May 2014, Vol 3, No 3

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Anti–PD-1/PD-L1 Therapy: New Immunotherapy Options for Patients With a Variety of Cancers

Sangmee Bae, MD


Sangmee Bae, MD, is a Resident in the Internal Medicine Department at the Ronald Reagan UCLA Medical Center in Los Angeles, California.

Bartosz Chmielowski, MD, PhD, is Clinical Assistant Professor in the Division of Hematology and Medical Oncology of the University of California at Los Angeles. He specializes in the treatment of patients with melanoma and sarcoma.

There is a continued need for the development of new therapies for cancer; immunotherapy, a treatment modality in which cancer cells are not targeted directly but rather through altered immune cells such as T cells, has been in testing for several decades. Despite hundreds of clinical trials using various forms of vaccines, cytokines, adoptive cell transfer, and checkpoint inhibitors, only a few agents (interferon, high-dose interleukin-2, ipilimumab, and sipuleucel-T) in certain types of cancer (melanoma, renal cell carcinoma [RCC], and prostate cancer) have been approved by the FDA, and not all of them showed an improvement in overall survival (OS) in randomized clinical trials. Recently, there has been increased enthusiasm that immunotherapeutic strategies designed to enhance endogenous antitumor properties of the adaptive immune system are becoming a therapeutic option for a variety of cancers. Ipilimu­mab (CTLA-4–blocking antibody; CD152) was the first drug that targeted one of the immune checkpoint proteins, which under normal physiological conditions is crucial to maintaining self-tolerance to prevent autoimmunity, and showed the treatment can lead to an improvement in OS and durable responses.1 There has been even more excitement with the targeting of programmed death protein 1 (PD-1; CD279), another inhibitory coreceptor expressed by activated T cells. Blockade of inhibitory immune checkpoint proteins would imply continued activation and amplification of tumor-specific T-cell responses and may lead to tumor elimination. In this review, we will focus on immunotherapeutic agents that target the PD-1 pathway.

Mechanism of Action
T cells have remained the major focus of cancer immunotherapy given their ability to selectively recognize and orchestrate various immune responses. There is a close bidirectional communication between T cells and antigen-presenting cells (APCs; namely the dendritic cells) when T-cell receptors recognize antigens presented by the major histocompatibility complex (MHC) molecule. Once the T-cell receptor/MHC-mediated first signal is delivered, many ligand-receptor interactions mediate secondary stimulatory or inhibitory signals to further fine-tune the immune response. Many of the secondary signals are mediated via the B7 molecule family on the surface of APCs binding with various receptors on the T-cell surface. Inhibitory signal mediators, namely CTLA-4 and PD-1, are frequently referred to as “immune checkpoints,” as such negative regulation is crucial in terminating the immune response and preventing inappropriate activation of immunity. There have been many studies regarding the mechanism of CTLA-4 blockade in cancer immunotherapy as a means to interrupt the negative signal mediated by CTLA-4 and restore T-cell activity against tumor antigens.2-5 Large clinical trials have validated the safety and efficacy of ipilimumab (MDX-010), a monoclonal antibody against CTLA-4, which led to its approval in melanoma, and further clinical trials are under way in other malignancies.6,7

The PD-1 receptor also mediates an inhibitory signal but unlike CTLA-4 is expressed by T cells during long-term antigen exposure and takes effect in the peripheral tissues. Thus, this signal is mainly implicated in T-cell exhaustion, which is characterized by impaired cytokine production, decreased proliferation, and reduced killing activity.8 There are 2 distinct ligands of PD-1, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), which are frequently expressed within the tumor microenvironment, and antibodies that block the interaction between PD-1 and PD-L1 result in preferential activation of cancer-specific T cells. Mouse models show that blocking PD-1/PD-L1 interaction between T cells and APCs leads to T-cell activation, and blocking the interaction between T cells and target cells leads to increased target cell elimination.9 Although the clinical experience with PD-1 blockade is less extensive compared with the CTLA-4 pathway, the initial results appear quite promising, and the PD-1 pathway­–targeted therapy is now viewed as a viable treatment option with less systemic toxicity given its increased selectivity and ability to predominantly target the effector phase of T cells.10,11

Drugs in Development
Anti–PD-1 Therapy
Nivolumab (BMS-936558, MDX-1106) is a human IgG4 antibody against the PD-1 receptor. Brahmer and colleagues presented the results of the first phase 1 study conducted with nivolumab at single doses of 0.3, 1, 3, and 10 mg/kg and reported evidence of clinical activity with a favorable safety profile in 39 patients with advanced melanoma, non–small cell lung cancer (NSCLC), colorectal cancer (CRC), castrate-resistant prostate cancer, and RCC.12 Based on this, a large phase 1 study was conducted in 296 patients with heavily pretreated solid malignancies receiving doses of 1, 3, and 10 mg/kg every 2 weeks in 8-week cycles. The study showed an objective response (complete and partial responses) in 18% to 28% of patients (14 of 76 in NSCLC, 26 of 94 in melanoma, and 9 of 33 in RCC), but no responses in patients with CRC or prostate cancer.13 Responses in the majority of patients were durable and evident by week 16; progression-free survival (PFS) at 24 weeks was 41% (95% CI, 30-51) for melanoma, 26% (95% CI, 16-36) for NSCLC, and 56% (95% CI, 39-73) for RCC. The maximum tolerated dose (MTD) was not defined; the most common adverse events (AEs) were fatigue, decreased appetite, nausea, vomiting, diarrhea, and rash; grade 3/4 AEs were observed in 14% of patients and included pneumonitis, vitiligo, colitis, hepatitis, thyroiditis, and hypophysitis. Immunohistochemical analysis showed a significant difference in response rates between PD-L1–negative and PD-L1–positive tumors, suggesting that a survival benefit may only be demonstrated in a select group of patients. Updated phase 1 trial (CA209-003) data on 129 patients with NSCLC presented at the 15th World Conference on Lung Cancer in October 2013 showed an overall response rate of 24.3%, with a median survival of 14.9 months. OS rates were 42% at 1 year and 24% at 2 years.

These encouraging results have led to extensive clinical development of nivolumab. Currently, single- agent nivolumab is in testing in multiple malignancies; the list of clinical trials includes a trial comparing nivolumab with chemotherapy in patients with melanoma whose disease progressed on standard therapies, trials of nivolumab versus chemotherapy as first-line or second-line treatment in patients with NSCLC, a trial of nivolumab versus everolimus in RCC, and single-agent trials of nivolumab in hepatocellular carcinoma, follicular lymphoma, diffuse large B-cell lymphoma, and hematologic malignancies.

Pembrolizumab (MK-3475; previously called lambrolizumab) is a highly selective humanized monoclonal IgG4 kappa isotype antibody against PD-1. First studied in a dose-escalation phase 1 study in patients with various advanced solid tumors, it was shown to be safe at doses up to 10 mg/kg every 2 weeks, with objective clinical responses noted.14 Based on this study, Hamid and colleagues reported the safety and efficacy data of pembrolizumab in 135 patients with advanced melanoma.15 Once patients reached 10 mg/kg every 2 weeks in the initial dose-escalation period, patients were enrolled to an expansion cohort and received either 10 mg/kg or 2 mg/kg every 3 weeks. The overall response rate was higher in the group that received the higher dose (52% vs 25%), as was the rate of AEs. Common AEs included fatigue, rash, pruritus, and diarrhea, but cases of pneumonitis, myocardial infarction, renal failure, hypothyroidism and hyperthyroidism, and adrenal insufficiency were also seen. Median PFS was estimated to be more than 7 months. The data were updated at the annual meeting of the Society for Melanoma Research in November 2013. The study showed that 74% of patients with melanoma experienced a reduction in tumor size; the overall response rate was 41% (51% in patients treated with 10 mg/kg every 2 weeks, 31% with 10 mg/kg every 3 weeks, and 40% with 2 mg/kg every 2 weeks), median PFS was 8.2 months (95% CI, 5.3-12.8), and most importantly, the 1-year survival rate was 81%. The preliminary report of pembrolizumab 10 mg/kg every 3 weeks in previously treated NSCLC showed an overall response rate of 24% using immune-related response criteria, 21% using
RECIST, and a median OS of 51weeks, while median PFS had not yet been reached in responders.16 AEs overall were manageable, with 53% of patients experiencing AEs such as rash, pruritus, fatigue, diarrhea, and arthralgia, but no grade 3/4 AEs or treatment-related deaths. These trials used different doses of pembroliz­umab (10 mg/kg and 2 mg/kg) and different schedules of drug administration (every 3 weeks and every 2 weeks). Nonrandomized data suggest that pembroliz­umab at the higher dose might be more active, but this question will be answered by the ongoing trials comparing higher and lower dosing.

Pembrolizumab is currently in clinical trials comparing its activity with chemotherapeutic agents and assessing its activity in other cancers such as breast, head and neck, gastric, and bladder, as well as in hematologic malignancies and in special patient populations such as patients with melanoma or NSCLC with brain metastasis.

Pidilizumab (CT-011) is a humanized IgG1 monoclonal antibody that was shown to induce a potent antigen-specific tumor response when combined with cyclophosphamide and vaccines in mouse models. A phase 1 study of pidilizumab in patients with advanced hematologic malignancies showed that treatment with pidilizumab with escalating doses from 0.2 to 6 mg/kg was generally well tolerated, and the MTD was not defined.17 Clinical benefit was seen in 33% (6 of 17) of the patients, with 1 complete response that was maintained for >68 weeks. Blood CD4+ levels remained elevated for up to 21 days following therapy. Ongoing clinical trials are evaluating combinations of pidilizu­mab with vaccines or chemotherapeutic agents in other solid malignancies.

AMP-224, a PD-L2/IgG1 fusion protein that targets PD-1 signaling, is currently undergoing phase 1 testing. This trial has an expansion cohort in patients with melanoma and ovarian cancer.

Anti–PD-L1 Therapy
In contrast to CTLA-4 ligands, PD-L1 is selectively expressed on cells in the tumor microenvironment and upregulated in solid tumors, inhibiting cytokine activity of tumor-targeting T cells.18-20 To further support the significance of the PD-1/PD-L1 pathway in immune tolerance, studies have demonstrated that the degree of PD-L1 expression on tumor cells correlated with poor clinical outcomes in various malignancies, including RCC and melanoma.21-24 Targeting the primary ligand of PD-1 is another way of blocking the PD-1 pathway, leading to ongoing antitumor activity.

MPDL3280A (RG7446) is a human anti–PD-L1 monoclonal antibody containing an engineered Fc domain. Because of the Fc optimization, the antibody does not induce either antibody-dependent cytotoxicity or complement-dependent cytotoxicity. Preliminary results from an ongoing phase 1 study with 85 heavily pretreated patients with advanced NSCLC showed that MPDL3280A was generally well tolerated, with grade 3/4 AEs in 12.6% of patients, including fatigue, dyspnea, nausea, and vomiting.25 Efficacy data were assessed in 53 patients, of whom 23% achieved an objective response, and 24-week PFS was 44.7%. Objective response as well as disease control rate were associated with PD-L1 expression levels. The responses were also seen in patients with RCC, melanoma, CRC, and gastric cancer. The data on use of the drug in patients with melanoma were presented at the annual meeting of the Society for Melanoma Research in November 2013. The expansion cohort of the phase 1 study of MPDL3280A included 45 patients with metastatic melanoma; 11 patients with cutaneous melanoma responded to the treatment, the 24-week PFS was 41%, and patients who previously received immunotherapy were more likely to benefit from the treatment with MPDL3280A (44% vs 19%). Based on these encouraging results, MPDL3280A is being studied in other malignancies such as melanoma and RCC, and so far, results appear quite promising with overall responses of 13% to 29% and AEs including hyperglycemia, increased liver enzymes, colitis, dyspnea, and fatigue. Ongoing phase 2 and 3 trials are looking at combination regimens as well as comparing the efficacy with current treatment options in advanced solid tumors and hematologic malignancies.

BMS-936559 (MDX-1105) is a high-affinity human PD-L1–specific IgG4 monoclonal antibody that inhibits the binding of PD-L1 to PD-1 but spares the interaction of PD-L2. The safety and efficacy has been studied in a phase 1 dose-escalation trial including 207 patients with advanced solid tumors (NSCLC, CRC, melanoma, RCC, ovarian, gastric, pancreatic, and breast cancer) who received escalating doses ranging from 0.3 to 10 mg/kg every 2 weeks.26 MTD was not reached, and median duration of therapy was 12 weeks. Objective responses were observed in 17% of melanoma, 10% of NSCLC, 6% of ovarian, and 12% of RCC patients, but no response was seen in patients with CRC or pancreatic cancer. Stable disease was observed in 12% to 41% at 24 weeks. Among patients who achieved an objective response, responses lasted for 1 year or more in 8 of 16 patients. Common AEs included fatigue, infusion reactions, diarrhea, arthralgia, and rash; grade 3/4 AEs were reported in 9% of patients, and 6% of patients discontinued therapy due to toxicity. Bristol-Myers Squibb has made the decision to concentrate on the development of nivolumab and not develop BMS-936559 in oncology.

MEDI4736 is another monoclonal antibody being studied against PD-L1. This antibody also has an optimized Fc region and therefore does not activate antibody-dependent cell-mediated cytotoxicity. Ongoing phase 1 and 2 studies are looking at the safety and efficacy of MEDI4736 as monotherapy as well as combination therapy in solid tumors.

Combination Therapy
The available results from treatment with PD-1/PD-L1 blocking agents are encouraging and have caused a lot of excitement, but there is still room for improvement. It is a natural development in oncology that after single-agent activity is seen with an agent, it is often later used in combination with other therapies. Multiple clinical trials with combination regimens are ongoing; they can be divided into 3 groups: 1) combination with another form of immunotherapy, 2) combination with standard chemotherapy, and 3) combination with targeted therapy.

The first data on combination treatment come from the trial of nivolumab plus ipilimumab. PD-1 blockade therapy has been shown to enhance efficacy of CD8 T-cell responses and regulate tumor growth, and thus it has been postulated that it may have synergistic effects when combined with other immunotherapeutic agents. CTLA-4 is another negative regulator of immune cell activation, and blockade of the CTLA-4 molecule has been shown to improve survival in patients with metastatic melanoma.6,7 Unlike PD-1 blocking agents, CTLA-4 blockers, such as ipilimumab, inhibit at earlier points of T-cell activation (during ligation with B7 costimulatory molecules) and also target regulatory T cells, leading to reduced T-cell regulatory activity. As CTLA-4 and PD-1 appear to play complementary roles in regulating T-cell function, combined blockade of PD-1 and CTLA-4 has been studied and suggested to have more pronounced antitumor activity than either agent alone in preclinical studies and in patients with chronic viral infections.27,28 Wolchok and colleagues reported the results of concurrent therapy with nivolu­mab-ipilimumab and showed that 53% of patients with advanced melanoma had achieved an objective response and a tumor burden reduction of 80% or more.29 The combination of nivolumab and ipilimu­mab was also associated with increased toxicity: serious treatment-related AEs were seen in 49% of patients, and the most common grade 3/4 events included hepatic events (15%), gastrointestinal events (9%), renal events (6%), elevation of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). The phase 3, blinded, randomized clinical trial comparing ipilimumab to nivolumab to the combination of both drugs has completed its accrual. This trial will confirm if the combination therapy is more active than either drug alone and if the combination results in increased toxicity.

Similarly, pembrolizumab is also being tested in combination with ipilimumab and also in combination with pegylated interferon-? in patients with melanoma and RCC. Preclinical data in the tumor mouse model showed that interferon-? increased PD-1 expression in tumor-infiltrating lymphocytes, which led to increased tumor activity.30

Other proposed immune escape mechanisms by tumor cells include LAG-3 and Tim-3 signaling pathways, which are also inhibitory molecules, and blocking antibodies have been shown to improve T-cell immunity in chronic infections.31-33 Combined blockade with PD-1 pathways synergistically restored the function of exhausted T cells, having positive antitumor effects in mouse models.34 The drugs blocking LAG-3 and Tim-3, as well as other molecules such as B7-H3 and B7-H4, are in early development, and trials combining nivolumab with an anti-KIR antibody, lirilumab, or with an anti–LAG-3 antibody have started accrual.

Other interesting approaches of combination immunotherapy currently in clinical trials include the combination of pidilizumab with dendritic cell vaccine in patients with multiple myeloma or RCC and with sipuleucel-T in patients with advanced prostate cancer.

Chemotherapy has been a standard treatment for all unresectable malignancies for several decades and is known to prolong life or provide palliation in patients with a variety of cancers. Therefore, there are attempts to improve efficacy of chemotherapy by combining it with anti–PD-1 therapy – pidilizumab and gemcitabine in pancreatic cancer, pidilizumab and FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) in colorectal cancer, and nivolumab or pembrolizumab and chemotherapy in NSCLC.
In the past decade, targeted therapy has emerged as the standard systemic therapy for patients with a variety of malignancies. Targeted therapy is usually very active, and rapid responses are achieved, but eventually tumors develop resistance. Immunotherapy is known to produce durable responses, if not a cure, in patients with metastatic cancer, but these responses are much less frequent and less rapid. Thus, it is not a surprise that there are ongoing attempts to combine immunotherapy with targeted therapy. In patients with melanoma, it was shown that treatment with a BRAF inhibitor or the combination of a BRAF inhibitor and a MEK inhibitor was associated with increased melanoma antigen expression, increased T-cell infiltration, decreased expression of immunosuppressive cytokines, and an increase in PD-L1 expression.35 This observation led to a clinical trial of the combination of MEDI4736 (anti–PD-L1 antibody) with dabrafenib and trametinib in patients with BRAF-mutated melanoma and with trametinib alone in patients with non–BRAF-mutated melanoma. Similar studies are being done with a combination of MPDL3280A and vemurafenib in patients with BRAF-mutated melanoma and with cobimetinib (GDC-0973; a MEK inhibitor) and vemurafenib in patients with solid tumors. Other clinical trials add anti–PD-1 therapy to standard targeted therapy in multiple cancers. There are attempts to combine MPDL- 3280A with bevacizumab in RCC or with erlotinib in NSCLC, nivolumab with sunitinib or pazopanib in RCC, pembrolizumab with pazopanib in RCC, and
pidilizumab with lenalidomide in multiple melanoma or with rituximab in follicular lymphoma.

Questions and Future Directions
The data from the early trials of the new PD-1/PD-L1 blocking agents are very encouraging. It appears that the responses are frequent, rapid, and probably durable. The experience with these new drugs shows that most, if not almost all, patients with cancer have T cells that can potentially eliminate the tumor, and only the tumor cells that developed an active mechanism of immune tolerance such as PD-L1 expression survive immune surveillance. It suggests that the combination of PD-1/PD-L1 blocking agents with other forms of immunotherapy or targeted therapy can be even more efficacious, and it is only a matter of time before the most active combinations are discovered. However, it is still unknown how durable these responses are and what the mechanisms of escape are when tumors progress after an initial response. We must expect that these mechanisms will be heterogeneous. Much research has been devoted to studying the expression of PD-L1 on the tumor cells as a biomarker for these new agents, and preliminary data suggest that the level of expression predicts for response, but we should remember that biomarkers must be tested with the same scrutiny as new therapeutic agents. u

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