotherapy via biomarker-based patient selection. However, until biomarkers are fully validated and prove to have clinical utility for patient selection, their use in immunotherapy in UC is currently investigational.
Written By: Petros Grivas, MD, PhD Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University
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21. KEYTRUDA® (pembrolizumab) is FDA Approved for Urothelial Carcinoma
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39. FDA approves first cancer treatment for any solid tumor with a specific genetic feature