The Role of Anti-PD-L1 Immunotherapy in Cancer

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 castrationresistant prostate cancer.

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 castrationresistant 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 PD-1/PD-L1 pathways will be reviewed in this supplement, including a comprehensive review of selected ongoing clinical trials to evaluate the potential of targeting immunotherapy in cancer drug development. Emerging clinical data discussed in this supplement suggest that targeting immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.

Introduction

Cancer is traditionally treated with either 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.1

More than a century ago, a series of primitive experiments hinted at the potential of harnessing the immune system to fight cancer.2 The immune system protects the body from foreign invading agents by recognizing “non-self” proteins (antigens) displayed on their surface that distinguish them from normal, healthy tissue. This subsequently initiates a protective response that neutralizes these organisms.3 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.2 Since then, a dyna mic and complex relationship between the immune system and cancer has been uncovered, and the concept of immunotherapy was born.

Cancer cells are normal cells that have acquired numerous hallmark abilities that allow them to become malignant; 4 thus, they are essentially “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 mounted. 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 refers to a diverse range of therapeutic approaches that aim to harness the immune system to re-establish 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.5-9

There are two 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.6 The development of hybridoma technology in the 1970s and the identification of tumor-specific 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 top three best-selling anticancer drugs in 2012 were mAbs.10 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 FDA for the treatment of NHL and chronic lymphocytic leukemia (CLL) in combination with chemotherapy.11 Another important mAb is trastuzumab (Herceptin; Genentech), which revolutionized the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer by targeting the expression of HER2.12

In order to actively drive an antitumor immune response, therapeutic cancer vaccines have been developed. Unlike the prophylactic vaccines that are used preventatively 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 the 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.13,14 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.15

Despite these successes, immunotherapy has previously faced skepticism and significant disappointment; however, it is now beginning to gather momentum, particularly since the discovery of the 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 the recognition of the significant role that immune evasion plays in malignant progression.16

Generation of an effective antitumor immune response involves a series of steps that ultimately leads to the death of cancer cells (Figure 1). In the first step, cancer-specific antigens are released from cancer cells and captured by dendritic cells (one type of antigen-presenting cell [APC]; step 1). 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.17

Figure 1. The generation of antitumor immunity

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 Immunity.17

APC indicates antigen-presenting cells; CTL, cytotoxic T lymphocite.

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 are alive after 1 year, and 24% after 2 years.18

A number of other checkpoint proteins are also being examined. The programmed-death 1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are part of the same family of coregulatory molecules as CTLA-4. In this supplement, we focus on the clinical development of PD-1/PD-L1-targeting agents.

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

Activation of T cells during an immune response is a two-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).8,19,20

The two 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 PD-L2 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.5,8,21

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 PDL1: 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 potentially be developed.22

CTLA-4 and PD-1 have distinct roles in regulating immunity (Figure 2), 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 in order to limit autoimmunity.5,8,17,23,24

Figure 2. Targeting the immune checkpoints for cancer immunotherapy

Activation of T cells is a two-step process that requires recognition of specific antigens presented by major histocompatibility complex (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 two 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. Adapted from N Engl Med. 2012;366(26):2517.24

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.5,8,22 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.7,25-28 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 (IFNg) 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.29

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 to block the PD-1 pathway, and several such agents are now in various stages of clinical development.

Select Clinical Trials of Immunotherapy in Cancer

Nivolumab (BMS-936558)

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 IgG4 mAb targeting PD-1. Nivolumab was first evaluated in a phase I multicenter trial involving small cohorts of 6 patients with advanced, treatment-refractory solid tumors treated with single doses of 0.3, 1, 3 or 10 mg/kg nivolumab, followed by an expansion cohort of 15 patients at 10 mg/kg nivolumab. Nivolumab induced a durable complete response (CR) in one patient with colorectal cancer (CRC) at dose of 3 mg/kg and partial responses in one patient with melanoma and renal cell carcinoma (RCC) at a dose of 10 mg/kg (NCT00441337).30

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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 after each 4-dose cycle, up to a maximum of 12 doses or until unacceptable toxicity, confirmed progression, or CR occurred. Durable objective responses (ORs) were observed (Table 1), with 28/54 responders having an OR lasting 1 year or longer. A sustained OS benefit was observed across tumor types, with 61/44% (melanoma), 43/32% (NSCLC), and 70/52% (RCC) of patients alive at 1 and 2 years, respectively (see Table 1 for median OS).31 In a separate assessment of NSCLC patients, prolonged ORs and OS benefit was also observed across histologies with 44/41% and 44/17% of squamous and non-squamous NSCLC patients alive at 1 and 2 years, respectively.32 AEs of any grade occurred in 41% (n = 53) of patients, while grade 3/4 AEs occurred in 5% (n = 6).32

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

Efficacy data

Agent

Phase

Patient population

Objective response rate (ORR)

Median PFS

Median OS

Nivolumab31,32

1

Patients with advanced or recurrent malignancies

(n = 306)

NSCLC (n = 129): 17.1%

Melanoma (n = 107): 31%

mRCC (n = 34): 29%

NS

NSCLC: 9.9 months;

1 yr OS = 42%; 2 yr OS = 24%

Melanoma: 16.8 months mRCC: >22 months

Nivolumab33

1

Advanced melanoma patients;

nivolumab + ipilimumab

(n = 53)

40%

NS

Not yet reached

Nivolumab34

1

Stage IIIB/IV NSCLC patients;

+ platinum-based doublet chemotherapy (n = 43)

+ Gemcitabine/cisplatin: 43%

+ Pemexetred/cisplatin: 40%

+ Carboplatin/paclitaxel: 31%

NS

NS

Nivolumab35

1/2

Unresectable melanoma; + multi-peptide vaccine (n=80)

25%

NS

NS

Pidilizumab37

2

Relapsed follicular lymphoma patients; + rituximab (n = 29)

66%

21.1 months

NS

MPDL3280A41,42,43

1

Patients with locally advanced or metastatic solid tumors

All patients (n = 175): 21%

NSCLC cohort (n = 53): 23%

Metastatic melanoma cohort (n = 35): 26%

NS

NS

MK-347538

1b

Expansion study in patients with previously treated NSCLC (n = 38)—interim results

24% irRc

21% RECIST 1.1

9.1 weeks

9.7 weeks

51 weeks RECIST 1.1

BMS-93655940

1

Patients with advanced cancer (n = 160)

Melanoma: 17%

RCC: 12%

NSCLC: 10%

Ovarian: 6%

NS

NS

irRC indicates immune-related response criteria; mRCC, metastatic renal cell carcinoma; NS, not specified; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors.

Nivolumab is also being evaluated in a phase I trial in combination with the CTLA-4-targeting agent ipilimumab (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 WHO [World Health Organization] criteria) that appeared to be distinct from monotherapy with either agent, with rapid and deep tumor regression observed in many patients. The objective response rates 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 ≥80%. Clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients.33

Two other phase I combination trials are currently underway with nivolumab (NCT01454102, 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, total ORs were 43% (gemcitabine/cisplatin), 40% (pemetrexed/ cisplatin), and 31% (carboplatin/paclitaxel).34 In the second trial, patients naïve to ipilimumab or who failed prior ipilimumab therapy were treated with nivolumab at 1, 3, or 10 mg/ kg in combination with a peptide vaccine. Response rates by RECIST were 28% in ipilimumab-naïve patients (n = 34) and 32% in patients who failed ipilimumab therapy (n = 46).35

A key question in the first clinical trials of PD-1 pathway agents was whether these agents had significant potential for inducing autoimmune adverse events (AEs) given previous clinical experience with ipilimumab, which induces moderateto- severe autoimmune-type AEs, including hepatitis, endocrinopathies, and dermatitis. However, PD-1 agents have been shown to be generally well tolerated and induce only a low rate of autoimmune-type AEs that are generally manageable with the use of immunosuppressants. In the phase I 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%.31

Combination therapy with ipilimumab was also associated with an acceptable level of AEs at the maximum doses. Drugrelated 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.33 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.34,35

Several phase II and III clinical trials in patients with NSCLC and melanoma have also recently been initiated for nivolumab but have not yet produced results (Table 2).

Pidlizumab (CT-011)

Pidlizumab (CT-011; CureTech) is a humanized anti-PD-1 IgG1- kappa mAb. Positive phase I clinical trials showed that a single dose of CT-011 (0.2-0.6 mg/kg) was generally safe and well tolerated, and preliminary clinical activity was observed, including one complete remission in a patient with follicular lymphoma (FL), four cases of stable disease, and one minimal response.36

An international phase II program was subsequently initiated to explore the safety and efficacy of pidlizumab in hematologic malignancies and solid tumors. A number of studies are ongoing (Table 2), while one study in patients with relapsed FL was recently completed. Results from this study were presented at the 2012 meeting of the Annual Society of Hematology. Thirty patients with rituximab-sensitive relapsed FL were treated with 3 mg/kg intravenous CT-011 every 4 weeks for 4 infusions in combination with rituximab dosed at 375 mg/m2 weekly for 4 weeks, starting 2 weeks after the first infusion of CT-011. An OR rate of 66% was achieved; CR was observed in 52% and PR in 14%, with measurable tumor regression in 86% of patients. Median time-to-response was 88 days, reflecting the delayed action of immunotherapies; indeed, 17% of patients achieved initial response >3 months after first treatment. Median progression-free survival (PFS) was 21.1 months and was not reached for patients who responded or showed measurable tumor regression. The combination of CT-011 and rituximab in this population was well tolerated and no grade 3/4 drugrelated AEs were observed.37

MK-3475

MK-3475 (Merck) is a humanized IgG4 anti-PD-1 mAb. MK-3475 is undergoing numerous phase I, II, and III trials (Table 2) in a variety of cancer types. Recently, there were two reports of interim results from a phase I study in patients with advanced, metastatic solid tumors (NCT01295827). In one report, the clinical safety and activity of MK-3475 as monotherapy in 38 patients with previously-treated NSCLC was described. Using immune-related response criteria (irRC) the OR rate was 24%, including squamous and non-squamous subtypes (most responses observed within 9 weeks from treatment initiation) and the median duration of response had not been reached. According to RECIST 1.1 the OR rate was 21%. MK-3475 was generally well tolerated, with any grade AEs observed in 21% (n = 8) of patients, most commonly fatigue, rash, and pruritus (16% each). Only one case of a grade 3/4 drug-related AE was reported (pulmonary edema).38

Table 2: NCT Clinical Trials Targeting PD-1/PD-L1 in Cancer

Agent

NCT identifier

Phase

Population

Regimen

Nivolumab

NSCLC

NCT01673867

3

Previously treated advanced or metastatic non-squamous non-small cell lung cancer

vs docetaxel

NCT01642004

3

Previously treated advanced or metastatic squamous nonsmall cell lung cancer

vs docetaxel

NCT01721759

2

Advanced/metastatic squamous cell non-small cell lung cancer who have received at least two prior systemic regimens

Monotherapy

NCT01928576

2

Recurrent, metastatic non-small cell lung cancer

Following azacitidine, entinostat, or oral azacitidine

NCT01454102

1

Stage IIB/IV non-small cell lung cancer

Monotherapy or+ gemcitabine/ Cisplatin+ pemetrexed/cisplatin + Carboplatin/paclitaxel + Bevacizumab maintenance + Erlotinib + Ipilimumab (First-line or switch maintenance)

Melanoma

NCT01844505

3

Previously untreated melanoma

Monotherapy/+ipilimumab vs ipilimumab alone

NCT01721772

3

Untreated, unresectable, or metastatic melanoma

vs dacarbazine

NCT01721746

3

Advanced melanoma patients that have progressed following anti-CTLA4 therapy

vs physician’s choice of either dacarbazine or carboplatin and paclitaxel

NCT01783938

2

Advanced or metastatic melanoma

Administered sequentially with ipilimumab

NCT01927419

2

Previously untreated, unresectable, or metastatic melanoma

+ Ipilimumab vs ipilimumab alone

NCT01621490

1

Advanced melanoma (unresectable or advanced)

Monotherapy

NCT01176474

1

Resected stage IIIC/IV melanoma

Vaccine + escalating doses of BMS- 936558

NCT01176461

1

Unresectable stage III/IV melanoma

+/- Peptide vaccine

NCT01024231

1

Unresectable stage III/IV malignant melanoma

+ Ipilimumab

Other

NCT01668784

3

Pre-treated advanced or metastatic clear-cell renal cell carcinoma

vs everolimus

NCT01354431

2

Advanced/metastatic clear-cell renal cell carcinoma

Monotherapy

NCT01928394

1/2

Advanced or metastatic solid tumors

Monotherapy or + ipilimumab

NCT00730639

1b

Advanced or recurrent malignancies

Monotherapy

NCT01592370

1

Relapsed/refractory hematologic malignancy

Monotherapy

NCT01358721

1

Metastatic renal cell carcinoma

Monotherapy

NCT01658878

1

Advanced hepatocellular carcinoma with or without chronic viral hepatitis

Monotherapy

NCT01472081

1

Metastatic renal cell carcinoma

+ Sunitinib, pazopanib or ipilimumab

NCT01714739

1

Advanced (metastatic/unresectable) solid tumors

+ Anti-KIR antibody lirilumab (BMS-986015)

NCT01968109

1

Select advanced solid tumors

+ Anti-LAG3 antibody (BMS-986016)

NCT01629758

1

Advanced or metastatic solid tumors

+ Recombinant interleukin-21 (BMS-982470)

Pidilizumab

Other

NCT00904722

2

Relapsed follicular lymphoma

+ Rituximab

NCT00904722

2

Relapsed follicular lymphoma

+ Rituximab

NCT01313416

2

Resected pancreatic cancer

+ Gemcitabine

NCT01067287

2

Multiple myeloma

+ Dendritic cell fusion vaccine

NCT01096602

2

Acute myelogenous leukemia

+ Dendritic cell/AML vaccine

NCT01441765

2

Renal cell carcinoma

+/- Dendritic cell/renal cell carcinoma fusion cell vaccination

NCT01420965

2

Advanced prostate cancer

+ Sipuleucel-T and cyclophosphamide

NCT01952769

1/2

Malignant gliomas

Monotherapy

MK-3475

NSCLC

NCT01905657

2/3

Non-small cell lung cancer patients who experienced disease progression after platinum-containing chemotherapy

vs docetaxel

NCT01840579

1

Advanced solid tumors (part A) and advanced non-small cell lung cancer (part B)

Monotherapy (part A)+ non-random assignment to cisplatin/pemetrexed or carboplatin/ paclitaxel (partB)

Melanoma

NCT01866319

3

Advanced melanoma

vs ipilimumab

NCT01704287

2

Advanced melanoma; progressed after prior therapy

vs standard chemotherapy

Other

NCT01876511

2

Microsatellite unstable tumors

Monotherapy

NCT01953692

1

Hematologic malignancies including myelodysplastic syndrome, smoldering multiple myeloma and non-Hodgkin lymphoma

Monotherapy

NCT01848834

1

Advanced solid tumors (triple-negative breast, head and neck, urothelial, and gastric cancers)

Monotherapy

NCT01295827

1

Progressive locally advanced or metastatic carcinoma, melanoma, or non-small cell lung carcinoma

Monotherapy

AMP-224

Other

NCT01352884

1

Adult patients with cancer that is not responding to standard therapy

Monotherapy

BMS936559

Other

NCT00729664

1

Multiple cancer indications

Monotherapy

MPDL3280A

NSCLC

NCT01903993

2

Advanced or metastatic non-small cell lung cancer after platinum failure

vs docetaxel

Melanoma

NCT01656642

1b

Previously untreated BRAFV600-mutation positive metastatic melanoma

+ Vermurafenib

Other

NCT01846416

2

PD-L1-positive locally advanced or metastatic breast cancer

Monotherapy

NCT01375842

1

Locally advanced or metastatic solid malignancies or hematologic malignancies

Monotherapy

NCT01633970

1

Advanced solid tumors

+ Bevacizumab + Bevacizumab/FOLFOX + Carboplatin/paclitacel + Carboplatin/pemetrexed + Carboplatin/nab-paclitaxel

MEDI4736

Other

NCT01693562

1

Advanced malignant melanoma, renal cell carcinoma, nonsmall cell lung cancer, or colorectal cancer

Monotherapy

The second report involved an expansion study of a cohort of 294 melanoma patients with (n = 179) or without (n = 115) previous ipilimumab treatment. MK-3475 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. OR rates per RECIST 1.1 and irRC were very similar and were >35% across all doses and schedules, including both ipilimumab-naïve and ipilimumabpretreated patients. Median duration of response had not yet been reached, while median PFS was longer than 8 months. MK-3475 was also well tolerated in this study, with manageable toxicity in melanoma patients, with grade 3/4 drug-related AEs reported in 10% of patients, including hypothyroidism and hyperthyroidism.39

BMS-936559

BMS-936559 (Bristol-Myers Squibb) is a fully human IgG4 anti-PD-L1 mAb that inhibits the binding of the PD-L1 ligand to both PD-1 and CD80. The results of a phase I clinical trial of BMS-936559 in patients with advanced cancer were reported at the 2012 American Society of Clinical Oncology meeting and were subsequently 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, 3, and 10 mg/kg). Objective response rates of 6% to 17% were observed depending on cancer type across all doses (Table 1).

For melanoma patients, the most significant OR was observed at a dose of 3 mg/kg (29%), while for other cancer types it was at 10 mg/kg. For NSCLC patients, similar response rates were seen for squamous and non-squamous histologies (8% and 11%, respectively), across all doses. The response in NSCLC was unexpected since NSCLC has been considered to be non-immunogenic and poorly responsive to immunotherapy. Observed responses were durable across the multiple tumor types, lasting for ≥1 year in half of the patients with at least 1 year of follow-up. This was highlighted by Brahmer and colleagues as 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 drugrelated toxicities in only 9% of patients.40

MPDL3280A

MPDL3280A (Roche) is a human anti-PD-L1 mAb that contains an engineered fragment crystallizable (Fc) domain designed to optimize efficacy and safety by minimizing antibody-dependent cellular cytotoxicity (ADCC). The theory is that this structure will allow inhibition of the PD-1/PD-L1 interaction, while minimizing ADCC-mediated depletion of activated T cells that is required for an effective antitumor immune response.5

MPDL3280A has been evaluated in a phase I trial in patients with locally advanced or metastatic solid tumors. A total of 175 patients had been recruited to date.41 The antibody was administered as a single agent at escalating doses of ≤1, 3, 10, 15, and 20 mg/kg for a median duration of 127 days. The results of two expansion cohorts have also been reported; a cohort of 85 patients (53 of whom were evaluable for efficacy) with squamous or non-squamous NSCLC and a cohort of 45 metastatic melanoma patients (35 of whom were evaluable for efficacy). In both cohorts doses of ≤1, 10, 15, and 25 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 Table 1. Of the 85 patients in the NSCLC cohort, 55% were heavily pretreated with at least three prior therapies, and 81% were smokers or ex-smokers and 19% were never-smokers. The 24-week PFS rate was 44% in squamous cell NSCLC and 46% in non-squamous cell NSCLC.42

All 175 patients in the initial trial and all patients in the NSCLC and melanoma expansion cohorts were evaluated for safety, and 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, elevation of alanine transaminase (ALT) levels, and elevation of aspartate transaminase (AST) levels. No grade 3/4 pneumonitis was reported in any patients.41-43

Potential Role of PD-L1 as a Biomarker

Research and ongoing clinical studies are being conducted to evaluate the potential significance of PD-L1 as a biomarker for cancer immunotherapy.42 PD-L1-positive cancers are associated with poorer prognoses than those that are PD-1 negative. A correlation of PD-L1 expression and OR rate 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%).42 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 I biomarker study, Th1-driven CD8 biology, intratumoral characteristics and adaptive PD-L1 enhancement with MPDL3280A correlated with observed clinical responses, as well as PD-L1 status.44 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.45 This was followed by the development of RECIST at the turn of the millennium to provide more simplified and standardized response definitions.46 Although they have been updated and modified throughout the years,47 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 guidelines assume that an increase in tumor growth and/or the appearance of new cancerous lesions early on in the course of treatment indicated progression, and it was recommended that treatment be stopped once this was observed. Thus, the term progression becomes synonymous with drug failure. However, with the development of immunotherapies that have a very different mechanism of action to 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 group of around 200 oncology, immunotherapy, and regulatory experts came together in a series of workshops in 2004 and 2005 to share their experiences and discuss 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 response. Thus, discontinuation of immunotherapy at the point of apparent progressive disease may not be an appropriate course of action.48,49

Based on these conclusions, a series of large, multinational studies were conducted using the most comprehensive data set available for immunotherapy: the phase II clinical program with ipilimumab, involving three studies totaling 487 patients with advanced melanoma.50-52 The group noted four distinct response patterns (two conventional and two that were unique to immunotherapy):

  1. immediate response
  2. durable stable disease
  3. response after tumor burden increase
  4. 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 immune-related response criteria (irRC) were developed.

A comparison of the conventional response criteria and the irRC is outlined in Table 3. Essentially, the irRC are based on modified WHO criteria and involve the use of bidimensional measurements on radiographic assessment 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 complete response until progression is confirmed.48,49

Table 3: Immune-Related Response Criteria (irRC)

Immune-related response criteria

Conventional criteria

Bidimensional assessment50

Unidimensional assessment49

New measurable lesions

Always represent progressive disease

Incorporated into tumor burden

New non-measurable lesions

Always represent progressive disease

Do not define progression (but preclude irRC)

Non-index lesions

Changes contribute to defining best overall response of CR, PR, SD, and PD

Contribute to defining irRC (complete disappearance required)

Measurement of each lesion

Longest diameter (cm)

Longest diameter x longest perpendicular diameter (cm2)

Longest diameter (cm)

“Measurable” lesions

≥10 mm in the longest diameter

≥5 x 5 mm2 (longest diameter x longest perpendicular diameter)/td>

≥10 mm in the longest diameter

Sum of the measurements

Sum of unidimensional measurements of all target lesions

Sum of bidimensional measurements of all target lesions and any new lesions

Sum of unidimensional measurements of all target lesions and any new lesions

Response assessment:

“Progressive disease” (irPD)

Increase in tumor volume ≥25% from nadir, and/or unequivocal progression of non-index lesions, and/or appearance of new lesions at any single time point

Increase in tumor volume ≥25% from nadir

Increase in tumor volume ≥20% from nadir

“Stable disease” (irSD)

Not meeting criteria for CR or PR, in absence of new lesions or unequivocal progression of non-index lesions

Not meeting criteria for CR or PR

Not specified

“Partial response” (irPR)

Decrease in tumor volume ≥50% relative to baseline, in absence of new lesions or unequivocal progression of non-index lesions

Decrease in tumor volume ≥50% relative to baseline

Decrease in tumor volume ≥30% relative to baseline

“Complete response” (irCR)

Complete disappearance of all lesions

Complete disappearance of all index and new measurable lesions

Complete disappearance of all index and new measurable lesions

New lesions

Presence of new lesions alone defines progression; new lesions not included in sum of measurements

Presence of new lesions alone does not define progression; measurement of new lesions included in sum of measurements

Confirmation

Confirmation at two consecutive timepoints at least 4 weeks apart is required in the absence of rapid clinical deterioration

Confirmation at two consecutive time-points at least 4 weeks apart is required in the absence of rapid clinical deterioration

Adapted from Clin Cancer Res. 2009;15(23):7412-742050 and Clin Cancer Res. 2013;19(14):3936-3943.49

CR indicates complete response; PR, partial response; PD, progressive disease; and SD, stable disease.

The irRC are considered clinically meaningful, as they appear to be related to favorable survival; however, they are still in the early stages of development, and prospective trials are needed to evaluate their use in clinical trials of other immunotherapies in different cancer types and to further investigate the potential association with survival. Recently, the use of the irRC using unidimensional measurements was evaluated (Table 3). Unidimensional measurements are advantageous as they are simpler and more reproducible, with less chance for misclassification of response. The study indicated that irRC using unidimensional measurements produced a very similar evaluation of response to bi-dimensional measurements, but with significantly less variability.49

Proven Clinical Rationale for Targeting Immunotherapy in Cancer

Immunotherapy for the treatment of cancer has evolved alongside our improved understanding of the immune system. In particular, an appreciation of the ability of cancer cells to subvert the antitumor immune response has provided a rationale for the development of novel immunotherapies that target immune checkpoints responsible for the regulation of T-cell activity.

Ipilimumab, a mAb targeting CTLA-4, was the first to receive regulatory approval from the FDA. In addition, agents that target the PD-1 receptor and the PD-L1 ligand are being developed, and data from early phase clinical trials suggest that they may be as effective as ipilimumab, with less toxic immune-related side effects. Development of anti-PD-1 and anti-PD-L1 agents also provides the opportunity for combination therapy with ipilimumab (and other types of immunotherapy or targeted cancer agents), and reports indicate that this may generate impressive responses in patients with a range of different cancer types.

The clinical rationale for targeting the PD-1/PD-L1 pathway is sound. PD-1 is a T-cell molecule that binds to the ligands PD-L1 or PD-L2. PD-L1 is typically expressed on tumor cells and is induced by gamma interferon secreted by activated T cells (Figure 3).53 In brief, the activated T cells that could kill tumors are specifically disabled by those tumors that express PD-L1, which binds to PD-1, and creates a phenotype known as T-cell exhaustion. Clinical data from studies of antibodies directed against PD-1 and PD-L1 have shown encouraging safety profiles and remarkable antitumor activity in subsets of patients with metastatic disease, including malignancies (such as lung cancer) that were previously thought to be unresponsive to immunotherapy.

Continued development of immune-related response criteria that more accurately reflect the unique responses observed with the anti-PD-1/anti-PD-L1 class of drugs will also help to further improve their clinical evaluation.

Figure 3. PD-1 Blockade: Binding to PD-L1 and PD-L2

PD-1 is a T-cell molecule that binds to the ligands PD-L1 or PD-L2. PD-L1 is typically expressed on tumor cells and is induced by gamma interferon secreted by activated T cells. The activated T cells that could kill tumors are specifically disabled by those tumors that express PD-L1 and bind to PD-1 to create a phenotype known as T-cell exhaustion. Adapted from Clin Cancer Res. 2013;19(19):1021-1034.53

References

  1. American Cancer Society. Cancer Facts and Figures, 2011. Available at: www. cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/ acspc-029771.pdf. Accessed October 30, 2013.
  2. Coley WB. The treatment of inoperable sarcoma with the mixed toxins of erysipelas and bacillus prodigiosus: immediate and final results in one hundred and forty cases. JAMA. 1898;31:389.
  3. Kirkwood JM, Butterfield LH, Tarhini AA. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012;62:309.
  4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57.
  5. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy- inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580.
  6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480.
  7. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116:1757.
  8. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate antitumor immunity. Curr Opin Immunol. 2012;24:207.
  9. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237.
  10. FiercePharma. Top 10 best-selling cancer drugs. Available at: www.fiercepharma. com/special-reports/top-10-best-selling-cancer-drugs/top-10-best-selling-cancer- drugs. Published May 15, 2012. Accessed October 30, 2013.
  11. Czuczman MS, Grillo-Lopez AJ, White CA. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17(1):268.
  12. Slamon D, Leyland-Jones B, Shak S. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med. 2001;344:782.
  13. Bilusic M, Madan RA. Therapeutic cancer vaccines: the latest advancement in targeted therapy. Am J Ther. 2012;19(6):e172.
  14. Kantoff PW, Higano CS, Shore ND. Sipuleucel-T immunotherapy for castrationresistant prostate cancer. New Engl J Med. 2010;363(5):411.
  15. Beck A, Wurch T, Bailly C. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10(5):345.
  16. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646.
  17. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1.
  18. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med. 2010;363:711.
  19. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336.
  20. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677.
  21. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2012;31:1021.
  22. Butte MJ, Keir ME, Phamduy TB, Freeman GJ, Sharpe AH. PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation. Immunity. 2007;27(1):111.
  23. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166.
  24. Ribas A. Tumor immunotherapy directed at PD-1. New Engl J Med. 2012;366(26):2517.
  25. Wang SF, Fouquet S, Chapon M, Salmon H, Regnier F, Labrouquere K. Early T cell signaling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors. PLoS One. 2011;6:e17621.
  26. Dong H, Stome SE, Salomao DR, Tamura H, Hirano F, Flies DB. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793.
  27. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10:5094.
  28. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110:296.
  29. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537.
  30. Brahmer JR, Drake CG, Wollner, I et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167.
  31. Topalian SL, Sznol M, Brahmer JR, et al. Nivolumab (anti-PD-1; BMS-936558; ONO- 4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial. J Clin Oncol. 2013;31(suppl; abstr 3002).
  32. Brahmer JR, Horn L, Antonia SJ, et al. Nivolumab (anti-PD-1; BMS-936558; ONO- 4538) in patients with non-small cell lung cancer: overall survival and long-term safety in a phase I trial. 15th World Conference on Lung Cancer. 2013; Sydney, Australia (abstr MO18.03).
  33. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122.
  34. Rizvi NA, Antonia SJ, Chow LQM et al. A phase I study of nivolumab (anti-PD-1; BMS-936558,ONO-4538) plus platinum-based doublet chemotherapy in chemotherapy- naive non-small cell lung cancer patients. J Clin Oncol. 2013;31(suppl; abstr 8072).
  35. Weber JS, Kudchadkar RR, Gibney GT, et al. Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab. J Clin Oncol. 2013;31(suppl; abstr 9011).
  36. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1 in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044.
  37. Westin JR, Chu F, Fayad LE, et al. Phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follic-ular lymphoma. 54th Annual Meeting of the American Society of Hematology. 2012; Atlanta, GA (abstr 793).
  38. Garon EB, Balmanoukian A, Hamid O, et al. Preclinical safety and activity of MK- 3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer. 15th World Conference on Lung Cancer. 2013; Sydney, Australia (abstr MO18.02).
  39. Ribas A, Robert C, Daud A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. J Clin Oncol. 2013;31(suppl; abstr 9009).
  40. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455.
  41. Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PDL1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl; abstr 3000).
  42. Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer: additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). European Cancer Congress. 2013; Amsterdam (abstr 3408).
  43. Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma. J Clin Oncol. 2013;31(suppl; abstr 9010).
  44. Kohrt H, Kowanetz M, Gettinger S, et al. Intratumoral characteristics of tumor and immune cells at baseline and on-treatment correlated with clinical responses to MPDL3280A, an engineered antibody against PD-L1. J Immunother Cancer. 2013; 1(suppl 1):O12.
  45. World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva, Switzerland: World Health Organization Offset Publication No.48; 1979.
  46. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92(3):205.
  47. Eisenhauer EA, Therasse, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228.
  48. Hoos A, Eggermont AMM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102(18):1376.
  49. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013;19:3936-3943.
  50. Wolchok JD, Hoos A, O’Day, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23)7412-7420.
  51. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591.
  52. O’Day S, Ibrahim R, DePril V. Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies. Proc Am Soc Clin Onc. 2008;26(20 suppl; abstr 9021).
  53. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19(19):1021-1034