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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.
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
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.
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
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.
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
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
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
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.
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):
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
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
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.
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