PD-1 Pathway Blockade May Shape the Future of Hodgkin Lymphoma Therapy

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mid increasing success for immune checkpoint blockade strategies in anticancer therapies, agents that target components of the programmed death-1 (PD-1) pathway are poised to make an impact on the treatment of patients with hematologic malignancies, particularly Hodgkin lymphoma (HL).

Early clinical trial success and preclinical evidence has created a huge buzz in the research community, with multiple reports of astounding and durable responses in patients with HL, prompting the FDA to award breakthrough therapy status to nivolumab (Opdivo) in an HL setting. Data recently presented at the 2014 American Society of Hematology Annual Meeting (ASH) has reinforced excitement over nivolumab and the anti-PD-1 agent pembrolizumab (Keytruda) in certain subtypes of the malignancy.

PD-1 Pathway Activity and Nivolumab Mechanism of Action

INF-κB indicates nuclear factor-Kappa B; IFNy, interferon gamma; IFNyR, interferon-gamma receptor; MHC, major histocompatibility complex. Adapted from Nourkeyhani H, George S. J Targeted Ther Cancer. 2014;3(5):46-50. www.targetedonc.com.

Enthusiasm over the potential for PD-1 inhibitors in blood cancers comes amid the continuing efficacy of therapies built on immune checkpoints, a plethora of inhibitory pathways that play a key role in regulating the duration and amplitude of the immune response and are co-opted by tumors as a means to evade the immune system.

Immune checkpoint inhibitors targeting components of these pathways have transformed the treatment landscape for metastatic melanoma. Ipilimumab (Yervoy), which inhibits cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), was the first such agent that the FDA approved in melanoma in 2011. Over just four months last year, the agency approved two PD-1 inhibitors, both pembrolizumab and nivolumab, for patients with metastatic disease.

While PD-1 blockade has already been successfully exploited in patients with metastatic melanoma, their potential efficacy in a range of different solid tumors, notably non—small cell lung cancer (NSCLC) and bladder cancer, has really set these agents apart from other forms of immunotherapy. Now, the range of tumor types where PD-1 pathway agents are being explored is expanding in hematologic malignancies (Table 1).

Immune Subterfuge: Exploiting Checkpoints

Tumor cells express many unique antigens on their surface that make them vulnerable to the host’s immune system. Therefore, survival of cancer cells depends on their ability to evade the antitumor immune response initiated by the host. A key mechanism of immune evasion is the direct inhibition of cytotoxic T cells. In this context, immune checkpoint pathways have emerged as important mediators of this evasive capacity.

Table 1. Ongoing PD-1/PD-L1 Trials In Hematologic Malignancies

Agent

Industry Sponsor

Ongoing Trials (clinicaltrials.gov identifier)

MEDI-0680 (AMP-514)

MedImmune/ AstraZeneca

Phase IB/II—In combination with anti-CD19 antibody MEDI-551 in patients with relapsed/refractory aggressive B-cell lymphomas who have failed 1-2 prior lines of therapy (NCT02271945)

Phase I—In combination with MEDI-4736 in patients with advanced malignancies, including hematologic malignancies (NCT02118337)

MEDI-4736

MedImmune/ AstraZeneca

Phase I—In patients with relapsed/refractory MDS after treatment with or who are intolerant to hypomethylating agents (NCT02117219)

Phase I—In combination with MEDI-0680 in patients with advanced malignancies, including hematologic malignancies (NCT02118337)

MPDL3280A

Genentech/Roche

Phase I—In combination with obinutuzumab in patients with relapsed/ refractory FL and DLBCL (NCT02220842)

Phase I—In patients with locally advanced/metastatic solid tumors or hematologic malignancies (NCT01375842)

Nivolumab

(Opdivo)

Bristol-Myers Squibb

Phase II—In patients with classical HL after failure of ASCT (CheckMate-205; NCT02181738)

Phase II—In patients with relapsed/refractory FL who failed therapy with both CD20 antibody and an alkylating agent (CheckMate-140; NCT02038946)

Phase II—In patients with relapsed/refractory DLBCL after failure of ASCT or after failure of at least 2 prior multiagent chemotherapy regimens in subjects who are not candidates for ASCT (CheckMate-139; NCT02038933)

Phase IB—In combination with dasatinib in patients with CML (NCT02011945)

Phase I—Alone or in combination with ipilimumab or lirilumab (targets KIR)&nbrelapsed/refractory lymphoma and multiple myeloma (NCT01592370)

Pembrolizumab

(Keytruda)

Merck

Phase I/II—In combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (NCT02289222)

Phase I—In combination with lenalidomide and dexamethasone, and with lenalidomide alone, in patients with multiple myeloma (KEYNOTE-023;

NCT02036502)^a

Pidilizumab (CT-011)

CureTech

Phase II—Alone or in combination with dendritic cell/myeloma vaccines following ASCT in patients with multiple myeloma (NCT01067287)^b

Phase II—In combination with dendritic cell/AML vaccine following chemotherapy-induced remission in patients with AML (NCT01096602)

Phase I/II—In combination with lenalidomide in patients with relapsed/ refractory multiple myeloma (NCT02077959)

AML indicates acute myeloid leukemia; ASCT, autologous stem cell transplant; CTCL, cutaneous T-cell lymphoma; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; KIR, killer-cell immunoglobulin-like receptor; MDS, myelodysplastic syndrome. ^aCelgene is collaborating on this study. bOngoing but not recruiting participants.

T-cell activation is two-step process: antigen recognition, followed by the generation of an antigen-independent coregulatory signal that determines whether the T cell will be switched on or off in response to the antigen. This second step is overseen by the immune checkpoint pathways, which are either stimulatory or inhibitory.

PD-1 is a cell—surface receptor belonging to the CD28 family of T-cell regulators that is expressed on activated T cells and other immune cells. Upon interaction with its ligands, PD-L1 and PD-L2, it initiates an inhibitory signaling network that switches off activated T cells and results in T cell exhaustion—a state of dysfunction that is defined by poor effector function, even in the presence of antigens.

In normal cells, the PD-1 pathway plays a protective role, serving as a mechanism by which the immune response is switched off at the appropriate time to maintain self-tolerance and limit collateral damage to healthy tissues. However, tumor cells are able to co-opt this pathway to protect themselves from the antitumor immune response. Oncogenic signaling in tumor cells induced by the inflammatory microenvironment drives overexpression of PD-1 ligands on their surface, enabling them to deactivate tumor-infiltrating activated T cells that express PD-1 receptor on their surface.

Various cancers have been shown to express high levels of PD-L1, which correlates with poor prognosis in many cases. The discovery of these pathways and their role in the ability of cancer cells to survive the host immune response directed at them has offered significant potential to develop drugs targeted at these pathways to place the reins of the immune system back in the hands of the host to fight off cancer.

PD-1 Expression in Blood Cancers

The expression of PD-1 pathway markers has been detected in multiple hematologic malignancies, including HL, plasma cell myeloma, anaplastic large cell lymphoma (ALCL), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL). Early clinical trial evidence suggesting that hematologic malignancies may respond to PD-1 blockade has sparked interest in the development of agents targeting the pathway for these types of cancer (Table 2).

In an interview with OncologyLive, Philippe Armand, MD, PhD, a hematology researcher whom the Lymphoma Foundation of America recently recognized with a Young Scientist Award, indicated that the potential for PD-1 pathway inhibition in blood cancers varies according to subtype.

Table 2. Clinical Trial Findings for Agents Targeting PD1/PD-L1 in Hematologic Malignancies

“In most hematologic malignancies, it’s a little bit of a shot in the dark, although there is a fair amount of preclinical evidence for at least the presence of PD-L1 on some of the malignant cells in some of the tumors,” said Armand, an associate professor of Medicine at Harvard Medical School.

Researchers have hypothesized that classical HL (cHL), in particular, might be uniquely vulnerable to PD-1 blockade since cHL frequently demonstrates genetic abnormalities in this pathway, perhaps making the cancer cells dependent on aberrations in the pathway for survival.

“There’s already very strong science to show that this disease [cHL] is different from the others,” said Armand. “cHL very often has a genetic abnormality which amplifies the genetic material on the short arm of the 9th chromosome, and this results in increased expression of the PD-1 ligands, specifically PD-L1 and PD-L2.” He said this occurrence not only is unique for hematologic malignancies, but also has never been seen in solid tumors either, and “implies that cHL may have a different behavior under PD-1 blockade than the other set of diseases.”

Two Agents Shine at ASH

The results of two separate phase I trials of nivolumab and pembrolizumab in patients with HL created a significant buzz at the 2014 ASH Annual Meeting in San Francisco in December. Based on the hypothesis that cHL may be particularly vulnerable to PD-1 blockade, patients with cHL were included as an independent expansion cohort in an ongoing phase 1B study of nivolumab in hematologic malignancies. Early results of this study contributed to the FDA’s decision to grant nivolumab breakthrough therapy status in May. The second study, KEYNOTE-013, evaluated the efficacy and tolerability of pembrolizumab in patients with cHL following failure of brentuximab vedotin.

Impressive overall response rates (ORRs) were achieved in both studies: 87% (with 17% complete remission [CR]) for nivolumab and 66% (with 21% CR) for pembrolizumab. Both agents were also well tolerated, with few treatment-related adverse events (AEs) and no serious AEs. In both studies, all patients were found to have genetic abnormalities driving overexpression of PD-L1.

“Both of these studies support a strong activity of these drugs, and they were both done in populations of patients with very advanced disease, most of whom had already failed prior transplant and brentuximab, which is one of the most active drugs in Hodgkin lymphoma,” said Armand, who was part of the research teams on both studies.

Responses Vary in Other Studies

The results of several studies in other hematologic malignancies have also been reported and, though promising, the responses have been significantly more variable.

CureTech’s pidilizumab (CT-011) has been evaluated in two phase II trials. In the first, 66 patients with primary mediastinal B-cell lymphoma and indolent B-cell lymphoma following autologous stem cell transplant had an ORR of 51%, including CR of 34%, following administration of single-agent pidilizumab. Meanwhile, an ORR of 66%, including 52% CR, was observed in 29 patients with FL who had relapsed following one to four lines of prior therapy and were treated with a combination of pidilizumab and rituximab. Single-agent pidilizumab and the combination therapy were both well tolerated.

At the ASH meeting, preliminary results were presented from the nivolumab study in multiple myeloma and a range of non-Hodgkin lymphoma (NHL) histologies, including FL, B-cell NHL, and T-cell NHL. The highest response rate was observed in patients with B-cell NHL (28%), with a 7% CR. There were no responses observed in the 27 patients with multiple myeloma.

“There were some histologies, like large cell lymphoma, follicular lymphoma, and T-cell lymphoma, where some of the patients responded, but the response rates were more in the 30%-40% range in a very small number of patients,” said Armand. “30% to 40% is certainly a strong signal, but they’re in a small number of patients and seem less durable, so there is more work needed to understand what biology underlies this phenomenon.”

Outside of cHL the responses are much less clear cut. Where responses were observed, they were significantly more variable and less durable, and in the case of multiple myeloma, there were no objective responses at all.

“There was quite disparate activity (with nivolumab). All of the rationale you can have doesn’t always equal clinical activity,” Alexander Lesokhin, MD, a myeloma specialist at Memorial Sloan Kettering Cancer Center who was involved in the nivolumab studies, said in an interview with OncologyLive.

This has raised a number of important questions that need to be addressed before the full potential of PD-1—targeting agents can be reached in hematologic malignancies. One question is whether a biomarker for response can be identified and used to guide treatment. Although a companion predictive biomarker could prove extremely useful, no clear biomarker has emerged as of yet to fully assess the effects of PD-1–targeting therapy.

This has raised a number of important questions that need to be addressed before the full potential of PD-1—targeting agents can be reached in hematologic malignancies. One question is whether a biomarker for response can be identified and used to guide treatment. Although a companion predictive biomarker could prove extremely useful, no clear biomarker has emerged as of yet to fully assess the effects of PD-1–targeting therapy.

PD-L1 expression levels would appear to be the most logical choice; however, prospective validation in clinical trials is lacking and, Lesokhin noted, studies that have measured PD-L1 expression have raised more questions than answers. These questions include which PD-L1 antibody should be used to most accurately and reproducibly measure PD-1 protein expression, which cutoff should be utilized to determine PD-L1 positivity/negativity, and where the PDL1 protein should be measured (in the tumor epithelium, the stroma, or both). Furthermore, as in solid tumors, it is unclear if PD-L1 as a biomarker should be used to exclude patients from therapy.

“Similar to the solid tumor experience, they may be helpful, but I don’t think they’ll be definitive,” Lesokhin explained. “Although all patients in the HL cohort from the nivolumab study were found to have high levels of PD-L1 expression, in other types of hematologic malignancies, responses were observed where PD-L1 overexpression was lacking.”

Another unanswered question is whether PD-1 agents in hematologic malignancies would be adequately effective as monotherapy or whether combination with other drugs might prove most beneficial and, if so, what the most rational combinations would be.

A variety of different combinations are already being evaluated in clinical trials. For example, preclinical evidence has suggested that there may be synergy between PD-1—targeting therapies and the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica). As a result, the pharmaceutical companies that manufacture these drugs announced recently they had initiated several clinical trial collaborations to assess the safety and efficacy of these combinations in patients with hematologic malignancies, including DLBCL and FL.

Lesokhin and Armand both believe that combination therapy is likely to be important,especially outside the context of cHL where responses with single-agent therapy are less definitive. As to the question of the most rational combinations, Lesokhin speculates that anything goes at the moment. “I think there are a number of combinations that can be tested,” he said. “There’s rationale for many of them to varying degrees.”

Key Research

• Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma [published online December 6, 2014]. N Engl J Med. doi:10.1056/NEJMoa1411087.
• Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial [published online October 14, 2013].
• J Clin Oncol. 2013;31(33):4199-4206.
• Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044-3051.
• Bryan LJ, Gordon LI. Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy [published online September 14, 2014]. Blood Rev. doi: http://dx.doi.org/ 10.1016/j.blre.2014.09.004.
• Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Presented at: 56th American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 291.
• Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Presented at: 56th American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 290.
• Ohaegbulam KC, Assal A, Lazar-Molnar E, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway [published online October 30, 2014]. Trends Mol Med. pii: S1471-4914(14)00183-X. doi:10.1016/j. molmed.2014.10.009
• Philips GK, Atkins M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies [published online October 16, 2014]. Int Immunol. 2015;27(1):39-46.
• Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial [published online December 11, 2013]. Lancet Oncol. 2014;15(1):69-77.