Nivolumab, a Novel Anti–PD-1 Monoclonal Antibody for the Treatment of Solid and Hematologic Malignancies

Emma Thornton

Uncategorized

Immunotherapy for the treatment of cancer has been an active area of research, with the recent approval of ipilimumab (Yervoy) in 2011. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), a cell surface molecule expressed solely on T cells required for self-tolerance. The rationale for blocking an immune blockade such as CTLA-4 is that previous efforts to treat cancer through enhancing antitumor immune responses have failed, but abrogating pathways that suppress T-cell–mediated immune responses might provide a viable approach to cancer treatment. Such has been the clinical experience with ipilimumab.1 Because self-tolerance is an important feature of immune regulation, other pathways contribute to it as well. Among these are T-cell–expressed programmed death–1 (PD-1) and its ligands, PD-1 ligand 1 (PD-L1) and PD-1 ligand 2 (PD-L2), which are expressed on antigen-presenting cells and tumors.2 Activated T cells in the periphery express PD-1 during long-term exposure to antigen. When PD-1 is bound by PD-L1 or PD-L2, T cells eventually become anergic.

Antibodies to PD-1, PD-L1, and PD-L2 are currently in clinical trials. These include anti–PD-1 antibodies pidilizumab (CT-011), nivolumab (BMS-936558), and pembrolizumab (MK-3475); anti–PD-L1 antibodies MEDI4736 and MPDL3280A; and anti–PD-L2 antibody AMP-224. Of these, nivolumab has advanced to phase 3 trials for solid tumors and is in trials for hematologic malignancies as well. This represents a new avenue for the treatment of patients with hematologic malignancies, whose key options have been immunomodulatory agents such as thalidomide derivatives and bone marrow transplantation.3-5 Among the solid tumors targeted by anti–PD-1/anti–PD-L1 antibodies are melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and others. This review will focus on 1 anti–PD-1 antibody in particular, nivolumab, which is in 9 phase 3 trials, among others. Results reported at the 2014 American Society of Clinical Oncology (ASCO) annual meeting show a favorable safety profile and therapeutic efficacy. In fact, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy status in May for the treatment of diffuse large B-cell lymphoma.6 Last year the FDA put nivolumab on fast track to approval for NSCLC. In Japan, nivolumab already has orphan drug status.6 Approval of nivolumab may be expected in the near future as a new treatment for many types of cancer.

PD-1 and Its Role in Cancer Progression
In contrast to CTLA-4, which acts primarily in lymph nodes, PD-1 acts peripherally. CTLA-4 dampens early memory, resting, or naive T-cell responses, whereas PD-1 dampens late and ongoing ones after T cells have been activated.7 Tumors alter normal T-cell response through a panoply of mechanisms known collectively as “immune editing.”8 The mechanisms by which tumors escape normal immune responses include downregulation of tumor antigen presentation, CD4+ T-cell tolerance, increased number and activity of regulatory T cells (Tregs), and CD8+ T-cell dysfunction.8

PD-1 is related to CD28 and is part of the immunoglobulin (Ig) gene superfamily.9 Besides activated T cells, it is expressed on B cells, monocytes, and natural killer cells. Its cognate ligands PD-L1 and PD-L2 are expressed by most antigen-presenting cells, including dendritic cells, and by a variety of nonlymphoid tissue.10 PD-L1 expression is low in normal cells and increased in tumor cells.11 PD-L2 on cells is limited mainly to antigen-presenting cells outside of cancer cell expression. Binding either ligand by PD-1 inhibits T-cell receptor-mediated signaling, expression of antiapoptotic gene products (eg, Bcl-XL), and expression of proinflammatory cytokines.7 Moreover, cell cycle progression is halted, preventing T-cell expansion. Mice deficient in PD-1 expression display autoimmunity, thereby establishing its role as a regulatory factor.12 In one series of experiments, researchers found that the PD-1 blockade prevented T-cell migration as well as activation and caused autoimmune diabetes.13 Investigations into the mechanism by which the tryptophan catabolic enzyme indoleamine 2,3-dioxy­genase (IDO) suppresses immune responses revealed that IDO markedly increased expression of PD-L1 and PD-L2 on dendritic cells.14

Under certain conditions, PD-1 ligation functions in a manner similar to CTLA-4, affecting tolerance at early stages of T-cell activation.15

In cancer, PD-1 is expressed by large numbers of tumor-infiltrating T lymphocytes (TILs), and PD-L1 and PD-L2 are expressed by most tumor types.7,15 Often the TILs are anergic, and a high proportion are Tregs.15 Much of what is known about PD-1 and its ligands in cancer comes from empirical evidence. Transgenic expression of PD-L1 by mouse tumor cells made them less susceptible to T-cell–mediated lysis; administration of an anti–PD-L1 antibody decreased tumorigenesis and tumor invasiveness.10 Cancer cell–associated PD-L1 increased apoptosis of tumor antigen-specific T cells, perhaps through the action of interferon-?.11 A blockade of anti–PD-L2 had similar effects in a mouse model of pancreatic cancer.16 Administration of anti–PD-L1 along with a second antitumor vaccine, one that increased expression of interferon-?, reduced tumor growth and enhanced systemic antitumor immunity.17 In a mouse model of glioblastoma, inhibition of PD-L1 led to increased survival.18 An anti–PD-L1 monoclonal antibody reactivated T cells in situ, leading to tumor rejection in a mouse melanoma model.19

Early experiments inhibiting PD-1 revealed that antitumor cytolytic T-cell (CTL) responses were enhanced through increased CTL proliferation rather than through decreased CTL apoptosis.20 Further experiments showed that the PD-1 blockade restored CTL-effector function and enhanced the responses to an antitumor lentiviral vaccine in a mouse melanoma model.21 Investigators using a monoclonal antibody to PD-1 in a mouse model of pancreatic cancer observed a marked antitumor effect that was enhanced by gemcitabine, resulting in complete responses without notable toxicity.22 These investigators found that the antitumor effects were mediated in large part by CD8+ T cells.22 Anti–PD-1 as a modality synergizes with CTLA-4 blockade. In a mouse model of melanoma, use of a peptide that blocked PD-1 binding to PD-L1 in the presence of an anti–CTLA-4 agent increased effector T-cell infiltration to the melanoma lesion, resulting in tumor rejection; the combination was more beneficial than either agent alone.23 These results provided an excellent rationale for examining anti–PD-1 modalities in cancer treatment.

PD-1 Blockade and Nivolumab as Treatment for Cancer
Beyond the preclinical evidence from animal models, further evidence was found for the role of PD-1 and PD-L1 in human cancer progression. PD-L1 expression correlated with poor prognosis in pancreatic cancer in a study of 51 patients.22 In a recent study of 339 patients with solid tumors (lung, breast, colon, rectum, ovary, prostate, endometrium, kidney, bladder, and pancreas), PD-1–positive infiltrating cells were found in the majority of specimens examined, and the tumors expressed PD-L1 as well.24 Increased PD-L1 expression on myeloma cells induced apoptosis of T cells, and PD-1 expression is increased on T cells from leukemia patients.25 PD-L1 expression on melanoma appears to be a predictive biomarker, and 17.3% of patients with melanoma had a long-term response to an anti–PD-L1 antibody.26,27 PD-L1 expression appears to vary by tumor type and was found most abundantly expressed on melanoma, NSCLC, and RCC.28 PD-L2 expression, furthermore, correlated with PD-L1 expression.28 Within melanomas, PD-L1 expression may drive infiltration by T cells, which may then become anergic. Increased interferon-? was found in regions where TILs associated with PD-L1–positive melanocytes.29 Patients with RCC whose tumors expressed high levels of PD-L1 had aggressive tumors and were 4.5 times more likely to die of RCC than patients with low levels of PD-L1.30 In hematologic malignancies, PD-1 expression was increased on peripheral T cells, and PD-L1 increased on myeloid cells from patients with chronic myeloid leukemia compared with those from healthy donors.31 Results from a murine leukemia model showed that cells bearing PD-L1 resisted lysis by CTLs, which could be reversed by administration of an anti–PD-L1 antibody.32 Relapsed or refractory myeloma patients often showed higher PD-L1 levels compared with other myeloma patients; such cells proliferated more and responded less to antimyeloma chemotherapy.33 Thus, there is a good body of evidence for targeting PD-1 and its ligands for cancer therapy.

As mentioned above, several drugs designed to inhibit PD-1, PD-L1, or PD-L2 are in current trials. Of the anti–PD-1 antibodies, nivolumab has advanced to phase 3 trials. Nivolumab is a fully humanized IgG4 monoclonal antibody with high affinity (its dissociation constant is about 3 nM) and specificity for PD-1.34 Nivolumab blocks binding to both PD-L1 and PD-L2. In the first-in-human trial for patients with refractory solid tumors, nivolumab showed a favorable safety profile and evidence of antitumor activity.35 Responses to nivolumab were durable, and reinduction therapy was successful when disease progressed.36 By 2012, 294 patients exhibited few drug-related adverse events (AEs; rate was 15%).37 Several of the AEs noted were thought to be related to immune response, such as rash, pruritus, and diarrhea.37

Table 1

In a study of 296 patients with solid tumors (NSCLC, melanoma, RCC, castration-resistant prostate cancer, and colorectal cancer [CRC]), nivolumab showed a good safety profile: only 14% of patients developed grade 3/4 AEs. No maximum tolerated dose (MTD) was defined in this study. Responses were durable, lasting more than 1 year.38 Notable in this study were the patients with metastatic RCC; 33 of the 296 patients had RCC. The overall response rate (ORR) was 27% at the 24-week follow-up; 5 of these patients had durable responses of more than 1 year.2 How well this population responds to nivolumab plus a tyrosine kinase inhibitor such as sunitinib will be demonstrated by a trial now under way (NCT01472081).

Historically, epithelial tumors such as NSCLC have been difficult to target.39 Thus anti–PD-1 antibodies such as nivolumab offer a unique opportunity to treat this cancer, especially if the therapy is combined with another modality.39 An initial trial of nivolumab in patients with advanced solid tumors included 6 heavily pretreated patients with NSCLC, 4 of whom showed significant tumor regressions.35,40 The MTD was not reached, and only 1 serious AE, inflammatory colitis, was reported.35 One durable complete response was obtained in a patient with CRC, and partial responses were seen in 2 patients with melanoma and RCC.35 The investigators concluded that intermittent dosing could balance antitumor activity with good tolerability in heavily pretreated patients.35 Results such as these may provide the rationale to try nivolumab as monotherapy or in combination with chemotherapy in NSCLC.41

For advanced refractory melanoma, 107 patients enrolled in a study wherein they received nivolumab for up to 96 weeks. Median overall survival (OS) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively.42 Among the 31% of patients whose tumors regressed, the estimated duration of response (by Kaplan-Meier estimate) was 2 years, meaning that responses endured after discontinuation of nivolumab.42 The safety profile, as with other studies, was favorable.

As has been noted, durable responses to nivolumab have been observed consistently in trials. The extent of nivolumab’s clinical benefit was studied in a small trial of patients with CRC, RCC, and melanoma.36 The patients with CRC had a complete response that continued more than 3 years; the patients with RCC had a partial response lasting more than 3 years while off nivolumab. The partial response later converted to a complete response, which was ongoing 12 months later at the time the paper was written detailing the study.36 A patient with melanoma reached a stable partial response that lasted for 16 months while off therapy; the patients responded successfully to reinduction therapy with nivolumab.36 These results are the most prolonged observations published of patients treated with nivolumab, and they also show that patients can be successfully retreated with nivolumab.36

Table 2

Recent Clinical Trials with Nivolumab and Results Presented at ASCO 2014
Based on the early clinical work presented above, nivolumab continues to be tested in trials prior to approval. Table 1 shows the current trials for nivolumab in hematologic malignancies. The malignancies include non-Hodgkin lymphoma, myeloma, and chronic myeloid leukemia. All are in the accrual stage, and the earliest completion date is February 2016. Two trials, one for relapsed or refractory follicular lymphoma and the other for relapsed or refractory diffuse large B-cell lymphoma, are in phase 2. The FDA has already granted nivolumab breakthrough therapy designation for the treatment of patients with Hodgkin lymphoma after an autologous stem cell transplant and brentuximab (anti–CD30; overexpressed in Hodgkin lymphoma) treatment failed.6 One might anticipate from this that the phase 2 trials, particularly NCT02038933 (Table 1), may form the basis for the New Drug Application for this indication.

The most recent results for nivolumab were just presented at the 2014 annual ASCO meeting, and some of the clinical trial abstracts are summarized in Table 2. In particular, Sznol and colleagues reported that in patients with advanced melanoma, nivolumab was equally active in patients with or without BRAF mutations (Table 2).43 The 1- and 2-year OS rates were 82% and 75%, respectively. Complete responses were seen in 17% of patients. Of the 22 patients who had objective responses, 64% had durable objective responses lasting more than 24 weeks.43 AEs were manageable and similar to what has been reported.43

In Japanese patients with platinum-resistant ovarian cancer treated with 1 mg/kg or 3 mg/kg of nivolumab, the median duration of therapy was 14 weeks; total response rate was 3/13 (23%), and the disease control rate was 7/13 (54%). Only 1 patient experienced severe AEs (Table 2).44

In RCC, tyrosine kinase inhibitors such as sunitinib have become common treatments. How well nivolumab synergizes with either sunitinib or pazopanib was demonstrated in a trial assigning 14 patients with metastatic RCC (who previously had at least 1 systemic therapy) to receive sunitinib or pazopanib plus nivolumab (Table 2).45 No dose-limiting toxicities were observed, and the MTD was not reached. Therefore the study was expanded to include a total of 33 patients. The ORRs were 52% for the sunitinib and nivolumab combination arm and 45% for the pazopanib and nivolumab combination arm. The progression-free survival (PFS) rates at 24 weeks were 78% for the sunitinib and nivolumab combination arm and 55% for the pazopanib and nivolumab combination arm.45 Thus, nivolumab plus either sunitinib or paz­opanib showed demonstrable antitumor activity with a manageable safety profile.45 Nivolumab plus ipilimumab combination therapy in RCC showed an ORR of 29% to 39% and a PFS of up to 28.1 weeks (Table 2).46 A dose-ranging study of nivolumab alone showed a median PFS of up to 4.2 months and an ORR of 22% (Table 2).47 Further, biomarker studies in patients with RCC showed that CD3+ and CD8+ T-cell infiltrates increased a median of 70% and 88%, respectively (Table 2).48

Several abstracts were presented covering the use of nivolumab in NSCLC. Nivolumab plus platinum-based doublet therapy showed an ORR of 33% to 50% (time frame was over 10 months), with 1-year OS rates of 59% to 87% (Table 2).49 Nivolumab plus ipilimumab combination therapy for NSCLC showed the feasibility of this regimen with an ORR of 22% and stable disease in 33% (Table 2).50 Interestingly, the ORR did not correlate with PD-L1 status in this trial.50 Survival and clinical activity by subgroup analysis for patients with NSCLC revealed that nivolumab activity manifested regardless of presence of EGFR or KRAS mutations (Table 2).51 The 1- and 2-year OS rates across doses were 32% to 56% and 12% to 45%, respectively.51 Finally, the design for a phase 3 nivolumab trial (NCT02041533) was described for patients with NSCLC (Table 2).52 These patients must have Eastern Cooperative Oncology Group performance status ?1 and no known EGFR or ALK mutations. The primary objective will be PFS in patients with strong PD-L1 expression; secondary objectives will be ORR and OS.52 The expected completion date is October 2017. Two addi­tional phase 3 trials in NSCLC, NCT01642004 and NCT01673867, have not yet begun recruiting patients.

Conclusion
PD-1 and its ligands form an important immune checkpoint, particularly in tumor biology. By providing suppressive signals to T cells, PD-1 promotes tumor growth and prevents tumor rejection. These features make PD-1 an exceptionally good molecule to exploit for cancer treatment. Thus, several antibodies to PD-1 and its ligands are in current trials. Of these, the anti–PD-1 monoclonal antibody nivolumab is of particular interest, as it progresses into phase 3 trials for NSCLC. The FDA designated it a breakthrough therapy for non-Hodgkin lymphoma. Recent ASCO presentations reveal consistent favorable AE profiles across patient populations. Along with these are durable responses, even after the drug regimen has concluded. More nivolumab trial results are eagerly anticipated.

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