 Immunotherapy has become an increasingly appealing therapeutic strategy for patients with cancer, with many late-stage clinical trials demonstrating overall survival (OS) advantages in melanoma and castration-resistant prostate cancer. More recently, non-small cell lung cancer (NSCLC) has become a focus for the next generation of immune-based therapeutic strategies. Immunotherapy, in particular the use of monoclonal antibodies that block inhibitory immune checkpoint molecules and therefore enhance the immune response to tumors, has shown clinical promise in advanced solid tumors. The clinical rationale for targeting the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathways will be reviewed in this supplement, including a comprehensive review of select ongoing clinical trials that evaluate the potential of targeted immunotherapy in cancer drug development. Emerging clinical data suggest that targeted immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.

Cancer is traditionally treated with conventional therapy (ie, chemotherapy or radiation therapy) or targeted drugs that directly kill tumor cells. While the number of patients who survive cancer has seen significant increases, the “war” rages on.

 More than a century ago, a series of primitive experiments hinted at the potential for harnessing the immune system to fight cancer.

 The immune system protects the body from foreign invading agents by recognizing “nonself” proteins (antigens) displayed on their surface that distinguish them from normal, healthy tissue (“self”). This subsequently initiates a protective response that neutralizes these organisms.

 William Coley was the first to draw a link between the immune system and cancer. He observed spontaneous remission in cancer patients following infection with a mixture of killed infectious agents, dubbed Coley’s toxins.

 In the years that followed, a dynamic and complex relationship between the immune system and cancer was uncovered, giving birth to the concept of immunotherapy.

Cancer cells are normal cells that have acquired numerous hallmark abilities that allow them to become malignant4; thus, they are essentially identified as “self”—part of the host. In spite of this, they often display unusual or inappropriate proteins on their cell surface that allow the immune system to identify them as “non-self,” and an antitumor immune response is often initiated. However, cancer cells have evolved a number of mechanisms to enable evasion of this immune response and render it ineffective. Typically, by the time a cancer becomes detectable, the balance of power between the immune system and the cancer has shifted in favor of the growing tumor, and a state of immune tolerance has been established. Immunotherapy comprises a diverse range of therapeutic approaches intended to harness the immune system to reestablish a targeted antitumor immune response. The goal of cancer immunotherapy is to enable the patient’s immune system to specifically recognize and kill cancer cells.

There are 2 distinct types of immunotherapy: passive immunotherapy uses components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating an immune response in the patient, while active immunotherapy actively triggers an endogenous immune response. Passive strategies include the use of the monoclonal antibodies (mAbs) produced by B cells in response to a specific antigen.

 The development of hybridoma technology in the 1970s and the identification of tumorspecific antigens permitted the pharmaceutical development of mAbs that could specifically target tumor cells for destruction by the immune system. Thus far, mAbs have been the biggest success story for immunotherapy; the 3 best selling anticancer drugs in 2013 were mAbs.

 Among them is rituximab (Rituxan, Genentech), which binds to the CD20 protein that is highly expressed on the surface of B-cell malignancies such as non-Hodgkin’s lymphoma (NHL). Rituximab is approved by the US Food and Drug Administration (FDA) for the treatment of NHL and chronic lymphocytic leukemia in combination with chemotherapy.

 Another important mAb is trastuzumab (Herceptin; Genentech), which revolutionized the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer by targeting the expression of HER2.

To actively drive an antitumor immune response, therapeutic cancer vaccines have been developed. Unlike the prophylactic vaccines that are used preventively to treat infectious diseases, therapeutic vaccines are designed to treat established cancer by stimulating an immune response against a specific tumor-associated antigen. In 2010, sipuleucel- T (Provenge; Dendreon Corporation) was approved by the FDA for the treatment of metastatic, castration-resistant prostate cancer based on results of the IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial in which it improved OS by 4.1 months and reduced the risk of death by 22% versus placebo.

 The advantage of active immunotherapies is that they have the potential to provide long-lasting anticancer activity by engaging both the innate and adaptive arms of the immune response. While mAbs are typically considered passive immunotherapies, there is increasing evidence that they also induce an adaptive immune response via a “vaccination-like” effect.

Despite these successes, immunotherapy has previously faced skepticism and significant disappointment; however, it is now beginning to gather momentum, particularly following the discovery of immune checkpoints and the success of their therapeutic targeting.

 Growing appreciation of the ability of cancer cells to evade the immune response and understanding of how this impacts the development of cancer and resistance to cancer therapy has led researchers to investigate the mechanisms by which immune evasion occurs. This has resulted in recognition of the significant role that immune evasion plays in malignant progression.

Generation of an effective antitumor immune response involves a series of steps that ultimately lead to the death of cancer cells 

 In the first step (step 1), cancerspecific antigens are released from cancer cells and captured by dendritic cells (a type of antigen-presenting cell [APC]). This step must be accompanied by immunogenic signals such as pro-inflammatory cytokines. Next, the dendritic cells present the captured antigen to the immune effector cells—cytotoxic T cells (step 2). This activates and primes the cytotoxic T cells to generate a specific immune response against the cancer-specific antigens (step 3). Activated T cells then traffic to (step 4) and infiltrate (step 5) the tumor and recognize cancer cells by their expression of the specific antigen. They then bind the specific antigen to their T-cell receptor (step 6). The cytotoxic T cell kills the cancer cell (step 7), which results in the release of additional cancer-specific antigens, thereby starting the whole process over again. This cycle ceases to function appropriately in patients with cancer, as tumors are able to break the cycle by affecting any of these 7 steps.

One of the mechanisms by which cancer cells break this cycle is by hijacking immune checkpoint pathways that regulate T-cell responses (step 3) or their function (step 7). As such, significant research efforts have focused on the development of mAbs targeting these proteins. The checkpoint protein that has garnered the most attention is cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab, an antibody that targets CTLA-4, is approved by the FDA. Ipilimumab (Yervoy; Bristol-Myers Squibb) was approved in 2011 for the treatment of melanoma, representing the first new treatment option for melanoma in more than a decade, after demonstrating a clear survival advantage for patients.

 Clinical trials demonstrated that 46% of patients treated with ipilimumab were alive after 1 year, and 24% after 2 years.

A number of other checkpoint proteins are also being examined. The PD-1 receptor and its ligands PD-L1 and PD-L2 are part of the same family of coregulatory molecules as CTLA-4. Several anti-PD-L1 agents are currently being investigated in both solid and hematologic cancers. In September 2014, pembrolizumab (Keytruda; Merck Sharp & Dohme Corp), previously known as MK-3475, was the first to be approved by the FDA. It is indicated for use in patients with advanced or unresectable melanoma who are no longer responding to other drugs.

 The safety profile of pembrolizumab in patients who did not achieve an adequate response to earlier ipilimumab treatment is similar to that observed in ipilimumab-naïve patients.

 Earlier in 2014, nivolumab (Bristol-Myers Squibb) was granted regulatory approval in Japan, also for unresectable melanoma.

 In this supplement, we focus on the clinical development of PD-1/ PD-L1-targeting agents.

		Figure 1. The Generation of Antitumor Immunity

		APC indicates antigen-presenting cell; CTL, cytotoxic T lymphocyte.

		Generation of an effective antitumor immune response involves a series of stepwise events that ultimately form a cyclical response that increases the depth and breadth of the immune response against tumor-associated antigens. In cancer patients, this cycle functions suboptimally, allowing cancer cells to avoid death.

		Reprinted with permission from Chen DS, Mellman I. 

The PD-1 and PD-L1 Pathway in Normal Human Physiology and Neoplasms

Activation of T cells during an immune response is a 2-step process: the first step gives the immune response specificity and requires interaction of T-cell receptors with a specific antigenic peptide-containing complex on APCs. This is followed by an antigen-independent coregulatory signal that determines if the T cell will be switched on or off. The secondary signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T cell, and in the absence of this signal (even in the presence of a target antigen), T cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T cells on) or inhibitory (switching them off).

The 2 known inhibitory checkpoint pathways involve signaling through the CTLA-4 and PD-1 receptors. These proteins are members of the CD28-B7 family of cosignaling molecules that play important roles throughout all stages of T-cell function. The PD-1 receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are expressed on the surface of APCs such as dendritic cells or macrophages. PD-L1 is the predominant ligand, while PDL2 has a much more restricted expression pattern. When the ligands bind to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses T-cell proliferation.

PD-L1 has also been shown to bind to B7-1 (CD80), an interaction that also suppresses T-cell proliferation and cytokine production; however, the exact relative contributions of the PD-L1:PD-1 and PD-L1:B7-1 pathways in cancer remain unclear. The PD-1-targeting agents currently in development inhibit both pathways. However, as the binding sites for PD-1 and B7-1 are adjacent but not overlapping, agents that specifically target one or the other may be developed.

CTLA-4 and PD-1 have distinct roles in regulating immunity

, with both temporally and spatially distinct expression patterns. CTLA-4 regulates T-cell activity at initial activation and acts as a signal dampener, regulating the amplitude of early activation of naïve and memory T cells, while PD-1 functions to limit the activity of already activated T cells in the periphery during the inflammatory response to infection to limit autoimmunity.

		Figure 2. Targeting the Immune Checkpoints for Cancer Immunotherapy

		CD28 indicates cluster of differentiation 28; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TCR, T-cell receptor.

		Activation of T cells is a 2-step process that requires recognition of specific antigens presented by MHC on the surface of cancer cells through their “primed” T-cell receptor, as well as a co-regulatory signal delivered by the B7 family of receptors (the so-called immune checkpoints). The 2 checkpoints that deliver inhibitor signals, CTLA-4 and PD-1, function at different points in T-cell function. CTLA-4 is upregulated shortly after activation and negatively regulates T-cell activation during the “priming” phase of T-cell response within the lymph nodes by binding to B7 molecules on the surface of antigen-presenting cells. Conversely, when these B7 molecules bind to CD28 instead, they generate the opposite, activating signals. PD-1 is expressed on T cells later on in the immune response, during the effector phase of T-cell response. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. Blockade of CTLA-4 or PD-1/PD-L1 with antibodies results in the preferential activation of T cells with specificity for cancer cells.

		From Ribas A. Tumor immunotherapy directed at PD-1. 

Cancer cells exploit the PD-1 pathway to create an immunosuppressive environment. There is often an increase in the production of inhibitory pathways and suppression of stimulatory pathways, allowing cancer cells to dampen down the immune response at inappropriate times to create an immunosuppressive environment in which they are able to thrive. Cancer cells drive high expression levels of PD-L1 on their surface, allowing activation of the inhibitory PD-1 receptor on any T cells that infiltrate the tumor microenvironment, effectively switching those cells off.

 Indeed, upregulation of PD-L1 expression levels has been demonstrated in many different cancer types (eg, melanoma [40%- 100%], NSCLC [35%-95%], and multiple myeloma [93%]), and high levels of PD-L1 expression have been linked to poor clinical outcomes.

 Furthermore, tumor-infiltrating T cells have been shown to express significantly higher levels of PD-1 than T cells that infiltrate normal tissue. It is thought that the tumor microenvironment may secrete pro-inflammatory cytokines, including interferon-gamma to upregulate the expression of PD-1 on tumor-infiltrating T cells to ensure that they can respond to the high levels of PD-L1 expressed on the tumor.

Designing therapies that specifically target mechanisms of immune evasion is an attractive therapeutic approach because the ability of the tumor to suppress the immune response can seriously undermine the clinical efficacy of cancer therapies. Confirmation of the pivotal role of the PD-1 pathway in immunosuppression provided a strong rationale for the development of mAbs that block the PD-1 pathway, and several such agents are now being assessed in clinical trials.

Select Clinical Trials of Immunotherapy in Cancer

Pembrolizumab (Merck) is a humanized immunoglobulin G4 anti-PD-1 mAb. Pembrolizumab was evaluated in numerous phase l to phase lll trials 

 There were 2 reports of interim results from a phase l study in patients with advanced, metastatic solid tumors (clinical trial identifier: NCT01295827). One report described the clinical safety and efficacy of pembrolizumab as monotherapy in 38 patients with previously treated NSCLC. Using immune-related response criteria (irRC), the objective response rate (ORR) was 24%, including squamous and non-squamous subtypes (most responses observed within 9 weeks of treatment initiation) and the median duration of response had not been reached. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, the ORR was 21%. Pembrolizumab was generally well tolerated, with adverse events (AEs) observed in 21% (n = 8) of patients, most commonly fatigue, rash, and pruritus (16% each). Only 1 case of a grade 3/4 drug-related AE was reported (pulmonary edema).

		Table 1. Phase II and III National Clinical Trials Targeting PD-1/PD-L1 in Cancer

		AML indicates acute myeloid leukemia; ASCT, autologous stem cell transplant; CTLA-4, cytotoxic T-lymphocyte antigen-4; DLBCL, diffuse large B-cell lymphoma; FOLFOX, folinic acid + fluorouracil + oxaliplatin; HER2, human epidermal growth factor receptor 2; MSI, microsatellite instability; NCT, national clinical trial; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck.

The second report involved an expansion study of a cohort of 294 patients with melanoma and with (n = 179) or without (n = 115) previous ipilimumab treatment. Pembrolizumab was administered intravenously as monotherapy at a dose of 2 mg/kg or 10 mg/kg every 2 or 3 weeks until disease progression or unacceptable toxicity was observed. ORRs per RECIST 1.1 and irRC were very similar and were greater than 35% across all doses and schedules, including both ipilimumab-naïve and ipilimumab-pretreated patients. Median duration of response had not yet been reached, while median progression-free survival (PFS) exceeded 8 months. Pembrolizumab was also well tolerated in this study, with manageable toxicity in patients with melanoma; grade 3/4 drug-related AEs were reported in 10% of patients, and included hypothyroidism and hyperthyroidism.

The KEYNOTE-001 program involves a very large, multipart phase l study designed to evaluate the safety and efficacy of pembrolizumab, at several doses, in patients with advanced melanoma and NSCLC.

 Data from the 1.5-year follow-up analysis to the initial dose-expansion cohort for melanoma were reported by Dr Richard Kefford at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting. This nonrandomized cohort of 135 patients received pembrolizumab at a dose of 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks. Ipilimumab-naïve (IPI-N) patients could also receive a dose 2 mg/kg every 3 weeks.

mutations were less common than expected (22%), lactic acid dehydrogenase was elevated in 31% of patients, and 58% of patients had stage M1c disease. Clinical activity was observed in both IPI-N and ipilimumab-refractory (IPI-R) patients. The overall complete response rate was 9% (IPI-N, 12%; IPI-R, 5%) and the ORR was 41% (IPI-N, 43%; IPI-R, 38%); 88% of responses were ongoing at the time of analysis, with median duration of response not reached. Overall median PFS was 7 months; the 6-month PFS rate was 51%. Median OS was not reached at any dose. PD-L1 staining by immunohistochemistry was observed in 71% of evaluable tumors (n = 125). PD-L1 expression correlated with response. ORR was 49% for PD-L1-positive patients versus 13% for PD-L1-negative patients.

Another analysis of the KEYNOTE-001 melanoma cohort compared patients who were IPI-N with those who were IPIR. Patients were randomized to receive pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. More than half of patients had stage M1c disease. Approximately half of the IPI-N patients received no prior treatment, whereas the majority of IPI-R patients received multiple lines of therapy. Median follow-up was 12 months in the IPI-N group (n = 103) and 8 months in the IPI-R group (n = 173). ORR and median PFS were similar between the 2-mg/kg and 10-mg/ kg doses. ORRs using RECIST 1.1 criteria by central review for the IPI-N patients receiving 2 mg/kg or 10 mg/kg were 33% and 40%, respectively. ORRs in IPI-R patients were 26% for each dose. Investigator review of irRC was comparable to central review of ORR and median duration of response was not reached. PFS rates at 12 months for the IPI-N group treated with the 2-mg/kg and 10-mg/kg doses of pembrolizumab were 50% and 48%, respectively. For IPI-R patients, 12-month PFS rates were 44% and 37%, respectively. The OS rate at 12 months was 68% in IPI-N patients and 60% in IPI-R patients. The maximum percent baseline change in tumor size was 71% for both IPI-N and IPI-R patients.

Although almost all patients reported AEs and approximately one-third were serious AEs, toxicity-related discontinuation of therapy was minimal, with most discontinuations occurring in the IPI-R group. Immune-mediated AEs were uncommon except for hypothyroidism, which was low grade and reported in 32 patients. Rash was reported in 18% of IPI-N patients and 18% of IPI-R patients. Grade 3/4 rash was rare. Overall, the results suggest that pembrolizumab is a promising treatment for advanced melanoma, with a recommended dosage of 2 mg/kg every 3 weeks.

Results from the IPI-R cohort were published in 

(Robert et al, 2014). Importantly, pembrolizumab at both doses evaluated was safe and effective in patients with advanced melanoma that progressed after treatment with ipilimumab, a BRAF or MEK inhibitor, or both. These findings are highly promising considering the lack of therapy options in this setting.

A pooled analysis of the 3 melanoma cohorts in KEYNOTE- 001 was reported by Dr Antoni Ribas at the 2014 ASCO Annual Meeting. The study included 411 patients and evaluated several pembrolizumab doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks). The ORR was 34%, with 88% of responses ongoing at the time of data lock. The ORR in IPI-N (ie, treatment-naïve) and ipilimumab-treated patients was 40% and 28%, respectively. Median PFS was 5.5 months. Median OS was not reached; the 12-month and 18-month OS rates were 69% and 62%, respectively. Clinical activity was observed at all doses evaluated. Serious treatment-related AEs were seen in 8% of patients; however, only 4% discontinued treatment because of drug-related toxicities. The most common toxicities of any grade were fatigue, pruritus, and rash.

 Lung cancer data from the KEYNOTE-001 study was also reported at the 2014 Annual Meeting by Dr Naiyer Rizvi. Pembrolizumab was evaluated as first-line therapy for locally advanced or metastatic NSCLC. Patients were randomized to pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks. The first 11 patients were randomized to a 2-mg/kg or 10-mg/kg dose. Of 84 patients, 57 had confirmed PD-L1-expressing tumors. The ORR was 26% by RECIST 1.1 criteria and 47% by irRC. Median PFS was 27 weeks by RECIST and 37 weeks by irRC. Almost all responses were maintained at the time of analysis. More than half of patients had treatment-related toxicities. However, most were grade 1/2. There were 2 grade 3 adverse events reported, pericardial effusion and pneumonitis, and 1 grade 4 adverse event, an increase in blood creatinine phosphokinase. These data suggest that pembrolizumab is well tolerated and clinically active as initial treatment for advanced NSCLC. Upcoming comparative studies planned for pembrolizumab in NSCLC include 1 study with platinum- based chemotherapy (KEYNOTE-024) and 1 study with docetaxel (KEYNOTE-010).

The first agent targeting the PD-1 pathway to enter clinical testing was BMS-936558 (nivolumab/ONO-4538, Bristol- Myers Squibb; formerly MDX-1106). It is a fully human immunoglobulin G4 mAb that targets PD-1. Nivolumab was first evaluated in a phase l multicenter trial involving small cohorts of 6 patients with advanced, treatment-refractory solid tumors treated with single doses of 0.3, 1.0, 3.0, or 10 mg/kg nivolumab, followed by an expansion cohort of 15 patients who received 10 mg/kg nivolumab. Nivolumab induced a durable complete response (CR) in 1 patient with colorectal cancer at a dose of 3 mg/kg and partial responses in 1 patient with melanoma and renal cell carcinoma (RCC) at a dose of 10 mg/kg (clinical trial identifier: NCT00441337).

A total of 304 heavily pretreated patients with advanced solid tumors have been enrolled since 2008, including those with NSCLC (n = 129), melanoma (n = 107), and RCC (n = 34). Patients received 0.1 to 10 mg/kg intravenous nivolumab every 2 weeks, and tumors were assessed by RECIST 1.0 criteria after each 4-dose cycle, up to a maximum of 12 doses or until unacceptable toxicity, confirmed progression, or a CR occurred. Durable objective responses were observed (

), with 28 of 54 responders having an objective response lasting 1 year or longer. A sustained OS benefit was observed across tumor types, with 61% and 44% (melanoma); 43% and 32% (NSCLC); and 70% and 52% (RCC) of patients alive at 1 and 2 years, respectively (see 

 In a separate assessment of patients with NSCLC, an OS benefit was also observed across histologies, with 39% and 43% of patients with squamous and non-squamous NSCLC alive after 1 year, respectively.

 AEs of any grade occurred in 41% (n = 53) of patients, while grade 3/4 AEs occurred in 5% (n = 6).

Updated results in the melanoma cohort were presented at the 2014 ASCO Annual Meeting. A total of 32% of the 107 patients experienced an objective response to nivolumab therapy (as determined by RECIST criteria) in all dose groups. The dose that will be used for the phase lll trial is 3 mg/kg, and in that cohort, the ORR was 41%. Overall, median PFS and OS were 3.7 months and 17.3 months, respectively.

In the 3 mg/kg group, median PFS and OS were 9.7 months and 20.3 months. Responses were enduring; median duration of response was 22.9 months. The OS rate at 1, 2, and 3 years was 63%, 48%, and 41%, respectively. Immune-related responses were similar to those assessed by RECIST criteria.

Results of an open-label, randomized phase lll study (Checkmate-037, clinical trial identifier: NCT01844505) were reported by Dr Jeffrey Weber at the European Society for Medical Oncology 2014 Congress. In this study, 370 patients with advanced melanoma that progressed after anti- CTLA-4 and BRAF-targeted therapy were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator’s choice chemotherapy (ICC). ORR by central review, reported after at least 6 months of follow-up in the first 120 nivolumabtreated patients and 47 chemotherapy-treated patients, was 32% and 11%, respectively. Duration of response was not reached for nivolumab-treated patients, with most responses ongoing, compared with 3.6 months among patients receiving chemotherapy. Grade 3/4 adverse events occurred in 9% of patients in the nivolumab group and in 31% of those in the ICC group. Nivolumab was well tolerated and was associated with durable responses, confirming the potential for immunotherapy in patients with advanced melanoma.

A randomized phase ll trial of nivolumab monotherapy showed promising efficacy in 168 patients with clear-cell metastatic renal cell carcinoma (mRCC). Patients were stratified by Memorial Sloan Kettering Cancer Center risk score and prior lines of therapy for metastatic disease and then randomized to nivolumab 0.3 mg/kg, 2 mg/kg, or 10 mg/kg.

No dose relationship was observed for PFS. Median PFS was 2.7, 4.0, and 4.2 months, respectively. Median OS was 18.2, 25.5, and 24.7 months, respectively, comparing favorably to studies of tyrosine kinase therapy in mRCC. Median OS in favorable-risk patients was not reached; median OS in intermediate- and poor-risk patients was 20.3 weeks and 12.5 weeks, respectively. For patients who received 1 line of prior therapy, OS was not reached, and for patients who received more than 2 lines of prior therapy, median OS was 18.7 months. Further research of nivolumab in mRCC includes 2 phase lll trials, 1 in previously treated patients comparing survival with everolimus and 1 in combination with ipilimumab in the first-line setting.

 In addition to being studied as monotherapy in patents with mRCC, nivolumab was evaluated in a phase I study in combination with sunitinib or pazopanib. Patients were randomized to treatment with sunitinib 50 mg or pazopanib 800 mg plus nivolumab 2 mg/kg every 3 weeks, with planned escalation to nivolumab 5 mg/kg. Almost half of the patients in the sunitinib group (n = 33) and all patients in the pazopanib group (n = 20) received previous therapy. The ORR was 52% for the sunitinib group and 45% for the pazopanib group. Median PFS was 48.9 and 31.4 weeks, respectively. Responses were evident at the 6-week assessment in 41.2% of sunitinib-treated patients and 55.6% of pazopanib-treated patients; 58.8% and 33.3% of responses, respectively, were ongoing at the time of analysis. The preliminary results appear promising, with efficacy better for combination therapy with nivolumab than for either agent alone. However, investigators are cautiously optimistic due to higher than expected liver and kidney toxicity.

PD-L1 expression is a poor prognostic factor in patients with ovarian cancer. Thus, PD-1/PD-L1 blockage serves as a rationale therapeutic target for this disease. At the 2014 ASCO Annual Meeting, Dr Junzo Hamanishi presented encouraging data for nivolumab in patients with advanced or relapsed, platinum-resistant ovarian cancer. Nivolumab was administered every 2 weeks at a dose of 1 mg/kg or 3 mg/kg for up to 4 cycles. The ORR was 23% in 13 treated patients, including 2 partial responses at the 1 mg/kg dose and 1 partial response at the 3-mg/kg dose.

Nivolumab is also being evaluated in a phase l trial in combination with the CTLA-4-targeting agent ipilimumab (clinical trial identifier: NCT01024231). The rationale for this study is that targeting a single inhibitory T-cell pathway may not be sufficient to reestablish correct T-cell functioning and that synergistic activity may be found by inhibiting both pathways simultaneously. Patients with advanced melanoma (n = 53) were treated with escalating doses of concurrent therapy with nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses. Combined treatment was then administered every 12 weeks for up to 8 doses. A sequenced regimen (n = 33) was also examined, in which patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. The combination of nivolumab and ipilimumab induced clinical activity (according to modified World Health Organization [WHO] criteria) that appeared to be distinct from monotherapy with either agent, with rapid and deep tumor regression observed in many patients.

ORRs were 40% and 20% in the concurrent-regimen and sequenced-regimen groups, respectively. In the concurrent regimen group, 53% of patients had an objective response, with all having tumor reduction of at least 80%. Clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients.

 In updated results reported at the 2014 ASCO Annual Meeting, 1- and 2-year OS rates in the concurrent therapy cohort were impressive, at 85% and 79%, respectively. Median ORR was 42%. Median PFS and OS were 27 weeks and 40 months, respectively. In the cohort of 17 patients receiving nivolumab 1 mg/kg and ipilimumab 3 mg/kg, 1- and 2-year OS rates were even higher, at 94% and 88%, respectively. No new safety signals were reported. Neither BRAF mutation status nor PD-L1 expression appeared to impact clinical activity. Phase 2/3 studies of combination therapy are ongoing.

Early results from another phase l study reported at the 2014 ASCO Annual Meeting looked at the combination of nivolumab and ipilimumab in 43 patients with either previously treated or untreated mRCC (clinical trial identifier: NCT01472081). Patients were randomized to treatment with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3 + I1) or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1 + I3) every 3 weeks for 4 doses. Both groups then received nivolumab 3 mg/kg every 2 weeks until progression or toxicity. The ORR was 29% for the N3 + I1 group and 39% for N1 + I3 group. Median PFS was 28.1 weeks and 26.1 weeks, respectively. A phase lll trial is planned in the first-line setting of mRCC based on the encouraging clinical activity and manageable safety profile reported from this study.

Two other phase l combination trials are currently under way with nivolumab (clinical trial identifiers: NCT01454102 and NCT01176461). In the first, nivolumab is combined with platinum-based chemotherapy (gemcitabine/cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel) in patients with chemotherapy-naïve advanced NSCLC. A total of 43 patients were treated with escalating doses of nivolumab, starting at 10 mg/kg every 3 weeks until progression and chemotherapy doublets for 4 cycles at standard dosing. According to RECIST 1.1 criteria, total ORRs were 43% (gemcitabine/ cisplatin), 40% (pemetrexed/cisplatin), and 31% (carboplatin/paclitaxel).

 In the second trial, patients naïve to ipilimumab or who failed prior ipilimumab therapy were treated with nivolumab at 1.0, 3.0, or 10 mg/kg in combination with a peptide vaccine. Response rates by RECIST criteria were 28% in ipilimumab-naïve patients (n = 34) and 32% in patients who failed ipilimumab therapy (n = 46).

 A key question in the first clinical trials of PD-1 pathway agents was whether they had significant potential for inducing autoimmune AEs given previous clinical experience with ipilimumab, which induces moderate-to-severe autoimmune-type AEs, including hepatitis, endocrinopathies, and dermatitis. However, PD-1 agents have been generally well tolerated and induce only a low rate of autoimmune-type AEs that are usually manageable with the use of immunosuppressants.

In the phase l trial of patients with advanced solid tumors, drug-related AEs of any grade occurred in 72% of patients, while grade 3/4 AEs occurred in 15%.

 Combination therapy with ipilimumab was also associated with an acceptable level of AEs at the maximum doses. Drug-related grade 3/4 AEs occurred in 53% of patients treated with concurrent therapy and in 18% of those treated with sequential therapy, with the most common AEs being rash, pruritus, fatigue, and diarrhea in the concurrent group and elevated lipase levels in the sequential group.

 Likewise, combination with platinum-based chemotherapy was well tolerated; 49% of patients experienced drug-related grade 3/4 AEs, including pneumonitis, rash, and colitis, which were manageable. The study in patients who had previously failed ipilimumab therapy indicated that nivolumab did not induce the same immune-related AEs as ipilimumab.

Several phase ll and lll clinical trials of nivolumab in patients with NSCLC and melanoma have also recently been initiated; results are not yet available 

Pidilizumab (CT-011; CureTech) is a humanized anti-PD-1 immunoglobulin G1-kappa mAb. Positive phase 1 clinical trials showed that a single dose of pidilizumab (0.2 to 0.6 mg/kg) was generally safe and well tolerated, and preliminary clinical activity was observed, including 1 complete remission in a patient with follicular lymphoma (FL), 4 cases of stable disease (various hematologic malignancies), and 1 minimal response in a patient with acute myeloid leukemia.

An international phase ll program was subsequently initiated to explore the safety and efficacy of pidilizumab in hematologic malignancies and solid tumors. A number of studies are ongoing 

, while 1 study in patients with relapsed FL was recently completed. Results from this study were presented at the 2012 American Society of Hematology Annual Meeting. Thirty patients with rituximab-sensitive relapsed FL were treated with 3 mg/kg intravenous pidilizumab every 4 weeks for 4 infusions in combination with rituximab dosed at 375 mg/m

 weekly for 4 weeks, starting 2 weeks after the first infusion of pidilizumab.

		Table 2. Clinical Efficacy Data for Agents Targeting PD-1/PD-L1

		DLBCL indicates diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; Ipi, ipilimumab; irRc, immune-related response criteria; mRCC, metastatic renal cell carcinoma; NA, not available/reported; Niv, nivolumab; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progressionfree survival; PMBCL, primary mediastinal large B-cell lymphoma; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors.

An ORR of 66% was achieved; a CR was observed in 52% of patients and a partial response in 14%, with measurable tumor regression in 86% of patients. Median time to response was 88 days, reflecting the delayed action of immunotherapies; indeed, 21% of patients achieved an initial response more than 4 months after first treatment. Median PFS was 18.8 months and was not reached for responders. The combination of pidilizumab and rituximab in this population was well tolerated, and no grade 3/4 drug-related AEs were observed.

In another phase ll study, Armand et al evaluated the use of pidilizumab in patients with diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma after autologous hematopoietic stem-cell transplantation. Results in 66 patients showed 34% to be in complete remission, with an ORR of 51% among patients with measurable disease after transplantation. The study met its prespecified primary end point, with a 16-month PFS of 72%. The 16-month OS for eligible patients was 85%. The outcomes of this study demonstrate safety and clinical activity of PD-1 blockade in patients with DLBCL.

Pidilizumab was also evaluated in the setting of metastatic melanoma in an open-label phase ll trial of heavily pretreated patients with stage IV progressive disease. The study randomized 103 patients to pidilizumab 1.5 mg/kg or 6.0 mg/kg; half of the patients in each group had received prior ipilimumab therapy. The ORR was 6%. Despite the low response rate, 12-month OS was 64.5%, which is comparable to results from studies of other PD-1 inhibitors in this setting. No significant difference in survival was seen based on exposure to ipilimumab. Pidilizumab was well tolerated; 4% of patients experienced serious AEs related to the study drug, including appendicitis, arthritis, hepatitis, and pneumonitis. Although initial results look promising for pidilizumab, the survival results of this study need confirmation in a randomized clinical trial.

MEDI4736 is a uniquely engineered human immunoglobulin G1-kappa monoclonal antibody targeting the PD-L1/ PD-1 pathway. It contains a triple mutation in the fragment crystallizable (Fc) domain to remove antibody-dependent cellular cytotoxicity (ADCC) activity and has high affinity and selectivity for PD-L1. MEDI4736 is currently being investigated in multiple advanced solid tumors as part of the nonrandomized phase 1/2 MEDI4736-1108 doseescalation and expansion study (clinical trial identifier: NCT01693562).

 Early results in 346 patients were reported at the 2014 ASCO Annual Meeting by Dr Neil Segal.

In the safety analysis, AEs were reported in 39% of patients, 6% of which were grade 3/4; 2% were serious AEs, with only 1 event leading to discontinuation of therapy. The most common events of any grade were fatigue (13%) and rash/pruritus (9%). Most notable were 3 cases of grade 3 aspartate transaminase (AST)/alanine transaminase (ALT) elevation.

Early and durable responses were attained, typical of those seen with other PD-1/PD-L1-targeted agents. Likewise, responses were correlated with PD-L1 expression status. For all patients treated with the 10-mg/kg dose, the ORR was 23% for PD-L1-positive patients and 4% in PD-L1-negative patients. In the NSCLC cancer cohort, ORRs were 39% and 5% for PD-L1-positive and -negative patients, respectively.

For patients in the head and neck squamous cell carcinoma (HNSCC) group, ORRs were 50% and 6%, respectively. To date, clinical activity with MEDI4736 has been observed in patients with NSCLC, HNSCC, pancreatic cancer, and gas troesophageal cancers.62 The randomized phase lll PACIFIC study will evaluate survival with MEDI4736 following concurrent chemoradiation in patients with stage III unresectable NSCLC (clinical trial identifier: NCT02125461). MEDI4736 is also being evaluated in combination with tremelimumab in patients with NSCLC.

BMS-936559 (Bristol-Myers Squibb) is a fully human immunoglobulin G4 anti-PD-L1 mAb that inhibits the binding of the PD-L1 ligand to both PD-1 and CD80. The results of a phase l clinical trial of BMS-936559 in patients with advanced cancer were reported at the 2012 ASCO Annual Meeting and were published in The New England Journal of Medicine later that year. A total of 207 patients including those with NSCLC (n = 75), melanoma (n = 55), RCC (n = 17), and ovarian cancer (n = 17) were treated with escalating doses of BMS-936559 (0.3, 1.0, 3.0, and 10 mg/kg). ORRs of 6% to 17% were observed depending on cancer type across all doses 

For patients with melanoma, the most significant objective response was observed at a dose of 3 mg/kg (29%), while for other cancer types it was observed with the 10- mg/kg dose. For patients with NSCLC, similar response rates were seen for squamous and non-squamous histologies (8% and 11%, respectively) across all doses. The response in NSCLC was unexpected because NSCLC has been considered to be non-immunogenic and poorly responsive to immunotherapy. Observed responses were durable across the multiple tumor types, and lasted for at least 1 year in half of the patients, with at least 1 year of followup.

Brahmer and colleagues found this particularly notable given the advanced stage of disease and number of previous treatments administered to patients. BMS-936559 was well tolerated, with grade 3/4 drug-related toxicities observed in only 9% of patients.

MPDL3280A (Roche) is a human anti-PD-L1 mAb that contains an engineered Fc domain designed to optimize efficacy and safety by minimizing ADCC.

 The theory is that this structure will allow inhibition of the PD-1/PD-L1 interaction while minimizing the ADCC-mediated depletion of activated T cells that is required for an effective antitumor immune response.

MPDL3280A has been evaluated in a phase l trial in patients with locally advanced or metastatic solid tumors. A total of 175 patients have been recruited to date. MPDL3280A was administered as a single agent at escalating doses of 1.0 or less, 3.0, 10, 15, and 20 mg/kg for a median duration of 127 days.

 The results of 2 expansion cohorts have also been reported; a cohort of 85 patients (53 of whom were evaluable for efficacy) with squamous or nonsquamous NSCLC and a cohort of 45 patients with metastatic melanoma (35 of whom were evaluable for efficacy).

In both cohorts, doses of 1.0 or less, 10, 15, and 20 mg/kg MPDL3280A were administered every 3 weeks for up to 1 year. MPDL3280A demonstrated durable responses and was well tolerated; efficacy data are summarized in 

 Of the 85 patients in the NSCLC cohort, 55% were heavily pretreated with at least 3 prior therapies, and 81% were smokers or ex-smokers. The 24-week PFS rate was 44% in squamous cell NSCLC and 46% in non-squamous cell NSCLC.

All 175 patients in the initial trial and all patients in the NSCLC and melanoma expansion cohorts were evaluated for safety; the incidence of grade 3/4 drug-related AEs was 39%, 34%, and 34%, respectively. In the NSCLC cohort, AEs included pericardial effusion, dehydration, and dyspnea, while in the melanoma cohort, they included hyperglycemia and elevations in ALT and AST levels. No grade 3/4 pneumonitis was reported in any patients.

Very encouraging results in 67 heavily pretreated patients with bladder cancer enrolled in the phase 1a expansion study were reported by Dr Thomas Powles at the 2014 ASCO Annual Meeting. Metastatic bladder cancer is an area of unmet need and is associated with a poor prognosis. After only 6 weeks of follow-up, MPDL3280A given at a dose of 15 mg/kg intravenously every 3 weeks for up to 16 cycles was associated with an ORR of 43% in patients with PD-L1- positive tumors. After 12 weeks of follow-up, the ORR was 52%. In patients with PD-L1-negative tumors, the ORR was 11%. Responses were rapid and enduring, with a median time to response of 42 days. Sixteen of 17 responses were ongoing at data cutoff, including 2 CRs. MPDL3280A was well tolerated, even in patients with renal insufficiency. Grade 3/4 AEs were rare (4%). Importantly, no renal toxicity was reported. Treatment with MPDL3280A was associated with transient increases in circulating CD8+Ki-67+ T cells and plasma proteins upstream of interferon gamma signaling, correlating to pharmacodynamic biomarkers of activity. MPDL3280A has now received breakthrough status from the FDA and research in bladder cancer is ongoing.

Research and ongoing clinical studies are being conducted to evaluate the potential significance of PD-L1 as a biomarker for cancer immunotherapy.

 PD-L1-positive cancers are associated with poorer prognoses than those that are PD-1 negative. A correlation of PD-L1 expression and ORR was demonstrated in patients with the highest levels of PD-L1 expression (IHC 3; defined as ≥10% PD-L1- positive tumor-infiltrating immune cells) at 83% (5 of 6 patients; 95% CI, 40.2-99.1).

 Overall, PD-L1 is expressed in tumors and is thought to function as a key component of the cancer-immunity cycle by preventing the immune system from destroying cancer cells. In a phase l biomarker study, Th1-driven CD8 biology, intratumoral characteristics, and adaptive PD-L1 enhancement with MPDL3280A correlated with observed clinical responses and PD-L1 status.

 The potential role of PD-L1 as a biomarker remains to be elucidated.

Defining Immune-Related Response Criteria 

In the late 1970s, the WHO developed response criteria to standardize the assessment of responses to cytotoxic anticancer agents in clinical trials and to facilitate the comparison of data between trials.

 This was followed by the development of RECIST criteria at the turn of the millennium to provide more simplified and standardized response definitions.

 Although they have been updated and modified throughout the years,

 researchers have relied on these response criteria for decades when assessing the impact of novel agents in the treatment of cancer—from conventional chemotherapies to targeted therapies.

These criteria assume that an increase in tumor growth and/or the appearance of new cancerous lesions early in the course of treatment indicates progression, and it was recommended that treatment be stopped once this was observed. Thus, the term progression became synonymous with drug failure. However, with the development of immunotherapies that have a mechanism of action very different from that of traditional cytotoxic anticancer agents, many clinicians began to note different patterns of response to these drugs that were not adequately described by the existing criteria.

A series of initiatives in the first decade of the 2000s brought together experts in oncology, immunotherapy, and regulatory areas to determine whether novel response criteria could be developed that would more accurately reflect the results of immunotherapy treatment. Their main conclusions were that clinical activity often appears to be delayed following immunotherapeutic treatment and a period of apparent progression (as defined by the existing response criteria) may occur, followed by a response. Thus, discontinuation of immunotherapy at the point of apparent progressive disease may not be an appropriate course of action.

Based on these conclusions, a series of large multinational studies were conducted using the most comprehensive data set available for immunotherapy: the phase ll clinical program with ipilimumab, involving 3 studies totaling 487 patients with advanced melanoma.

 The group noted 4 distinct response patterns, 2 conventional ones (immediate response and durable stable disease), and 2 that were unique to immunotherapy (response after tumor burden increase and response in the presence of new lesions). These unique responses probably reflect the dynamics of the immune system, which is engaged by immunotherapeutic agents. Rather than direct cytotoxic activity on tumor cells, immunotherapies have a more delayed mechanism of action, driving the expansion of T cells, which then infiltrate the tumor and kill tumor cells. Thus, the early increase in tumor burden that is often observed may be a result of the infiltration of T cells into the tumor. To more effectively capture these novel responses, the irRC were developed.

A comparison of the conventional response criteria and the irRC is presented in 

 Essentially, the irRC are based on modified WHO criteria and involve the use of bidimensional measurements on radiographic assessments of cancerous lesions (the longest diameter and the longest perpendicular diameter), as opposed to the unidimensional measurements employed by RECIST. Importantly, the irRC assess tumor burden differently: tumor burden is considered a continuous variable and the irRC incorporate measurements of both preexisting lesions (index lesions) and new lesions, as opposed to conventional criteria, which only consider index lesions. Thus, while new lesions always define progressive disease according to RECIST/WHO criteria, according to the irRC, in the absence of rapid clinical deterioration, they merely preclude a CR until progression is confirmed.

		Table 3. Immune-Related Response Criteria (irRC)

Articles

Immunotherapy for the treatment of cancer has evolved alongside our improved understanding of the immune system.

Role of Anti-PD-1/PD-L1 Immunotherapy in Cancer

 Surgical intervention, chemotherapeutic regimens, and radiation therapy have been the primary weapons in the frontline fight against cancer. However, immunotherapy, a fourth therapeutic modality, now holds the promise of a new age in the battle against even the most resistant cancers. Bladder cancer, in particular, has carried a poor prognosis in late-stage and metastatic disease. Current treatments have been inadequate with only minimal success. The discovery of checkpoint proteins, along with a better understanding of the role they play in tumor evasion mechanisms, has opened the door to mobilizing a significant immune response in patients with cancer. Using monoclonal antibodies (mAbs) to block the inhibitory signals of the programmed death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) pathway has the potential to change traditional treatment pathways. This supplement will review the traditional treatments of bladder cancer, describe PD-1 and PD-L1 pathways, and present evidence from clinical trials evaluating the specific role of drugs targeting the PD-1 pathway in bladder cancer.

Bladder cancer is the fourth-most common cancer in the United States,

 In 2014, 74,690 new cases and 15,580 deaths are projected to occur in the United States.

 This represents 4.5% of all new US cancer cases and 2.7% of all US cancer deaths.

 Also, in 2011, approximately 571,518 patients were living with bladder cancer.

 The median age of diagnosis is 65 years; in fact, diagnoses in patients under the age of 40 years are considered rare.

Bladder cancer is a broad term that encompasses a variety of cancer types that involve the epithelial lining of the urinary bladder. Bladder cancers can be classified into 1 of 3 tumor types: (1) nonmuscle invasive; (2) muscle invasive; and (3) metastatic tumors.

 In the United States, 90% of urothelial tumors begin in the bladder, while only 8% originate in the renal pelvis and 2% in the ureter and urethra.

 The most common subtype of bladder cancer in the United States is urothelial or transitional cell carcinoma. This subtype develops anywhere transitional urothelial epithelium exists, including the renal pelvis, ureter, bladder, the beginning two-thirds of the urethra, and anywhere in between. The remaining section of the urethra contains squamous epithelium; tumors located here are the cause of squamous cell tumors, which comprise just 3% of tumors in the United States.

According to the American Cancer Society, smoking is the leading contributing factor to a diagnosis of bladder cancer. Overall, approximately 50% of bladder cancer cases can be attributed to smoking. Carcinogens from tobacco smoke are filtered by the kidneys, thus leading to bladder cell damage due to concentrations of these carcinogens in the urine. Therefore, people who smoke are 3 times more likely to develop bladder cancer compared with nonsmokers.

Exposure to certain industrial chemicals has also been linked to developing bladder cancer. Those occupations associated with an increased risk of bladder cancer include painters, machinists, printers, hairdressers, truck drivers, and any occupation that involves handling dye. The risk of developing bladder cancer increases significantly when industrial exposure is paired with smoking.

Other risk factors include race, age, sex, bladder birth defects, genetics, long-term chemotherapy with cyclophosphamide, pelvic radiation, and having taken pioglitazone for diabetes for more than 1 year.

Non—muscle invasive disease (NMID) tumors comprise nearly 70% of newly detected cases of bladder cancer. Of these NMID tumors, 70% are confined to the mucosa, 25% are confined to the submucosa, and less than 5% are carcinoma in situ (CIS), which are flat, high-grade lesions. Characteristics of NMID tumors include being friable with high bleeding tendencies and a likely recurrence in the same area or a different area of the bladder.1 The rate of recurrence within 5 years for patients with tumors confined to the mucosa or submucosa is approximately 31% to 78%.

Most often, patients with bladder cancer present with microscopic or gross hematuria. They may also present with frequent urination or a urinary tract infection as their primary complaint, albeit less frequently. Pain or an upper tract obstruction may also be a presenting symptom, but this is often indicative of a more advanced lesion.

 In-office cystoscopy is typically performed in patients presenting with pain or upper urinary tract obstruction to determine whether or not a lesion is present.

Urine cytology may also be performed, which can detect abnormal cells in the urine. If the cystoscopy fails to identify a primary lesion and abnormal cells are detected with urine cytology, this warrants further investigation of areas of the urinary tract. If a lesion is observed during cystoscopy, a transurethral resection of the bladder tumor (TURBT) should be performed to confirm a diagnosis and evaluate the extent of the disease.

 However, depending on the appearance of the tumor, a computerized tomography (CT) scan or magnetic resonance imaging may be warranted before TURBT.

Tumors that are determined to be high grade, invasive, or sessile (solid) need diagnostic studies prior to the TURBT. While there are many tests available to evaluate upper tracts, CT urography is considered the best modality, assuming the patient has no restrictions to receiving contrast.

 Further diagnostic testing is driven based on findings during the initial evaluation. For example, a bone scan may be necessary if elevated levels of alkaline phosphatase are detected; chest imaging if the disease is considered invasive.

 TURBT with a bimanual examination under anesthesia (EUA) is used in the diagnosis, staging, and treatment of visible tumors. For CIS, biopsies, including of the surrounding muscles, should be collected during the procedure, to determine whether the cancer is invasive. In male patients, additional biopsies should be considered, including a transurethral resection biopsy of the prostate.

 Utilizing the tumor, node, metastasis (TNM) staging system shown in the 

 the cancer can be classified clinically or pathologically, which is noted with a “c” or “p.”

 Two grading systems are currently employed to assign tumor grades. The 1973 World Health Organization (WHO) classification is the most widely utilized system; however, a new WHO system was introduced in 2004. Although the newer system may allow for more precise prognostic significance, it requires pathologists to determine classification and has yet to be validated by clinical trials.

Traditional treatment options for bladder cancer include surgery, radiation, chemotherapy, and biologic therapy. Treatment decisions are dependent on the type of bladder cancer, clinical stage and grade, and pathology.

Types of surgery include TURBT, radical cystectomy, partial cystectomy, and urinary diversion.

 As previously mentioned, TURBT is used in patients with observed lesions to confirm a diagnosis, assist in staging, and treat visible tumors.

TURBT can be performed with an EUA to resect any visible tumor and establish if muscle invasion has occurred.

 Radical cystectomy includes removal of the bladder, lymph nodes, and nearby organs to which the cancer has spread.

 This procedure involves a cystoprostatectomy in males to remove the prostate and seminal vesicles.

 Typically, but not always, a hysterectomy is also performed in women.

 Once the bladder has been removed, the surgeon will form a urinary diversion to create a new way for urine to exit the body.

Types of urinary diversions include ileal conduits, a urinary reservoir, a continent cutaneous reservoir, or a neobladder. A urinary diversion using an ileal conduit consists of the surgeon removing a section of the bowel and repositioning it, thus allowing urine to drain from the ureters to a stoma and then out of the body into an external pouch.

 Another option for urinary diversion is the use of an internal reservoir formed from a section of bowel. An external pouch is not necessary because urine drains into an internal reservoir. A neobladder is intended to act similarly to a native bladder; however, it is associated with an increased risk of nocturnal incontinence or urinary retention. Unfortunately, urinary retention may result in the patient needing to insert a catheter through the urethra to ensure the neobladder is completely emptied.

 A partial removal of the bladder is less common than a radical cystectomy and is surgically feasible in approximately 5% of cases.

 Both radical and partial cystectomies involve the removal of pelvic lymph nodes.

Chemotherapy, drugs used to halt cancer cell growth by killing cells or inhibiting the cells from dividing, can be given systemically or intravesically, depending on the type and stage of bladder cancer. Often, a combination of drugs is used.

Mitomycin C, thiotepa, doxorubicin, valrubicin, gemcitabine, and epirubicin may be used intravesically in bladder cancer. Of these, mitomycin C is most commonly used, although randomized trials have not demonstrated one agent to be superior to another.

Additionally, randomized trials have not demonstrated a reduction in progression or mortality with intravesical chemotherapy. A meta-analysis published in 1996 demonstrated a decreased tumor recurrence with intravesical chemotherapy but no decrease in disease progression or mortality.

 A more recent analysis, published in 2012, suggested that intravesical chemotherapy with gemcitabine may be more effective and less toxic than intravesical mitomycin C. Compared with intravesical immunotherapy with Bacillus Calmette-Guerin (BCG), the effects of intravesical gemcitabine were similar in intermediate-risk patients, less effective in high-risk patients, and superior in patients who were refractory to BCG therapy.

		Table. AJCC TNM Staging System for Bladder Cancer

		AJCC indicates American Joint Committee on Cancer.

		Republished with permission of the American Joint Committee on Cancer from Edge S, Byrd DR, Compton CC, et al. 

. 7th ed. New York, NY: Springer; 2010. Permission conveyed through Copyright Clearance Center, Inc.

Both neoadjuvant and adjuvant systemic chemotherapy regimens are utilized in bladder cancer, yet evidence for using neoadjuvant therapy is stronger.

 An intergroup, randomized phase III study assessed survival in patients treated with cystectomy alone versus 28-day cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) before cystectomy. Over 11 years, 317 patients were enrolled and randomized.

 Median survival was 46 months (95% CI, 25-60) in patients receiving the cystectomy alone compared with 77 months (95% CI, 55-104) in those receiving chemotherapy prior to cystectomy.

 Increased survival has been noted in studies with adjuvant therapy consisting of MVAC; methotrexate, vinblastine, epirubicin, and cisplatin (MVEC); and cyclophosphamide, doxorubicin, and cisplatin (CAP). Yet, due to the heterogeneity in methodology, whether or not this finding applies to all patients with urothelial tumors is questionable.

For patients with advanced or metastatic disease, 3 types of chemotherapy agents are generally utilized: cisplatin, taxanes, and gemcitabine. Gemcitabine plus cisplatin (GC) and dose-dense MVAC is the most common combination. Two large randomized phase III studies compared standard MVAC to dose-dense MVAC. Study results demonstrated that standard MVAC was inferior to the dose-dense regimen in terms of overall survival and toxicity among patients with locally advanced or metastatic disease. Additionally, standard MVAC was associated with higher mortality than GC due to drug toxicity, and offered no additional overall survival or progressionfree survival benefit; therefore, standard MVAC is no longer recommended.

 The preferred treatment recommendation, according to the National Comprehensive Cancer Network (NCCN) guidelines for metastatic disease, is GC and dose-dense MVAC.

 Based on results from studies showing that taxanes are effective as both first-line and palliative treatments, 2- and 3-drug combinations, with or without cisplatin, are being investigated for use as first-line treatment. It is important to keep in mind that the benefits of adding paclitaxel to regimens do not outweigh the risks associated with its use.

The third type of treatment available for patients with bladder cancer is biologic therapy (also referred to as biotherapy or immunotherapy). BCG, administered intravesically, is the only immunotherapy currently approved for bladder cancer by the FDA.

 Although treatment with BCG is largely more effective when compared with intravesical chemotherapy, the associated toxicity limits its use as first-line therapy in all patients.

 However, therapy with BCG is preferred over chemotherapy for adjuvant treatment of high-grade lesions.

 Drugs targeting the PD-1/PD-L1 pathway are also a type of immunotherapy, but these agents are still under investigation for use as bladder cancer therapy. External or internal radiation may also be considered, and its use varies given the type and stage of bladder cancer.

The standard of care for Ta, T1, and Tis tumors is TURBT followed by TUR. For high-grade T1 tumors and, in some cases, Ta tumors, this may be followed by biopsy of the prostate, and a possible second TUR of the prostate.

 After a complete resection, prophylactic or adjuvant intravesical therapy may be warranted. Due to the somewhat high risk of recurrence for cTa (low-grade tumors), the guidelines recommend considering giving a single dose of immediate intravesical chemotherapy within 24 hours, possibly followed by a 6-week induction of intravesical chemotherapy. If a patient’s risk of recurrence is minimal, the immediate dose may be adequate. (Immunotherapy should not be used in patients who do not have high-grade tumors.1) However, in patients with high-grade tumors, NCCN guidelines support intravesical BCG over treatment with intravesical mitomycin C.

In contrast to the previously mentioned tumor types, cT1 tumors have a higher risk for recurrence and progression. TURBT is also recommended for this tumor type, and follow-up TUR is strongly advised—except in cases of high-risk tumors when cystectomy is recommended instead. After the second TUR, immunotherapy with BCG or cystectomy is recommended if residual disease is present.

 If no residual disease is present, intravesical BCG or mitomycin C can be administered instead.

 Given that primary CIS or Tis is a precursor of invasive disease, the usual course of therapy is TURBT followed by intravesical BCG administered weekly for 6 weeks. For patients unable to tolerate BCG therapy, mitomycin may be considered.

Patients with recurrent or persistent cTa, cT1, and Tis disease who had an initial TURBT should have another TURBT followed by intravesical adjuvant therapy. Patients who responded to intravesical therapy after initial treatment with positive results at their 3-month follow-up may be given a second induction course of BCG or mitomycin, but no more than 2 consecutive induction courses should be administered. If residual disease is still noted 3 months after the second induction course, the patient should undergo another TURBT. If recurrence involves Tis or cTa tumors post TURBT, intravesical therapy with a different agent may be considered as an alternative to cystectomy, although experts disagree on whether valrubicin is of value.

In patients with recurrence of high-grade cT1 disease, following TURBT and induction of BCG therapy, cystectomy is recommend as first-line therapy; for nonsurgical candidates, concurrent chemoradiation, use of a different intravesical agent, or a clinical trial may be considered.

 After 1 or 2 courses of intravesical treatment, patients with no residual disease at follow-up may be candidates for BCG maintenance therapy (usually for 1-3 years). Although NCCN panelists do not believe that this should be routine practice, they do agree that maintenance therapy should be an available option.

 If patients with no documented recurrence have cytologypositive cystoscopy with negative imaging, TUR needs to be performed with biopsies.

 For biopsy-positive disease, intravesical BCG therapy should be considered, potentially followed by maintenance BCG therapy. Patients who fail to respond to BCG therapy or only have a partial response should be given alternative options, such as cystectomy, a different intravesical agent, or enrollment into a clinical trial.

Most muscle-invasive tumors are high-grade urothelial carcinomas; therefore, in contrast to nonmuscle-invasive disease, muscle-invasive disease always requires TURBT with follow-up therapy, such as cystectomy, neoadjuvant or adjuvant therapy, bladder-preserving approaches, or chemotherapy. Available surgical treatments include radical cystectomy and partial cystectomy; however, the partial procedure is generally reserved for tumors on the dome of the bladder, for which less than about 5% of cases are actual candidates. Patients with lesions in the trigone or bladder neck should not have a partial cystectomy, as presence of a Tis tumor in other areas is a relative contraindication to partial cystectomy.

Select patients with T2 and T3a urothelial carcinomas may be candidates for bladder-preserving therapy. These treatment approaches include aggressive endoscopic TUR, TUR followed by chemotherapy, radiotherapy monotherapy, or a combination of chemotherapy with radiotherapy.

 The International Consultation on Urologic Diseases-European Association of Urology evidence- based guidelines recommend the previously discussed bladder-preserving treatment modalities for patients who are medically unfit for surgery and therefore seeking an alternative to cystectomy.

 This endorsement may be attributed to the underutilization of bladderpreserving treatment for those who are not candidates for surgery, such as the elderly and racial minorities.

Plus, it has been estimated that between 23% and 50% of patients over the age of 65 years with muscle-invasive bladder cancer receive no treatment or receive nonaggressive treatment.

 However, if a lesion is solitary, less than 2 centimeters in size, or has minimally invaded the muscle and there is no associated in situ component, palpable mass, or hydronephrosis, TURBT may be a treatment option. If this option is chosen, a re-resection should occur within 4 weeks to guarantee that no residual disease is present.

Chemotherapy monotherapy after TUR is not recommended. More patients can avoid complete resection of the bladder when chemotherapy is instead combined with concurrent radiotherapy,

 unless comorbidities prevent them from tolerating a cystectomy or chemotherapy.

 A phase III randomized trial of 360 patients with stage T2, T3, or T4a bladder cancer demonstrated that radiotherapy plus mitomycin C and fluorouracil (5-FU) resulted in a significantly higher locoregional diseasefree survival rate than radiotherapy alone (67% vs 54%, respectively; 

 = .01), with an absolute difference of approximately 12 percentage points (95% CI, 1.3-20) for 2-year recurrence-free rates.

Evidence does not support the use of neoadjuvant chemotherapy before treatment with bladder-preserving chemotherapy given concurrently with radiation.

 Radiotherapy with concurrent cisplatin-based chemotherapy as a radiosensitizer is the most commonly used and most extensively studied chemoradiation regimen for patients with muscle-invasive bladder disease. Radiation is given after TURBT, along with 2 doses of concurrent chemotherapy in weeks 1 and 4. If no disease is noted at follow-up, additional radiation with 1 dose of cisplatin is administered.

 Cisplatin, cisplatin with 5-FU, 5-FU with mitomycin C, and cisplatin with paclitaxel are all practical options for bladder-preserving chemoradiation.

Results from clinical trials demonstrate that immunotherapy is ready to take center stage in the fight against bladder cancer. 

June 2015 | Special Issues

Role of Anti-PD-1/PD-L1 Immunotherapy in Cancer

Role of Anti-PD-1/PD-L1 Immunotherapy in Bladder Cancer

Anti-PD-L1 Immunotherapy: Emerging Clinical Data

A Focus on Pathways: Evolving Role of Oncolytic Immunotherapy in Melanoma

Role of Anti-PD-1 / PD-L1 Immunotherapy in Lung Cancer