Emerging clinical data suggest that targeted immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.
Immunotherapy has become an increasingly appealing therapeutic strategy for patients with cancer, with many late-stage clinical trials demonstrating overall survival (OS) advantages in melanoma and castration-resistant prostate cancer. More recently, non-small cell lung cancer (NSCLC) has become a focus for the next generation of immune-based therapeutic strategies.
Immunotherapy, in particular the use of monoclonal antibodies that block inhibitory immune checkpoint molecules and therefore enhance the immune response to tumors, has shown clinical promise in advanced solid tumors. The clinical rationale for targeting the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathways will be reviewed in this supplement, including an update on the results of select clinical trials that evaluate the potential of targeted immunotherapy as presented at the 2015 American Association of Cancer Research (AACR) Annual Meeting. Emerging clinical data suggest that targeted immunotherapy in cancer will become an integral part of the clinical management strategy for solid tumors.
Cancer is traditionally treated with conventional therapy (ie, chemotherapy or radiation therapy) or targeted drugs that directly kill tumor cells. While the number of patients who survive cancer has seen significant increases, the “war” rages on.1 More than a century ago, a series of primitive experiments hinted at the potential for harnessing the immune system to fight cancer.2 The immune system protects the body from foreign invading agents by recognizing “nonself” proteins (antigens) displayed on their surface that distinguish them from normal, healthy tissue (“self”). This subsequently initiates a protective response that neutralizes these organisms.3 William Coley was the first to suspect 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 In the years that followed, a dynamic and complex relationship between the immune system and cancer was uncovered, giving birth to the concept of immunotherapy.
Cancer cells are normal cells that have acquired numerous hallmark abilities that allow them to become malignant 4; thus, they are essentially identified as “self”—part of the host. In spite of this, they often display unusual or inappropriate proteins on their cell surface that allow the immune system to identify them as “non-self,” and an antitumor immune response is often initiated. However, cancer cells have evolved a number of mechanisms to enable evasion of this immune response and render it ineffective. Typically, by the time a cancer becomes detectable, the balance of power between the immune system and the cancer has shifted in favor of the growing tumor, and a state of immune tolerance has been established. Immunotherapy comprises a diverse range of therapeutic approaches intended to harness the immune system to reestablish a targeted antitumor immune response. The goal of cancer immunotherapy is to enable the patient’s immune system to specifically recognize and kill cancer cells.5-9 There are 2 distinct types of immunotherapy: passive immunotherapy uses components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating an immune response in the patient, while active immunotherapy actively triggers an endogenous immune response. Passive strategies include the use of the monoclonal antibodies (mAbs) produced by B cells in response to a specific antigen.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.
To actively drive an antitumor immune response, therapeutic cancer vaccines have been developed. Unlike the prophylactic vaccines that are used preventively to treat infectious diseases, therapeutic vaccines are designed to treat established cancer by stimulating an immune response against a specific tumor-associated antigen. In 2010, sipuleucel- T (Provenge; Dendreon Corporation) was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic, castration-resistant prostate cancer based on results of the IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial in which it improved OS by 4.1 months and reduced the risk of death by 22% versus placebo.10,11 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.12
Despite these successes, immunotherapy has previously faced skepticism and significant disappointment; however, it is now beginning to gather momentum, particularly following the discovery of immune checkpoints and the success of their therapeutic targeting.13 The growing appreciation for the ability of cancer cells to evade the immune response and an increased understanding of how this impacts the development of cancer and resistance to cancer therapy has led researchers to investigate the mechanisms by which immune evasion occurs. This has resulted in recognition of the significant role that immune evasion plays in malignant progression.14 Generation of an effective antitumor immune response involves a series of steps that ultimately lead to the death of cancer cells (Figure 1).15 In the first step (step 1), cancer-specific antigens are released from cancer cells and captured by dendritic cells (a type of antigen-presenting cell [APC]). This step must be accompanied by immunogenic signals such as pro-inflammatory cytokines. Next, the dendritic cells present the captured antigen to the immune effector cells—cytotoxic T cells (step 2).
This activates and primes the cytotoxic T cells to generate a specific immune response against the cancer-specific antigens (step 3). Activated T cells then traffic to (step 4) and infiltrate (step 5) the tumor and recognize cancer cells by their expression of the specific antigen. They then bind the specific antigen to their T-cell receptor (step 6). The cytotoxic T cell kills the cancer cell (step 7), which results in the release of additional cancer-specific antigens, thereby starting the whole process over again. This cycle ceases to function appropriately in patients with cancer, as tumors are able to break the cycle by affecting any of these 7 steps.15
One of the mechanisms by which cancer cells break this cycle is the hijacking of 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.16 In clinical trials, 46% of patients treated with ipilimumab were alive after 1 year, and 24% after 2 years.17
A number of other checkpoint proteins are also being examined. The PD-1 receptor and its ligands PD-L1 and PDL2 are part of the same family of coregulatory molecules as CTLA-4. Several anti-PD-L1 agents are currently being investigated in both solid and hematologic cancers. In September 2014, pembrolizumab (Keytruda; Merck Sharp & Dohme Corp), previously known as MK-3475, was the first to be approved by the FDA. It is indicated for use in patients with advanced or unresectable melanoma who are no longer responding to other drugs.18 The safety profile of pembrolizumab in patients who did not achieve an adequate response to earlier ipilimumab treatment is similar to that observed in ipilimumab-naïve patients.19 In March 2015, nivolumab (Opdivo; Bristol-Myers Squibb) was approved by the FDA for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Nivolumab is also indicated for metastatic squamous NSCLC with progression on or after platinum-based chemotherapy.20
The PD-1 and PD-L1 Pathway in Normal Human Physiology and Neoplasms
Activation of T cells during an immune response is a 2-step process: the first step gives the immune response specificity and requires interaction of T-cell receptors with a specific antigenic peptide—containing complex on APCs. This is followed by an antigen-independent coregulatory signal that determines if the T cell will be switched on or off. The secondary signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T cell, and in the absence of this signal (even in the presence of a target antigen), T cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T cells on) or inhibitory (switching them off).8,21,22
The 2 known inhibitory checkpoint pathways involve signaling through the CTLA-4 and PD-1 receptors. These proteins are members of the CD28-B7 family of cosignaling molecules that play important roles throughout all stages of T-cell function. The PD-1 receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are expressed on the surface of APCs such as dendritic cells or macrophages. PD-L1 is the predominant ligand, while 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. 5,8,23
PD-L1 has also been shown to bind to B7-1 (CD80), an interaction that also suppresses T-cell proliferation and cytokine production; however, the exact relative contributions of the PD-L1: PD-1 and PD-L1:B7-1 pathways in cancer remain unclear. The PD-1-targeting agents currently in development inhibit both pathways. However, as the binding sites for PD-1 and B7-1 are adjacent but not overlapping, agents that specifically target one or the other may be developed. 24
APC indicates antigen-presenting cell CTL, cytotoxic T lymphocyte.
Generation of an effective antitumor immune response involves a series of stepwise events that ultimately form a cyclical response that increases the depth and breadth of the immune response against tumor-associated antigens. In cancer patients, this cycle functions suboptimimally, allowing cancer cells to avoid death.
Reprinted with permission from Chen DS, Mellman I. Immunity. 2013;39:1-10.
CTLA-4 and PD-1 have distinct roles in regulating immunity (Figure 2 25), with both temporally and spatially distinct expression patterns. CTLA-4 regulates T-cell activity initial activation and acts as a signal dampener, regulating the amplitude of early activation of naïve and memory T cells, while PD- functions to limit the activity of already activated T cells in the periphery during the inflammatory response to infection to limit autoimmunity. 5,8,15,25,26
Cancer cells exploit the PD-2 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.5,8,24 Indeed, upregulation of PD-L1 expression levels has been observed 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.7,27-30 Furthermore, tumor-infiltrating T cells have been shown to express significantly higher levels of PD-1 than T cells that infiltrate normal tissue. It is thought that the tumor microenvironment may secrete pro-inflammatory cytokines, including interferon-gamma, to upregulate the expression of PD-1 on tumor-infiltrating T cells to ensure that they can respond to the high levels of PD-L1 expressed on the tumor.31
Designing therapies that specifically target mechanisms of immune evasion is an attractive therapeutic approach because the ability of the tumor to suppress the immune response can seriously undermine the clinical efficacy of cancer therapies. Confirmation of the pivotal role of the PD-1 pathway in immunosuppression provided a strong rationale for the development of mAbs that block the PD-1 pathway, and several such agents are now being assessed in clinical trials.
Activation of T cells is a 2-step process that requires recognition of specific antigens presented by MHC on the surface of cancer cells through their “primed” T-cell receptor, as well as a co-regulatory signal delivered by the B7 family of receptors (the so-called immune checkpoints). The 2 checkpoints that deliver inhibitor signals, CTLA-4 and PD-1, function at different points in T-cell function. CTLA-4 is upregulated shortly after activation and negatively regulates T-cell activation during the “priming” phase of T-cell response within the lymph nodes by binding to B7 molecules on the surface of antigen-presenting cells. Conversely, when these B7 molecules bind to CD28 instead, they generate the opposite, activating signals. PD-1 is expressed on T cells later on in the immune response, during the effector phase of T-cell response. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. Blockade of CTLA-4 or PD-1/PD-L1 with antibodies results in the preferential activation of T cells with specificity for cancer cells.
From Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012; 366(26):2517-2519. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission.
Select Anti—PD-1/PD-L1 Immunotherapies
The anti-PD-L1 immunotherapies MPDL3280A, nivolumab, and pembrolizumab have shown promise in early studies. Several clinical trials are under way to further evaluate the safety and efficacy of these immune checkpoint inhibitors.
MPDL3280A is a human mAb that targets PD-L1, thereby preventing its binding to its receptors (PD-1 and B7-1)32 and restoring antitumor T-cell activity and proliferation. It also can improve T-cell priming.24 MPDL3280A contains an engineered fragment crystallizable (Fc) domain designed to optimize efficacy and safety.33 In theory, this structure will allow inhibition of the PD-1/PD-L1 pathway while minimizing the antibody-dependent cellular cytotoxicity-mediated depletion of activated T cells that is required for an effective antitumor immune response.34
An ongoing phase l expansion study is evaluating participants with renal cell carcinoma, melanoma, NSCLC, urothelial bladder cancer (UBC), and other tumor types. Preliminary data were presented at the European Society for Medical Oncology meeting in Madrid, Spain, in September 2014. Participants with UBC received MPDL3280A 15 mg/kg intravenously every 3 weeks for up to 16 cycles. Of the 70 participants with UBC, 33 were PD-L1-positive and 36 were PD-L1-negative; 1 patient had unknown PD-L1 status. Of the efficacy evaluable population, 91% of participants received prior platinum-based therapy (mostly cisplatin) and 49% already had a cystectomy. The median age of participants was 65 years, and 73% were male.34 Treatment with MPDL3280A was well tolerated, with no grade 5 treatment-related adverse events (AEs) reported; only 5% of participants experienced a grade 3 or grade 4 AE. Therapy with MPDL3280A for UBC was not associated with renal toxicity, and no investigator-assessed immune-related toxicities were observed. The most common AEs reported were fatigue (15%), decreased appetite (12%), and nausea (11%). Other AEs included pruritus, pyrexia, asthenia, chills, dry skin, influenza-like illness, lethargy, and rash.34 The median follow-up was 6 months for participants who were PD-L1-positive. Nineteen out of 22 responders had an ongoing response at the time of data cutoff. The objective response rate based on PD-L1 immunohistochemistry (IHC) was 60% for IHC 3 (n = 10), 48% for IHC 2 (n = 23), 17% for IHC 1, and 8% for IHC 0.24 The median time to first response in PD-L1-positive patients (n = 17) was 43 days compared with 83 days for PD-L1-negative patients (n = 5). However, for the 22 participants evaluated, the median duration of response had not yet been reached.34 Investigators observed that median progression-free survival (PFS) appeared to be associated with PD-L1 expression (24 weeks in IHC 2/3 participants vs 8 weeks in IHC 0/1 participants, comparing PD-L1-positive to PD-L1-negative).34 A phase ll, single-arm study is currently open for enrollment. This study consists of 2 cohorts: 1 of treatment-naïve patients ineligible for platinum- containing therapy and 1 of patients who progressed during or after a prior platinum-based therapy. Participants in both cohorts will receive MPDL3280A 1200 mg intravenously every 3 weeks for 16 cycles, or 12 months. Patients in this study will be followed for up to 2 years.35
In a phase l expansion study, investigators assessed the effects of MPDL3280A in patients with squamous or nonsquamous NSCLC at a range of doses (1-20 mg/kg) for up to 1 year of treatment. Of the 53 patients evaluable in early 2013, the median age was 61 years; the majority had a good performance status (Eastern Cooperative Oncology Group [ECOG] 0 to 1); and most had undergone prior surgery (89%), radiotherapy (55%), or systemic therapy (98%). Grade 3 and 4 AEs occurred in 34% of the patients and included pericardial effusion (6%), dehydration (4%), dyspnea (4%), and fatigue (4%) but did not include any cases of grade 3 to 5 pneumonitis or diarrhea. The objective response rate in 37 evaluable NSCLC patients who enrolled before July 1, 2012, was 24% (9/37), and 24-week PFS was 48%. Further, patients with PD-L1-positive tumors had an objective response rate of 100% (4/4), and none of these 4 patients experienced progressive disease (PD). Patients with PD-L1-negative tumors had an objective response rate of 15% (4/26) and a PD rate of 58% (15/26). Thus, PD-L1 tumor status was shown to correlate with response to MPDL3280A. 36 While the phase l study is ongoing, it has been concluded that treatment with MPDL3280A is tolerable and provides rapid and durable responses.36,37 Phase lb trials are currently evaluating the combinations of MPDL3280A with vemurafenib (Zelboraf) in treatment-naïve metastatic melanoma38 and MPDL3280A with bevacizumab in advanced solid tumors, including NSCLC.39
A phase ll study (FIR) of MPDL3280A in patients with PD-L1-positive locally advanced or metastatic NSCLC is ongoing, 40 and a second phase ll study (BIRCH) in metastatic NSCLC is currently recruiting participants.41 Both trials are multicenter, single-arm studies that will evaluate the efficacy and safety of MPDL3280A therapy in lung cancer patients, who will receive intravenous (IV) treatment once every 3 weeks until disease progression.40,41 Also ongoing is a multicenter, open-label, randomized phase ll trial (POPLAR) comparing MPDL3280A with docetaxel in patients with advanced or metastatic NSCLC who have failed platinum- based chemotherapy.42 Finally, a phase lll trial (OAK) is currently enrolling patients with locally advanced or metastatic NSCLC. This multicenter, open-label, randomized, controlled study will also compare MPDL3280A with docetaxel in patients with NSCLC after failure with platinum- based chemotherapy.43
Nivolumab (BMS-936558) (Bristol-Myers Squibb)
Nivolumab was the first PD-1/PD-L1 immune checkpoint inhibitor to enter clinical testing. It is a fully human immunoglobulin G4 (IgG4) mAb targeted against PD-1 on activated T and B cells. Blocking PD-1 prevents these activated lymphocytes from undergoing anergy, or immunologic inactivation. In this way, PD-1 blockers help maintain antitumor immunologic activity.44,45 Pharmacokinetic studies of nivolumab included single ascending dose and multiple ascending dose studies in patients with advanced solid malignancies. Investigators reported that the half-life of nivolumab is 17 to 25 days (consistent with that of endogenous IgG4), mean volume of distribution ranged from 83 to 113 mL/kg, and mean clearance ranged from 0.13 to 0.19 mL/h/kg.45
Nivolumab has been studied extensively in patients with NSCLC and other tumors. A phase l study evaluated the activity, pharmacokinetics, and safety of nivolumab in refractory solid tumors. A total of 39 patients with advanced metastatic NSCLC (n = 6), melanoma (n = 10), colorectal cancer (CRC) (n = 14), castration-resistant prostate cancer (CRPC) (n = 8), or renal cell carcinoma (RCC) (n = 1) received nivolumab therapy at several dosage levels. Median age was 62 years, and all patients in this study had progressive treatment-refractory disease. One patient with NSCLC (and another with melanoma) experienced lesional regression or regression of the primary tumor, but had progression at other tumor sites. Pharmacokinetic findings included a 12- to 20-day half-life and 72% mean plateau occupancy (range, 59%-81%) of PD-1 on T cells that appeared to be dose-independent. Investigators also found preliminary evidence that the level of PD-1 expression on tumor cells correlates with response. In terms of safety, nivolumab was well tolerated to the maximum planned dose of 10 mg/kg. The most common grade 2 and greater AEs were decreased CD4-positive T-cell counts (35.9%), lymphopenia (25.6%), fatigue (15.4%), and musculoskeletal events (15.4%). No grade 3 or 4 immune-related AEs occurred in the 28 days after the first dose of nivolumab.46
Additional studies further demonstrated the acceptable safety profile of nivolumab in NSCLC and other cancers. In a study of the activity and safety of nivolumab in 240 patients with several types of tumors (melanoma [n = 95], RCC [n = 33], CRC [n = 19], CRPC [n = 17], NSCLC [n = 75], or unknown cancer type [n = 1]) who received nivolumab for a median of 15 weeks, grade 3 and 4 AEs occurred in 13% of patients and included pneumonitis, hypophysitis, hepatitis, colitis, and thyroiditis; there were 2 deaths due to pulmonary toxicity. This study also found PD-L1 expression to be potentially predictive of response because 50% (16/29) of patients with PD-L1-positive tumors achieved an objective response compared with no patients with tumors lacking PD-L1. Also, durable activity was recorded in patients with advanced melanoma, RCC, or NSCLC.47
Safety data and initial OS for NSCLC patients from another phase l study of nivolumab in advanced solid tumors48 were reported. Patients with at least 1 prior chemotherapy regimen received nivolumab (1 to 10 mg/kg IV every 2 weeks) for at least 12 cycles (4 doses/8-week cycle) or until discontinuation criteria were met. In 127 evaluable patients, long-term drug-related AEs included decreased appetite (9%), anemia (8%), diarrhea (7%), nausea (7%), and pruritus (7%). The most common grade 3 or 4 AEs (2% each) were fatigue, pneumonitis, and elevated levels of aspartate aminotransferase (AST). Median OS across all dose cohorts was 9.2 months for patients with squamous NSCLC and 9.6 months for non-squamous NSCLC. Median OS was not reached at the time the report was published in patients receiving the 3 mg/kg dose (the dose that will be evaluated in phase lll trials) for patients with either histology. Sustained OS was observed, with 44% of patients with squamous NSCLC alive at both 1 and 2 years, and 41% and 17% of patients with non-squamous NSCLC alive at 1 and 2 years, respectively.49
In a third study evaluating intravenous (IV) nivolumab for a median of 11 weeks in 162 patients (melanoma [n = 53], RCC [n = 17], CRC [n = 18], ovarian cancer [n = 17], pancreatic cancer [n = 7], or NSCLC [n = 50]), common AEs (occurring in ≥5% of patients) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3 and 4 AEs was 8.6% and included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis. No patients died because of drug treatment. Clinical activity was observed in melanoma, RCC, and NSCLC. Of 16 patients experiencing objective response, 7 patients experienced objective responses lasting 1 year or more.50
Phase III trials are also investigating the utility of nivolumab in lung cancer. An open-label, randomized, phase lll trial (CheckMate-026) is recruiting to show whether nivolumab will improve PFS in subjects with stage IV or recurrent PD-L1-positive NSCLC compared with the investigators’ choice of chemotherapy. This trial will assess the clinical activity of first-line nivolumab monotherapy in treatment-naïve patients.51,52 CheckMate-153 is a phase lll safety trial set to estimate the incidence and characterize the outcome of select high-grade AEs. Patients include those who have advanced or metastatic NSCLC and who have progressed during or after receiving at least 1 prior systemic regimen.53 In Check- Mate-017, an open-label, phase lll trial of 264 patients with advanced or metastatic squamous cell carcinoma who have failed platinum-based chemotherapy, patients are randomized in a 1:1 ratio to receive either nivolumab every 2 weeks or docetaxel every 3 weeks until disease progression or unacceptable toxicity. Investigators will evaluate objective response, OS, PFS, and benefits stratified by PD-L1 expression in cancer tissue.54,55 Similarly, the phase 3 study CheckMate-057 is comparing the OS of nivolumab and docetaxel in patients with metastatic or recurrent non-squamous NSCLC. A total of 574 previously treated patients will receive nivolumab or docetaxel in a 1:1 ratio until disease progression or unacceptable toxicity. OS, objective response rate, PFS, disease-related symptom progression, and benefits stratified by PD-L1 expression in cancer tissue will be assessed.56,57
Pembrolizumab (Keytruda) (Merck)
Pembrolizumab is a humanized IgG4 mAb that targets the PD-1 receptor.58 Pembrolizumab was approved by the FDA in 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression after previous treatment with certain other drugs (ipilimumab and BRAF inhibitors).59 The drug was approved for this indication through the FDA’s accelerated approval program because of the tumor response rate (26% overall response rate) and durability of response (88% of responses ongoing at a median follow-up of 8 months) in advanced melanoma patients in the phase 1 KEYNOTE-001 study.59,60
This agent has no cytotoxic activity, but does have a low occurrence of antidrug antibodies, which has no impact on its pharmacokinetic properties. Pharmacokinetic studies demonstrate that pembrolizumab can be dosed every 2 or 3 weeks.61
CD28 indicates cluster of differentiation 28; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TCR, T-cell receptor.
KEYNOTE-012, a phase lb multi-cohort study of pembrolizumab in patients with PD-L1-positive advanced solid tumors, evaluated the safety, tolerability, and antitumor activity of pembrolizumab in participants with advanced triple- negative breast cancer, advanced head and neck cancer, advanced urothelial cancer, or gastric cancer.62 The urothelial cohort evaluated participants with recurrent or metastatic cancer of the renal pelvis, ureter, bladder, or urethra with transitional or nontransitional histology. Participants had to have PD-L1-positive disease, which was defined as staining in the stroma or in 1% or more of tumor cells using a prototype immunohistochemistry assay and the 22C3 antibody clone. Candidates receiving systemic steroid therapy were excluded from the trial, as were those with an autoimmune disease or active brain metastases. Additionally, participants had to have an ECOG performance status score of 0 to 1.
Phase ll and lll studies in lung cancer are under way. The activity of pembrolizumab in NSCLC or melanoma patients with untreated brain metastases is being studied in a phase ll trial (NCT02085070) currently recruiting participants.63 Additionally, a randomized phase ll/lll study (KEYNOTE- 010) is comparing 2 doses of pembrolizumab therapy with docetaxel in NSCLC patients who progressed after platinum-based chemotherapy; the study is ongoing. OS, PFS, and AEs will be reported.64,65 Finally, 2 phase lll trials (KEYNOTE-024 and -042) are evaluating the efficacy and safety of pembrolizumab compared with platinum-based chemotherapies in the treatment of patients with PD-L1- positive advanced or metastatic NSCLC.66,67
Pembrolizumab is also being evaluated in combination with other agents. Studies include a phase l/ll study (KEYNOTE-021) that aims to determine the safety, tolerability, and efficacy of pembrolizumab in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic NSCLC.68 KEYNOTE-037 is a phase l/ll study of the combination of pembrolizumab and INCB024360 (an oral inhibitor of indoleamine 2,3-dioxygenase). The second phase of this study will include only patients with advanced NSCLC and will be randomized, double-blind, and placebo-controlled.69 In addition, investigators are enrolling for a phase lb open-label study of the combination of tremelimumab and pembrolizumab in advanced NSCLC.70 This dose escalation and expansion study will evaluate the safety, pharmacodynamics, and preliminary activity of this combination in immunotherapy-naïve and -pretreated cohorts. In 3 patients (follow-up of 8-10 weeks), related AEs included a grade 2 asymptomatic elevated amylase. No grade 3/4 AEs or dose-limiting toxicities were reported. Thus, the safety profile supports continued dose escalation. Pharmacokinetic and pharmacodynamics data are being analyzed.71
Update on Anti—PD-L1 Immunotherapy From the 2015 AACR Annual Meeting
Adding Nivolumab to Frontline Ipilimumab Improves PFS by 60% in Melanoma
Frontline immunotherapy with nivolumab plus ipilimumab delayed disease progression by 60% compared with ipilimumab alone in patients with advanced melanoma, according to data from the phase ll CheckMate-069 trial presented at the 2015 AACR Annual Meeting.72 The results, which were simultaneously published online in The New England Journal of Medicine,73 showed that the checkpoint inhibitor combination had an overall response rate of 61% in a subgroup of BRAF V600 wild-type (WT) patients.
“These data are unprecedented in advanced melanoma, showing efficacy results that have not previously been observed with immuno-oncology agents,” F. Stephen Hodi, MD, lead study author and associate professor of medicine at Dana-Farber Cancer Institute, said in a statement. “With the Opdivo plus Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate-069 demonstrate the potential of this regimen in patients with metastatic melanoma.”
The double-blind CheckMate-069 trial randomized 142 treatment-naïve patients with stage III/IV melanoma in a 2:1 ratio to 3 mg/kg of the CTLA-4 inhibitor ipilimumab plus 1 mg/kg of the anti—PD-1 agent nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for 4 doses, followed by nivolumab at the same dose or placebo every 2 weeks until disease progression or unacceptable toxicity.
Median patient age was 65 years, two-thirds of patients were males, and all but 2 patients had an ECOG performance status of 0 or 1. Three percent of patients had a history of brain metastases.
Patient randomization was stratified by BRAF status, with the primary end point of the trial being overall response rate among BRAF WT patients. Secondary outcome measures included PFS in all patient cohorts, overall response rate in BRAF-positive patients, and safety.
Among BRAF WT patients (n = 109), PFS was not yet reached in the nivolumab/ipilimumab group (n = 72) versus 4.4 months in the ipilimumab arm (n = 37; HR, 0.40; 95% CI, 0.23-0.68; P <.001). Similar PFS data were observed among BRAF-positive patients (n = 33), at 8.5 versus 2.7 months in the combination (n = 23) and control (n = 10) arms, respectively (HR, 0.38; 95% CI, 0.15-1.00).
Forty-four BRAF WT patients (61%) receiving the checkpoint combination had objective responses, including complete responses (CRs) in 22% of patients (n = 16) and partial responses (PRs) in 39% (n = 28; odd ratio, 12.96; 95% CI, 3.91-54.49; P <.001). There were no CRs and 4 PRs with single-agent ipilimumab. Stable and progressive disease rates in WT patients for the combination versus monotherapy arms were 12% versus 35% and 14% versus 41%, respectively.
The overall response rate in WT patients receiving the combination was independent of PD-L1 status; however, response rates with ipilimumab alone were higher in patients with PD-L1—positive tumors (18% vs 4%).
In BRAF-positive patients, the overall response rate was 52% with the 2-drug regimen versus 10% with monotherapy. Responses in the dual-checkpoint arm included 5 CRs and 7 PRs, and 13% of patients had stable disease. Seventy percent of BRAF-positive patients in the control arm had progressive disease compared with 22% of patients receiving the combination.
Safety data were available for 140 patients. Rates of all-grade AEs were similar between the combination and monotherapy arms at 91% and 93%, respectively. Grade 3/4 AEs were 54% versus 24% in the dual checkpoint versus the control arm, leading to 36 and 6 discontinuations, respectively. Hodi noted that 68% of patients who discontinued combination therapy due to AEs continued to experience CRs or PRs.
The most common grade 3/4 AEs in patients receiving nivolumab/ipilimumab were colitis (17%), diarrhea (11%), elevated alanine transaminase (11%), increased lipase (9%), and elevated aspartate transaminase (7%). There were 3 treatment-related deaths in the combination arm versus none with ipilimumab alone.
“In general, and as might be expected, side effects were more prevalent in patients who received the combination therapy,” said Hodi. “This is something that will have to be studied further.” He added that the safety profile for the combination was as expected based on what was seen with phase 1 data, “with no real new safety signals.”
This was the second trial presented at AACR that showed an improvement over frontline ipilimumab in advanced melanoma. Data from the phase lll KEYNOTE-006 study showed that the PD-1 inhibitor pembrolizumab (Keytruda) improved outcomes versus ipilimumab in treatment-naïve patients with melanoma.
At this time, of the 3 immunotherapies, only ipilimumab is approved by the FDA for use in the frontline setting. Hodi said there are trials that have been completed that should add further clarity in terms of the optimal use of these agents. One is a phase lll study comparing nivolumab plus ipilimumab versus nivolumab alone or ipilimumab alone. The other is a sequencing study comparing nivolumab followed by ipilimumab versus ipilimumab followed by nivolumab.
In the meantime, Michael Giordano, MD, senior vice president, head of development, oncology, at Bristol-Myers Squibb, the developer of ipilimumab and nivolumab, shared his optimism about the progress of the 2 agents. “The CheckMate-069 results reinforce our belief that the future lies in the combination of immuno-oncology agents, including Opdivo and Yervoy, that can leverage the immune system in order to offer cancer patients options with greater efficacy beyond current treatment approaches,” Giordano said in a statement. “Our strategy has always been to build upon the success achieved with Yervoy. In 2011, long-term survival for metastatic melanoma patients was unheard of, but the introduction of Yervoy has helped to make this a reality for some patients. Now we are building on this success with Opdivo, which was the first PD-1 inhibitor to demonstrate an improved survival benefit.”
Anti-PD-L1 Agent MPDL3280A Shows Durable Responses in Triple-Negative Breast Cancer
The PD-L1 inhibitor MPDL3280A demonstrated a 19% objective response rate with 75% of responses ongoing in pretreated patients with metastatic triple-negative breast cancer (TNBC), according to findings from an ongoing phase l study presented at the 2015 AACR Annual Meeting.74
“This is very exciting because longer responses are not typical of what occurs when patients with metastatic triple- negative breast cancer are treated with chemotherapy, which is the standard of care for this population,” lead author Leisha A. Emens, MD, PhD, member of the Cancer Immunology and Breast and Ovarian Cancer programs at the Johns Hopkins Kimmel Cancer Center, said in a statement. “The emergence of approaches for harnessing the immune system to fight cancer is creating a lot of excitement for oncologists and immunologists because many of the responses that are being achieved are prolonged.”
In the multicenter phase la study, 54 patients with metastatic TNBC received IV MPDL3280A at 15 mg/kg, 20 mg/ kg, or a flat 1200 mg dose every 3 weeks. At baseline, PD-L1 expression was measured using IHC on tumor-infiltrating lymphocytes from fresh or archival samples, with 69% testing positive for greater than 5% PD-L1 expression (IHC 2 >5%; IHC 3 >10%).
The median age of patients enrolled in the study was 48 years. Patients had an ECOG performance status of 0 or 1, 59% had visceral metastases and 11% had bone metastases, according to the abstract. In addition, 85% received 4 or more prior systemic regimens, including taxanes (82%), anthracyclines (78%), carboplatin (41%), and cisplatin (15%).
Among 21 evaluable patients who were PD-L1-positive, the investigator-assessed objective response rate by RECIST criteria was 19%. This was composed of 9.5% CRs and 9.5% PRs. At the time of analysis, 75% of responses were ongoing, with a median not yet reached (range: 18-56+ weeks).
The 24-week PFS rate in the PD-L1-positive population was 27%. The median duration of survival follow-up was 40 weeks (range: 2-85 weeks). The data cutoff for the AACR presentation was December 2, 2014.
Three patients with PD-L1-positive TNBC (14%) experienced pseudoprogression with MPDL3280A and were indicated as having progressive disease by RECIST criteria. However, these patients continued to receive treatment and later demonstrated responses in the target and newly formed lesions. If these patients were included as responders, the objective response rate could be as high as 33%.
“There were 3 patients who were recorded as progressive disease who appeared to experience a phenomenon known as pseudoprogession, which is an atypical response pattern seen in some patients treated with this class of agents,” Emens said. “These are patients who exhibited a durable shrinkage of their target lesions, while at the same time developing new lesions at other sites. They remained clinically well with this pattern of response.”
The safety analysis for the trial included data from all 54 patients. All-grade AEs were evident in 63% of patients. Overall, 11% of patients experienced a grade 3 AE, which included low potassium level, low white blood cell count, dyspnea, and adrenal insufficiency. There was 1 grade 4 event of pneumonitis.
“MPDL3280A was safe and well-tolerated, with the most common treatment-related adverse events consisting of fatigue, nausea, fever, decreased appetite, and asthenia,” Emens said. “Two deaths, which are assessed as related by the investigators, are currently under further investigation by the sponsor [Genentech/Roche].”
MPDL3280A is an engineered monoclonal antibody that binds to the ligand PD-L1, preventing the activation of PD-1. The antibody is modified to prevent the induction of antibody-dependent cytotoxicity or complement-dependent cytotoxicity.
“Inhibiting these interactions between PD-L1 and its receptors PD-1 and B7.1 can enhance T-cell priming and restore antitumor T-cell activity,” Emens explained. “In addition, MPDL3280A leaves the PD-L2/PD-1 interaction intact, thereby potentially maintaining immune homeostasis and potentially preventing some of the autoimmunity that can be associated with targeting this particular pathway.” When active, PD-1 limits the expansion and survival of CD8+ T cells, suggesting that blocking this pathway should result in increased levels of CD8 cells and enhance the immune response. To explore this mechanism of action, peripheral biomarkers were assayed using FACS and multiplex immunoassays. This analysis revealed a transient elevation in plasma cytokines and proliferating CD8 cells following MPDL3280A treatment.
At the time of the analysis, data were not available for patients with PD-L1-negative or equivocal TNBC (IHC 0/1). This portion of the study was opened secondarily to the PD-L1-positive group. Further evaluation of the trial is ongoing, and the study continues to enroll participants (NCT01375842).
MPDL3280A has received a breakthrough therapy designation from the FDA as a treatment for patients with bladder cancer and non-small cell lung cancer. At this time, pivotal clinical trials are currently under way for MPDL3280A for these cancer types.
A randomized phase III study will assess MPDL3280A in combination with nab-paclitaxel as a first-line therapy for patients with metastatic TNBC, according to Emens.
Pembrolizumab Nears 50% Response in High PD-L1— Expressing NSCLC
Pembrolizumab had an overall response rate of 45.2% among a cohort of patients with high PD-L1-expressing NSCLC in the phase l KEYNOTE-001 trial. Regardless of PD-L1 expression, the PD-1 inhibitor was shown to be safe and effective, with an overall response rate of nearly 20% in the overall study population. The results were presented at the 2015 AACR Annual Meeting75 and simultaneously published online in The New England Journal of Medicine.76
“These results have the potential to substantively change the way that lung cancer is treated,” said lead author Edward Garon, MD. “The effectiveness of pembrolizumab in treating patients with NSCLC and the prolonged duration of their responses is quite exciting,” added Garon, who is medical director of thoracic oncology at UCLA’s Jonsson Comprehensive Cancer Center.
The KEYNOTE-001 trial included 495 previously treated and treatment-naïve patients with advanced or metastatic NSCLC. The total population comprised a training set of 182 patients and a validation set of 313 patients. Pembrolizumab was administered at 3 dosages: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. The researchers assessed patient responses every 9 weeks. In the entire study population, the overall response rate was 19.4% and median OS and PFS were 12.0 and 3.7 months, respectively. The median duration of response was 12.4 months.
“The median duration of response exceeded a year among responders regardless of the degree of PD-L1 expression, which is one of the exciting outcomes with this class of drug,” said Garon.
In the validation group, researchers were able to evaluate PD-L1 expression in 204 patients using an IHC clinical trial assay. Patients were divided into 3 groups, based on whether they had membranous PD-L1 expression in their tumor cells of 50% or higher (n = 73), 1% to 49% (n = 103), or less than 1% (n = 28).
The overall response rate in the 3 groups was 45.2%, 16.5%, and 10.7%, respectively. The results were comparable but slightly better among patients who had not received prior therapy versus those who were previously treated. Survival data were also presented at AACR for 356 patients in the total population whose PD-L1 levels were evaluable by the CTA. After a median follow-up of 10.9 months, OS was not yet reached in the high PD-L1 group (n = 119) and was 8.8 months in both the intermediate (n = 161) and low (n = 76) PD-L1 groups. PFS was 6.3, 3.3, and 2.3 months in the 3 groups, respectively. The duration of response was similar in the 3 cohorts at 12.4 months, 10.3 months, and not yet reached.
“In addition to being the largest data set of lung cancer patients treated with this type of drug, this is the first independent validation that PD-L1 expression in tumors is clearly a marker of response,” said Garon. Overall, pembrolizumab was considered tolerable. Grade 3 or higher AEs occurred in 9% of patients. Immune-related AEs reported in 2% or more of the population included pneumonitis, hypothyroidism, and infusion reactions. Pneumonitis was the cause of the 1 treatment-related death in the study.
Garon seemed to indicate he would welcome pembrolizumab as an addition to the lung cancer armamentarium. “Neither the drug nor the biomarker test [used in KEYNOTE- 001] is approved for use in this setting at this time, but if I had a patient whose tumor had PD-L1 expression on at least half of the cells and if pembrolizumab was available, I think that I would find the data compelling to look at the drug as the treatment option for that patient.”
Frontline Pembrolizumab Trumps Ipilimumab in Head-to- Head Melanoma Trial
Pembrolizumab elicited significantly better outcomes compared with ipilimumab in a randomized phase lll trial of patients with advanced melanoma. Results from the study, the first head-to-head comparison of the 2 FDA-approved checkpoint inhibitors, were presented April 19 at the 2015 AACR Annual Meeting.77
In the trial, named KEYNOTE-006, 2 separate dosing regimens of pembrolizumab demonstrated superiority over ipilimumab for all primary (OS and PFS) and secondary end points (overall response rate and toxicity).
“This is the first clinical trial to compare head-to-head 2 immune checkpoint inhibitors, which unleash an immune response against the cancer,” Antoni Ribas, MD, PhD, who presented the results, said in a statement. “We are delighted that we found that pembrolizumab is superior to ipilimumab as first-line therapy by improving responses and survival.” Ribas is a professor of hematology and oncology and director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center.
Patients enrolled in the trial had unresectable stage III or IV advanced melanoma and had received no more than 1 prior systemic therapy. In total, 834 patients were randomized to receive 4 cycles of ipilimumab 3 mg/kg every 3 weeks (the approved dosage), 10 mg/kg of pembrolizumab every 3 weeks (Q3W), or 10 mg/kg of pembrolizumab every 2 weeks (Q2W). Both dosing regimens of pembrolizumab are higher than the FDA-approved regimen of 2 mg/kg every 3 weeks. Response was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. Median follow-up was 8 months.
PFS rates after 6 months of treatment were 47.3% for pembrolizumab Q3W, 46.4% for pembrolizumab Q2W, and 26.5% for ipilimumab, according to the second interim analysis. Six-month OS rates were 84.8%, 87.6%, and 74.6%, respectively. Both PFS and OS benefits were seen across all subgroups.
Further, overall response rate was also improved among patients treated with pembrolizumab. The overall response rate was 33.7% for pembrolizumab Q2W (P = .00013), 32.9% for pembrolizumab Q3W (P = .00002), and 11.9% for ipilimumab. The toxicity profiles of the agents were consistent with what has been previously observed, the study authors noted. Although pembrolizumab was administered for a longer duration, rates of grade 3 to 5 AEs were numerically lower than in the ipilimumab arm (11.7% vs 19.9%).
The most common side effects associated with pembrolizumab (occurring in ≥20% of patients) are fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea, according to results from KEYNOTE- 001, the trial that led to the agent’s approval in 2014. Currently, ipilimumab and pembrolizumab are approved for the treatment of metastatic melanoma in the first and second lines, respectively. Ribas said he hopes this will change. Ribas said results from KEYNOTE-006 could lead to a frontline indication for pembrolizumab. “Our thinking about how to use the immune system to treat cancer began to change dramatically 2 decades ago, when the focus shifted from turning on the immune system to releasing the brakes that limit immune responses to cancer,” Ribas said in a statement. “This led to the development of both ipilimumab and pembrolizumab, and now we have clear evidence that this approach helps improve the lives of people with advanced melanoma.”
Investigator Caroline Robert, MD, PhD, anticipates that these results will help pembrolizumab gain regulatory approval in Europe. “As of today, pembrolizumab is still not on the market in Europe, except in the context of an expanded access program after failure of ipilimumab,” Robert, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, said in a statement. “We also look forward to having pembrolizumab in Europe as a frontline therapy for metastatic melanoma, and we hope that these results are going to accelerate the process.”
Both ipilimumab and pembrolizumab continue to progress. Ipilimumab is demonstrating long-term benefit and is now moving into later lines of therapy. According to ClinicalTrials. gov, more than 75 open studies are looking at the agent in melanoma. Pembrolizumab is being examined in nearly 20 open melanoma studies and is expanding into other tumor types, including metastatic TNBC and classical Hodgkin lymphoma.